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Li K, Wei W, Wang Y, Zhang N, Bao J, Zhang X, Zheng X, Zhao F, Yang X, Peng J, Gao C, Zhong S. Association between 5-HTRs gene polymorphism and alcohol use disorder in Han males from Yunnan, China. Alcohol 2025; 124:55-63. [PMID: 39889837 DOI: 10.1016/j.alcohol.2025.01.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2024] [Revised: 01/26/2025] [Accepted: 01/27/2025] [Indexed: 02/03/2025]
Abstract
Alcohol use disorder (AUD) has become a very serious medical and social problem. It is found that genetic polymorphisms of the 5-hydroxytryptamine receptors (5-HTRs) genes were associated with the risk of AUD. However, the results are controversial among different ethnic groups. At present, the correlation between 5-HTRs gene polymorphism and AUD in Han population from Yunnan Province remains unclear. In this study, 13 single nucleotide polymorphisms (SNPs) of HTR1B, HTR2A, HTR3A, HTR3B and HTR7 were detected by universal fluorescent probe technique. The CT genotype frequency of HTR3A rs1062613 was significantly higher in AUD case group than that in control group (P = 0.037, OR = 2.193, 95% CI: 1.048-4.366). The study indicated that the genetic polymorphisms of 5-HTRs were significantly associated with risk of AUD in Han male from Yunnan, China. In addition, this study further demonstrated the impact of alcohol on human health, especially liver damage, by analyzing the blood biochemical indicators of patients with AUD and combining them with their medical history.
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Affiliation(s)
- Kuan Li
- School of Forensic Medicine, Kunming Medical University, Kunming, Yunnan, China
| | - Wei Wei
- School of Forensic Medicine, Kunming Medical University, Kunming, Yunnan, China; Yunnan Qiansheng Judicial Expertise Center, Kunming, Yunnan, China
| | - Yue Wang
- School of Forensic Medicine, Kunming Medical University, Kunming, Yunnan, China
| | - Ning Zhang
- School of Forensic Medicine, Kunming Medical University, Kunming, Yunnan, China
| | - Jianjun Bao
- Alcohol and Drug Dependence Treatment Department, The Mental Hospital of Yunnan Province, Kunming, Yunnan, China; Alcohol and Drug Dependence Treatment Department, Mental Health Center Affiliated With Kunming Medical University, Kunming, Yunnan, China; The Second Department of Geriatrics, The Mental Hospital of Yunnan Province, Kunming, Yunnan, China; The Second Department of Geriatrics, Mental Health Center Affiliated With Kunming Medical University, Kunming, Yunnan, China
| | - Xulan Zhang
- Alcohol and Drug Dependence Treatment Department, The Mental Hospital of Yunnan Province, Kunming, Yunnan, China; Alcohol and Drug Dependence Treatment Department, Mental Health Center Affiliated With Kunming Medical University, Kunming, Yunnan, China; Psychotherapy Department, Fuqing Weikang Hospital, Fuqing, Fujian, China
| | - Xinjian Zheng
- School of Forensic Medicine, Kunming Medical University, Kunming, Yunnan, China
| | - Fei Zhao
- School of Forensic Medicine, Kunming Medical University, Kunming, Yunnan, China; Forensic Lab 1, Jiangxi Shenzhou Judicial Identification Center, Nanchang, Jiangxi, China
| | - Xiaopei Yang
- School of Forensic Medicine, Kunming Medical University, Kunming, Yunnan, China; School of Basic Medicine, Kunming Medical University, Kunming, Yunnan, China
| | - Jiahui Peng
- School of Forensic Medicine, Kunming Medical University, Kunming, Yunnan, China
| | - Changqing Gao
- Children's Mental Department, The Mental Hospital of Yunnan Province, Kunming, Yunnan, China; Children's Mental Department, Mental Health Center Affiliated With Kunming Medical University, Kunming, Yunnan, China.
| | - Shurong Zhong
- School of Forensic Medicine, Kunming Medical University, Kunming, Yunnan, China; Forensic Biology Identification Laboratory, Judicial Identification Center of Kunming Medical University, Kunming, Yunnan, China; NHC Key Laboratory of Drug Addiction Medicine, School of Forensic Medicine, Kunming Medical University, Kunming, Yunnan, China.
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2
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Beheshti M, Rabiei N, Taghizadieh M, Eskandari P, Mollazadeh S, Dadgostar E, Hamblin MR, Salmaninejad A, Emadi R, Mohammadi AH, Mirazei H. Correlations between single nucleotide polymorphisms in obsessive-compulsive disorder with the clinical features or response to therapy. J Psychiatr Res 2023; 157:223-238. [PMID: 36508934 DOI: 10.1016/j.jpsychires.2022.11.025] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 11/08/2022] [Accepted: 11/18/2022] [Indexed: 11/25/2022]
Abstract
Obsessive-compulsive disorder (OCD) is a debilitating neuropsychiatric disorder, in which the patient endures intrusive thoughts or is compelled to perform repetitive or ritualized actions. Many cases of OCD are considered to be familial or heritable in nature. It has been shown that a variety of internal and external risk factors are involved in the pathogenesis of OCD. Among the internal factors, genetic modifications play a critical role in the pathophysiological process. Despite many investigations performed to determine the candidate genes, the precise genetic factors involved in the disease remain largely undetermined. The present review summarizes the single nucleotide polymorphisms that have been proposed to be associated with OCD symptoms, early onset disease, neuroimaging results, and response to therapy. This information could help us to draw connections between genetics and OCD symptoms, better characterize OCD in individual patients, understand OCD prognosis, and design more targeted personalized treatment approaches.
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Affiliation(s)
- Masoumeh Beheshti
- Pathophysiology Laboratory, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Nikta Rabiei
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Taghizadieh
- Department of Pathology, School of Medicine, Center for Women's Health Research Zahra, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Pariya Eskandari
- Department of Biology, School of Basic Sciences, University of Guilan, Rasht, Iran
| | - Samaneh Mollazadeh
- Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Ehsan Dadgostar
- Behavioral Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran; Student Research Committee, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, 2028, South Africa
| | - Arash Salmaninejad
- Regenerative Medicine, Organ Procurement and Transplantation Multi Disciplinary Center, Razi Hospital, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran; Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Raziye Emadi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran.
| | - Amir Hossein Mohammadi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
| | - Hamed Mirazei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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3
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Pourhamzeh M, Moravej FG, Arabi M, Shahriari E, Mehrabi S, Ward R, Ahadi R, Joghataei MT. The Roles of Serotonin in Neuropsychiatric Disorders. Cell Mol Neurobiol 2022; 42:1671-1692. [PMID: 33651238 PMCID: PMC11421740 DOI: 10.1007/s10571-021-01064-9] [Citation(s) in RCA: 140] [Impact Index Per Article: 46.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 02/12/2021] [Indexed: 12/22/2022]
Abstract
The serotonergic system extends throughout the central nervous system (CNS) and the gastrointestinal (GI) tract. In the CNS, serotonin (5-HT, 5-hydroxytryptamine) modulates a broad spectrum of functions, including mood, cognition, anxiety, learning, memory, reward processing, and sleep. These processes are mediated through 5-HT binding to 5-HT receptors (5-HTRs), are classified into seven distinct groups. Deficits in the serotonergic system can result in various pathological conditions, particularly depression, schizophrenia, mood disorders, and autism. In this review, we outlined the complexity of serotonergic modulation of physiologic and pathologic processes. Moreover, we provided experimental and clinical evidence of 5-HT's involvement in neuropsychiatric disorders and discussed the molecular mechanisms that underlie these illnesses and contribute to the new therapies.
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Affiliation(s)
- Mahsa Pourhamzeh
- Division of Neuroscience, Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Fahimeh Ghasemi Moravej
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehrnoosh Arabi
- Division of Neuroscience, Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Radiology and Medical Physics, Faculty of Paramedicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Elahe Shahriari
- Faculty of Medicine, Department of Physiology, Iran University of Medical Sciences, Tehran, Iran
| | - Soraya Mehrabi
- Division of Neuroscience, Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
- Faculty of Medicine, Department of Physiology, Iran University of Medical Sciences, Tehran, Iran
| | - Richard Ward
- Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin, USA
| | - Reza Ahadi
- Department of Anatomy, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Mohammad Taghi Joghataei
- Division of Neuroscience, Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.
- Department of Anatomy, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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4
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Berens S, Dong Y, Fritz N, Walstab J, D'Amato M, Zheng T, Wahl V, Boekstegers F, Bermejo JL, Martinez C, Schmitteckert S, Clevers E, Engel F, Gauss A, Herzog W, Spiller R, Goebel-Stengel M, Mönnikes H, Andresen V, Thomas F, Keller J, Pehl C, Stein-Thöringer C, Clarke G, Dinan TG, Quigley EM, Sayuk G, Simrén M, Tesarz J, Rappold G, van Oudenhove L, Schaefert R, Niesler B. Serotonin type 3 receptor subunit gene polymorphisms associated with psychosomatic symptoms in irritable bowel syndrome: A multicenter retrospective study. World J Gastroenterol 2022; 28:2334-2349. [PMID: 35800179 PMCID: PMC9185212 DOI: 10.3748/wjg.v28.i21.2334] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 08/21/2021] [Accepted: 04/22/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Single-nucleotide polymorphisms (SNPs) of the serotonin type 3 receptor subunit (HTR3) genes have been associated with psychosomatic symptoms, but it is not clear whether these associations exist in irritable bowel syndrome (IBS). AIM To assess the association of HTR3 polymorphisms with depressive, anxiety, and somatization symptoms in individuals with IBS. METHODS In this retrospective study, 623 participants with IBS were recruited from five specialty centers in Germany, Sweden, the United States, the United Kingdom, and Ireland. Depressive, anxiety, and somatization symptoms and sociodemographic characteristics were collected. Four functional SNPs - HTR3A c.-42C>T, HTR3B c.386A>C, HTR3C c.489C>A, and HTR3E c.*76G>A - were genotyped and analyzed using the dominant and recessive models. We also performed separate analyses for sex and IBS subtypes. SNP scores were calculated as the number of minor alleles of the SNPs above. The impact of HTR3C c.489C>A was tested by radioligand-binding and calcium influx assays. RESULTS Depressive and anxiety symptoms significantly worsened with increasing numbers of minor HTR3C c.489C>A alleles in the dominant model (F depressive = 7.475, P depressive = 0.006; F anxiety = 6.535, P anxiety = 0.011). A higher SNP score (range 0-6) was linked to a worsened depressive symptoms score (F = 7.710, P-linear trend = 0.006) in IBS. The potential relevance of the HTR3C SNP was corroborated, showing changes in the expression level of 5-HT3AC variant receptors. CONCLUSION We have provided the first evidence that HTR3C c.489C>A is involved in depressive and anxiety symptoms in individuals with IBS. The SNP score indicated that an increasing number of minor alleles is linked to the worsening of depressive symptoms in IBS.
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Affiliation(s)
- Sabrina Berens
- Department of General Internal Medicine and Psychosomatics, University Hospital Heidelberg, Heidelberg 69120, Germany
| | - Yuanjun Dong
- Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg 69120, Germany
- Department of General Internal Medicine and Psychosomatics, Internal Medicine II, University Hospital Heidelberg, Heidelberg 69120, Germany
| | - Nikola Fritz
- Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg 69120, Germany
| | - Jutta Walstab
- Department of Human Molecular Genetics, University of Heidelberg, Heidelberg 69120, Germany
| | - Mauro D'Amato
- Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Derio 48160, Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao 48001, Spain
- Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm 17177, Sweden
| | - Tenghao Zheng
- Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm 17177, Sweden
| | - Verena Wahl
- Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg 69120, Germany
| | - Felix Boekstegers
- Institute of Medical Biometry and Informatics, Heidelberg University, Heidelberg 69120, Germany
| | - Justo Lorenzo Bermejo
- Institute of Medical Biometry and Informatics, Heidelberg University, Heidelberg 69120, Germany
| | - Cristina Martinez
- Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg 69120, Germany
- Lleida Institute for Biomedical Research Dr. Pifarré Foundation (IRBLleida), Av. Alcalde Rovira Roure, Lleida 25198, Spain
| | - Stefanie Schmitteckert
- Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg 69120, Germany
| | - Egbert Clevers
- Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven 3000, Belgium
| | - Felicitas Engel
- Department of General Internal Medicine and Psychosomatics, Internal Medicine II, University Hospital Heidelberg, Heidelberg 69120, Germany
| | - Annika Gauss
- Department of Gastroenterology, Infectious Diseases and Intoxications, University of Heidelberg, Heidelberg 69120, Germany
| | - Wolfgang Herzog
- Department of General Internal Medicine and Psychosomatics, Heidelberg University, Heidelberg 69120, Germany
| | - Robin Spiller
- Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham NG7 2QL, United Kingdom
| | | | - Hubert Mönnikes
- Department of Medicine, Institute of Neurogastroenterology (H.M.), Martin-Luther-Hospital, Belin 14193, Germany
| | - Viola Andresen
- Israelitisches Krankenhaus in Hamburg, Hamburg 22297, Germany
| | - Frieling Thomas
- Internal Medicine II, Helios Klinikum Krefeld, Krefeld 47805, Germany
| | - Jutta Keller
- Israelitisches Krankenhaus Hamburg, Hamburg 22297, Ghana
| | | | | | - Gerard Clarke
- Department of Psychiatry and Neurobehavioral Science, University College Cork, Cork T23, Ireland
| | - Timothy G Dinan
- Department of Psychiatry and Neurobehavioral Science, University College Cork, Cork T23, Ireland
| | - Eamonn M Quigley
- Medicine in Digestive Disorders, Department of Medicine, Lynda K. and David M. Underwood Center for Digestive Disorders, Houston Methodist, Houston, TX 77030, United States
| | - Gregory Sayuk
- Division of Gastroenterology, Washington University School of Medicine, Department of Psychiatry, School of Medicine, John Cochran Veteran Affairs Medical Center, St. Louis, MO 63110, United States
| | - Magnus Simrén
- Department of Internal Medicine, Section of Gastroenterology and Hepatology, Sahlgrenska University Hospital, Gothenburg SE-41685, Sweden
| | - Jonas Tesarz
- Department of General Internal Medicine and Psychosomatics, Internal Medicine II, University Hospital Heidelberg, Heidelberg 69120, Germany
| | - Gudrun Rappold
- Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg 69120, Germany
- Interdisciplinary Center for Neurosciences (IZN), University of Heidelberg, Heidelberg 69120, Germany
| | - Lukas van Oudenhove
- Cognitive and Affective Neuroscience Lab, Department of Psychological and Brain Sciences, Dartmouth College, Hanover, NH 03748, United States
- Laboratory for Brain-Gut Axis Studies, Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism, and Ageing, KU Leuven, Leuven 3000, Belgium
| | - Rainer Schaefert
- Department of General Internal Medicine and Psychosomatics, Internal Medicine II, University Hospital Heidelberg, Heidelberg 69120, Germany
- Department of Psychosomatic Medicine, Division of Internal Medicine, University Hospital Basel, Basel CH-4031, Switzerland
| | - Beate Niesler
- Interdisciplinary Center for Neurosciences (IZN), University of Heidelberg, Heidelberg 69120, Germany
- Department of Human Molecular Genetics, Heidelberg University, Heidelberg 69120, Germany
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5
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Fritz N, Berens S, Dong Y, Martínez C, Schmitteckert S, Houghton LA, Goebel-Stengel M, Wahl V, Kabisch M, Götze D, D’Amato M, Zheng T, Röth R, Mönnikes H, Tesarz J, Engel F, Gauss A, Raithel M, Andresen V, Keller J, Frieling T, Pehl C, Stein-Thöringer C, Clarke G, Kennedy PJ, Cryan JF, Dinan TG, Quigley EMM, Spiller R, Beltrán C, Madrid AM, Torres V, Mayer EA, Sayuk G, Gazouli M, Karamanolis G, Bustamante M, Estivil X, Rabionet R, Hoffmann P, Nöthen MM, Heilmann-Heimbach S, Schmidt B, Franke A, Lieb W, Herzog W, Boeckxstaens G, Wouters MM, Simrén M, Rappold GA, Vicario M, Santos J, Schaefert R, Lorenzo-Bermejo J, Niesler B. The serotonin receptor 3E variant is a risk factor for female IBS-D. J Mol Med (Berl) 2022; 100:1617-1627. [PMID: 36121467 PMCID: PMC9592668 DOI: 10.1007/s00109-022-02244-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 07/18/2022] [Accepted: 08/04/2022] [Indexed: 12/14/2022]
Abstract
Irritable bowel syndrome (IBS) is a gut-brain disorder of multifactorial origin. Evidence of disturbed serotonergic function in IBS accumulated for the 5-HT3 receptor family. 5-HT3Rs are encoded by HTR3 genes and control GI function, and peristalsis and secretion, in particular. Moreover, 5-HT3R antagonists are beneficial in the treatment of diarrhea predominant IBS (IBS-D). We previously reported on functionally relevant SNPs in HTR3A c.-42C > T (rs1062613), HTR3C p.N163K (rs6766410), and HTR3E c.*76G > A (rs56109847 = rs62625044) being associated with IBS-D, and the HTR3B variant p.Y129S (rs1176744) was also described within the context of IBS. We performed a multi-center study to validate previous results and provide further evidence for the relevance of HTR3 genes in IBS pathogenesis. Therefore, genotype data of 2682 IBS patients and 9650 controls from 14 cohorts (Chile, Germany (2), Greece, Ireland, Spain, Sweden (2), the UK (3), and the USA (3)) were taken into account. Subsequent meta-analysis confirmed HTR3E c.*76G > A (rs56109847 = rs62625044) to be associated with female IBS-D (OR = 1.58; 95% CI (1.18, 2.12)). Complementary expression studies of four GI regions (jejunum, ileum, colon, sigmoid colon) of 66 IBS patients and 42 controls revealed only HTR3E to be robustly expressed. On top, HTR3E transcript levels were significantly reduced in the sigma of IBS patients (p = 0.0187); more specifically, in those diagnosed with IBS-D (p = 0.0145). In conclusion, meta-analysis confirmed rs56109847 = rs62625044 as a risk factor for female IBS-D. Expression analysis revealed reduced HTR3E levels in the sigmoid colon of IBS-D patients, which underlines the relevance of HTR3E in the pathogenesis of IBS-D.
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Affiliation(s)
- Nikola Fritz
- grid.5253.10000 0001 0328 4908Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany
| | - Sabrina Berens
- grid.5253.10000 0001 0328 4908Department of General Internal Medicine and Psychosomatics, Heidelberg University Hospital, Heidelberg, Germany
| | - Yuanjun Dong
- grid.5253.10000 0001 0328 4908Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany
| | - Cristina Martínez
- grid.5253.10000 0001 0328 4908Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany ,grid.420395.90000 0004 0425 020XInstitut de Recerca Biomèdica de Lleida (IRBLleida), Lleida, Spain ,Lleida Institute for Biomedical Research Dr, Pifarré Foundation (IRBLleida), Lleida, Spain
| | - Stefanie Schmitteckert
- grid.5253.10000 0001 0328 4908Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany
| | - Lesley A. Houghton
- grid.443984.60000 0000 8813 7132University of Leeds, St. James’s University Hospital, Leeds, UK ,grid.417467.70000 0004 0443 9942Mayo Clinic, Jacksonville, FL USA
| | - Miriam Goebel-Stengel
- grid.411544.10000 0001 0196 8249Department of Psychosomatic Medicine, University Hospital Tübingen, Tübingen, Germany ,Department of Internal Medicine and Gastroenterology, HELIOS Clinic Rottweil, Rottweil, Germany
| | - Verena Wahl
- grid.5253.10000 0001 0328 4908Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany
| | - Maria Kabisch
- grid.7700.00000 0001 2190 4373Institute of Medical Biometry and Informatics, Heidelberg University, Heidelberg, Germany
| | - Dorothea Götze
- grid.5253.10000 0001 0328 4908Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany
| | - Mauro D’Amato
- grid.4714.60000 0004 1937 0626Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden ,grid.420175.50000 0004 0639 2420Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Bilbao, Derio Spain ,grid.424810.b0000 0004 0467 2314IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Tenghao Zheng
- grid.4714.60000 0004 1937 0626Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Ralph Röth
- grid.5253.10000 0001 0328 4908Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany ,grid.5253.10000 0001 0328 4908nCounter Core Facility, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany
| | - Hubert Mönnikes
- grid.461755.40000 0004 0581 3852Martin-Luther-Hospital, Berlin, Germany
| | - Jonas Tesarz
- grid.5253.10000 0001 0328 4908Department of General Internal Medicine and Psychosomatics, Heidelberg University Hospital, Heidelberg, Germany
| | - Felicitas Engel
- grid.5253.10000 0001 0328 4908Department of General Internal Medicine and Psychosomatics, Heidelberg University Hospital, Heidelberg, Germany
| | - Annika Gauss
- grid.7700.00000 0001 2190 4373Department of Gastroenterology, Infectious Diseases and Intoxications, Heidelberg University, Heidelberg, Germany
| | - Martin Raithel
- grid.5330.50000 0001 2107 3311University of Erlangen, Erlangen, Germany
| | - Viola Andresen
- grid.414844.90000 0004 0436 8670Israelitisches Krankenhaus, Hamburg, Germany
| | - Jutta Keller
- grid.414844.90000 0004 0436 8670Israelitisches Krankenhaus, Hamburg, Germany
| | | | | | | | - Gerard Clarke
- grid.7872.a0000000123318773Department of Psychiatry and Neurobehavioral Science, University College Cork, Cork, Ireland ,grid.7872.a0000000123318773APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Paul J. Kennedy
- grid.7872.a0000000123318773Department of Psychiatry and Neurobehavioral Science, University College Cork, Cork, Ireland ,grid.7872.a0000000123318773APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - John F. Cryan
- grid.7872.a0000000123318773Department of Psychiatry and Neurobehavioral Science, University College Cork, Cork, Ireland ,grid.7872.a0000000123318773APC Microbiome Ireland, University College Cork, Cork, Ireland ,grid.7872.a0000000123318773Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | - Timothy G. Dinan
- grid.7872.a0000000123318773Department of Psychiatry and Neurobehavioral Science, University College Cork, Cork, Ireland ,grid.7872.a0000000123318773APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Eamonn M. M. Quigley
- grid.7872.a0000000123318773APC Microbiome Ireland, University College Cork, Cork, Ireland ,grid.63368.380000 0004 0445 0041Lynda K. and David M. Underwood Center for Digestive Disorders, Houston Methodist Hospital, Weill Cornell Medical College, Houston, TX USA
| | - Robin Spiller
- grid.4563.40000 0004 1936 8868Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK
| | - Caroll Beltrán
- grid.412248.90000 0004 0412 9717Gastroenterology Unit, Medicine Department, Hospital Clínico Universidad de Chile, Universidad de Chile, Santiago de Chile, Chile
| | - Ana María Madrid
- grid.412248.90000 0004 0412 9717Gastroenterology Unit, Medicine Department, Hospital Clínico Universidad de Chile, Universidad de Chile, Santiago de Chile, Chile
| | - Verónica Torres
- grid.412248.90000 0004 0412 9717Gastroenterology Unit, Medicine Department, Hospital Clínico Universidad de Chile, Universidad de Chile, Santiago de Chile, Chile
| | - Emeran A. Mayer
- grid.19006.3e0000 0000 9632 6718Oppenheimer Center for Neurobiology of Stress, University of California, Los Angeles, CA USA
| | - Gregory Sayuk
- grid.4367.60000 0001 2355 7002Washington University School of Medicine, St. Louis, MO USA
| | - Maria Gazouli
- grid.5216.00000 0001 2155 0800Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - George Karamanolis
- grid.5216.00000 0001 2155 0800Academic Department of Gastroenterology, Medical School, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece
| | - Mariona Bustamante
- grid.11478.3b0000 0004 1766 3695CRG, Centre for Genomic Regulation, Barcelona, Spain ,grid.434607.20000 0004 1763 3517ISGlobal, Barcelona, Spain
| | - Xavier Estivil
- grid.5841.80000 0004 1937 0247Department of Genetics, Microbiology and Statistics, Faculty of Biology, IBUB, Universitat de Barcelona, CIBERER, IRSJD, Barcelona, Spain
| | - Raquel Rabionet
- grid.5841.80000 0004 1937 0247Department of Genetics, Microbiology and Statistics, Faculty of Biology, IBUB, Universitat de Barcelona, CIBERER, IRSJD, Barcelona, Spain
| | - Per Hoffmann
- grid.435715.10000 0004 0436 7643Life and Brain Center, Bonn, Germany
| | - Markus M. Nöthen
- grid.435715.10000 0004 0436 7643Life and Brain Center, Bonn, Germany
| | | | - Börge Schmidt
- grid.410718.b0000 0001 0262 7331Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, Essen, Germany
| | - André Franke
- Institute of Clinical Molecular Biology, Kiel, Germany
| | - Wolfgang Lieb
- grid.417834.dInstitute of Epidemiology, Kiel, Germany
| | - Wolfgang Herzog
- grid.5253.10000 0001 0328 4908Department of General Internal Medicine and Psychosomatics, Heidelberg University Hospital, Heidelberg, Germany
| | - Guy Boeckxstaens
- grid.410569.f0000 0004 0626 3338TARGID, University Hospital Leuven, Louvain, Belgium
| | - Mira M. Wouters
- grid.410569.f0000 0004 0626 3338TARGID, University Hospital Leuven, Louvain, Belgium
| | - Magnus Simrén
- grid.8761.80000 0000 9919 9582Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Gudrun A. Rappold
- grid.5253.10000 0001 0328 4908Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany ,grid.7700.00000 0001 2190 4373Interdisciplinary Center for Neurosciences (IZN), Heidelberg University, Heidelberg, Germany
| | - Maria Vicario
- grid.411083.f0000 0001 0675 8654Institut de Recerca Vall d Hebron, Hospital Vall d Hebron, Passeig de la Vall d Hebron, Barcelona, Spain ,grid.419905.00000 0001 0066 4948Nestlé Institute of Health Sciences, Nestlé Research, Société Des Produits Nestlé S.A, Vers-chez-les-Blanc, Lausanne, Switzerland
| | - Javier Santos
- grid.411083.f0000 0001 0675 8654Institut de Recerca Vall d Hebron, Hospital Vall d Hebron, Passeig de la Vall d Hebron, Barcelona, Spain
| | - Rainer Schaefert
- grid.410567.1Department of Psychosomatic Medicine, Division of Theragnostics, University Hospital Basel, Basel, Switzerland ,grid.6612.30000 0004 1937 0642Faculty of Medicine, University of Basel, Basel, Switzerland
| | - Justo Lorenzo-Bermejo
- grid.7700.00000 0001 2190 4373Institute of Medical Biometry and Informatics, Heidelberg University, Heidelberg, Germany
| | - Beate Niesler
- grid.5253.10000 0001 0328 4908Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany ,grid.5253.10000 0001 0328 4908nCounter Core Facility, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany ,grid.7700.00000 0001 2190 4373Interdisciplinary Center for Neurosciences (IZN), Heidelberg University, Heidelberg, Germany
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6
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Hengen KM, Alpers GW. Stress Makes the Difference: Social Stress and Social Anxiety in Decision-Making Under Uncertainty. Front Psychol 2021; 12:578293. [PMID: 33692716 PMCID: PMC7937725 DOI: 10.3389/fpsyg.2021.578293] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 01/05/2021] [Indexed: 01/04/2023] Open
Abstract
Stress and anxiety can both influence risk-taking in decision-making. While stress typically increases risk-taking, anxiety often leads to risk-averse choices. Few studies have examined both stress and anxiety in a single paradigm to assess risk-averse choices. We therefore set out to examine emotional decision-making under stress in socially anxious participants. In our study, individuals (N = 87) high or low in social anxiety completed an expanded variation of the Balloon Analogue Risk Task (BART). While inflating a balloon to a larger degree is rewarded, a possible explosion leads to (a) a loss of money and (b) it is followed by an emotional picture (i.e., a calm vs. an angry face). To induce stress before this task, participants were told that they would have to deliver a speech. We operationalized risk-taking by the number of pumps during inflation and its functionality by the amount of monetary gain. In addition, response times were recorded as an index of decisional conflict. Without the stressor, high socially anxious compared to low socially anxious participants did not differ in any of the dependent variables. However, under stress, the low socially anxious group took more risk and earned more money, while high socially anxious individuals remained more cautious and did not change their risk-taking under social stress. Overall, high socially anxious individuals made their decisions more hesitantly compared to low socially anxious individuals. Unexpectedly, there were no main effects or interactions with the valence of the emotional faces. This data shows that stress affects socially anxious individuals differently: in low socially anxious individuals stress fosters risk-taking, whereas high socially anxious individuals did not alter their behavior and remained risk-averse. The novel eBART is a promising research tool to examine the specific factors that influence decision-making.
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Affiliation(s)
| | - Georg W. Alpers
- Department of Psychology, School of Social Science, University of Mannheim, Mannheim, Germany
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7
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Fakhfouri G, Rahimian R, Dyhrfjeld-Johnsen J, Zirak MR, Beaulieu JM. 5-HT 3 Receptor Antagonists in Neurologic and Neuropsychiatric Disorders: The Iceberg Still Lies beneath the Surface. Pharmacol Rev 2019; 71:383-412. [PMID: 31243157 DOI: 10.1124/pr.118.015487] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
5-HT3 receptor antagonists, first introduced to the market in the mid-1980s, are proven efficient agents to counteract chemotherapy-induced emesis. Nonetheless, recent investigations have shed light on unappreciated dimensions of this class of compounds in conditions with an immunoinflammatory component as well as in neurologic and psychiatric disorders. The promising findings from multiple studies have unveiled several beneficial effects of these compounds in multiple sclerosis, stroke, Alzheimer disease, and Parkinson disease. Reports continue to uncover important roles for 5-HT3 receptors in the physiopathology of neuropsychiatric disorders, including depression, anxiety, drug abuse, and schizophrenia. This review addresses the potential of 5-HT3 receptor antagonists in neurology- and neuropsychiatry-related disorders. The broad therapeutic window and high compliance observed with these agents position them as suitable prototypes for the development of novel pharmacotherapeutics with higher efficacy and fewer adverse effects.
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Affiliation(s)
- Gohar Fakhfouri
- Department of Psychiatry and Neuroscience, Faculty of Medicine, CERVO Brain Research Centre, Laval University, Quebec, Quebec, Canada (G.F., R.R.); Sensorion SA, Montpellier, France (J.D.-J.); Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran (M.R.Z.); and Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada (J.-M.B.)
| | - Reza Rahimian
- Department of Psychiatry and Neuroscience, Faculty of Medicine, CERVO Brain Research Centre, Laval University, Quebec, Quebec, Canada (G.F., R.R.); Sensorion SA, Montpellier, France (J.D.-J.); Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran (M.R.Z.); and Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada (J.-M.B.)
| | - Jonas Dyhrfjeld-Johnsen
- Department of Psychiatry and Neuroscience, Faculty of Medicine, CERVO Brain Research Centre, Laval University, Quebec, Quebec, Canada (G.F., R.R.); Sensorion SA, Montpellier, France (J.D.-J.); Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran (M.R.Z.); and Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada (J.-M.B.)
| | - Mohammad Reza Zirak
- Department of Psychiatry and Neuroscience, Faculty of Medicine, CERVO Brain Research Centre, Laval University, Quebec, Quebec, Canada (G.F., R.R.); Sensorion SA, Montpellier, France (J.D.-J.); Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran (M.R.Z.); and Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada (J.-M.B.)
| | - Jean-Martin Beaulieu
- Department of Psychiatry and Neuroscience, Faculty of Medicine, CERVO Brain Research Centre, Laval University, Quebec, Quebec, Canada (G.F., R.R.); Sensorion SA, Montpellier, France (J.D.-J.); Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran (M.R.Z.); and Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada (J.-M.B.)
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8
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Kutlubaev MA, Mendelevich VD. The problem of aggressive behavior in epilepsy: clinical and neurobiological aspects. Zh Nevrol Psikhiatr Im S S Korsakova 2018; 118:94-100. [DOI: 10.17116/jnevro20181187194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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9
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Hadjikhani N, Zurcher NR, Lassalle A, Hippolyte L, Ward N, Johnels JÅ. The effect of constraining eye-contact during dynamic emotional face perception-an fMRI study. Soc Cogn Affect Neurosci 2017; 12:1197-1207. [PMID: 28402536 PMCID: PMC5490673 DOI: 10.1093/scan/nsx046] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Revised: 03/09/2017] [Accepted: 03/27/2017] [Indexed: 11/25/2022] Open
Abstract
Eye-contact modifies how we perceive emotions and modulates activity in the social brain network. Here, using fMRI, we demonstrate that adding a fixation cross in the eye region of dynamic facial emotional stimuli significantly increases activation in the social brain of healthy, neurotypical participants when compared with activation for the exact same stimuli observed in a free-viewing mode. In addition, using PPI analysis, we show that the degree of amygdala connectivity with the rest of the brain is enhanced for the constrained view for all emotions tested except for fear, and that anxiety and alexithymia modulate the strength of amygdala connectivity for each emotion differently. Finally, we show that autistic traits have opposite effects on amygdala connectivity for fearful and angry emotional expressions, suggesting that these emotions should be treated separately in studies investigating facial emotion processing.
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Affiliation(s)
- Nouchine Hadjikhani
- MGH/HMS/HST A. A. Martinos Center for Biomedical Imaging, Harvard Medical School, Charlestown, MA 02129, USA
- Gillberg Neuropsychiatry Center, University of Gothenburg, Gothenburg 41119, Sweden
| | - Nicole R. Zurcher
- MGH/HMS/HST A. A. Martinos Center for Biomedical Imaging, Harvard Medical School, Charlestown, MA 02129, USA
| | - Amandine Lassalle
- MGH/HMS/HST A. A. Martinos Center for Biomedical Imaging, Harvard Medical School, Charlestown, MA 02129, USA
- ARC, Department of Psychiatry, Cambridge University, Cambridge CB2 8AH, UK
| | - Loyse Hippolyte
- Centre Hospitalier Universitaire Vaudois, Lausanne 1010, Switzerland
| | - Noreen Ward
- MGH/HMS/HST A. A. Martinos Center for Biomedical Imaging, Harvard Medical School, Charlestown, MA 02129, USA
| | - Jakob Åsberg Johnels
- Gillberg Neuropsychiatry Center, University of Gothenburg, Gothenburg 41119, Sweden
- Section for Speech and Language Pathology, University of Gothenburg, Gothenburg 455 405 30, Sweden
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10
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Look me in the eyes: constraining gaze in the eye-region provokes abnormally high subcortical activation in autism. Sci Rep 2017; 7:3163. [PMID: 28600558 PMCID: PMC5466661 DOI: 10.1038/s41598-017-03378-5] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Accepted: 04/27/2017] [Indexed: 12/22/2022] Open
Abstract
Individuals with Autism Spectrum Disorder (ASD) seem to have difficulties looking others in the eyes, but the substrate for this behavior is not well understood. The subcortical pathway, which consists of superior colliculus, pulvinar nucleus of the thalamus, and amygdala, enables rapid and automatic face processing. A specific component of this pathway – i.e., the amygdala – has been shown to be abnormally activated in paradigms where individuals had to specifically attend to the eye-region; however, a direct examination of the effect of manipulating the gaze to the eye-regions on all the components of the subcortical system altogether has never been performed. The subcortical system is particularly important as it shapes the functional specialization of the face-processing cortex during development. Using functional MRI, we investigated the effect of constraining gaze in the eye-region during dynamic emotional face perception in groups of participants with ASD and typical controls. We computed differences in activation in the subcortical face processing system (superior colliculus, pulvinar nucleus of the thalamus and amygdala) for the same stimuli seen freely or with the gaze constrained in the eye-region. Our results show that when constrained to look in the eyes, individuals with ASD show abnormally high activation in the subcortical system, which may be at the basis of their eye avoidance in daily life.
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11
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Genetic polymorphisms and their association with brain and behavioural measures in heterogeneous stock mice. Sci Rep 2017; 7:41204. [PMID: 28145470 PMCID: PMC5286500 DOI: 10.1038/srep41204] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Accepted: 12/16/2016] [Indexed: 12/30/2022] Open
Abstract
Although the search for quantitative trait loci for behaviour remains a considerable challenge, the complicated genetic architecture of quantitative traits is beginning to be understood. The current project utilised heterogeneous stock (HS) male mice (n = 580) to investigate the genetic basis for brain weights, activity, anxiety and cognitive phenotypes. We identified 126 single nucleotide polymorphisms (SNPs) in genes involved in regulation of neurotransmitter systems, nerve growth/death and gene expression, and subsequently investigated their associations with changes in behaviour and/or brain weights in our sample. We found significant associations between four SNP-phenotype pairs, after controlling for multiple testing. Specificity protein 2 (Sp2, rs3708840), tryptophan hydroxylase 1 (Tph1, rs262731280) and serotonin receptor 3A (Htr3a, rs50670893) were associated with activity/anxiety behaviours, and microtubule-associated protein 2 (Map2, rs13475902) was associated with cognitive performance. All these genes except for Tph1 were expressed in the brain above the array median, and remained significantly associated with relevant behaviours after controlling for the family structure. Additionally, we found evidence for a correlation between Htr3a expression and activity. We discuss our findings in the light of the advantages and limitations of currently available mouse genetic tools, suggesting further directions for association studies in rodents.
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12
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Raab K, Kirsch P, Mier D. Understanding the impact of 5-HTTLPR, antidepressants, and acute tryptophan depletion on brain activation during facial emotion processing: A review of the imaging literature. Neurosci Biobehav Rev 2016; 71:176-197. [DOI: 10.1016/j.neubiorev.2016.08.031] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Revised: 07/28/2016] [Accepted: 08/26/2016] [Indexed: 12/22/2022]
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Celli J, Rappold G, Niesler B. The Human Serotonin Type 3 Receptor Gene (HTR3A-E) Allelic Variant Database. Hum Mutat 2016; 38:137-147. [PMID: 27763704 DOI: 10.1002/humu.23136] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Revised: 10/11/2016] [Accepted: 10/15/2016] [Indexed: 12/17/2022]
Abstract
Serotonin type 3 (5-HT3 ) receptors are ligand-gated ion channels formed by five subunits (5-HT3A-E), which are encoded by the HTR3A, HTR3B, HTR3C, HTR3D, and HTR3E genes. Functional receptors are pentameric complexes of diverse composition. Different receptor subtypes confer a predisposition to nausea and vomiting during chemotherapy, pregnancy, and following surgery. In addition, different subtypes contribute to neurogastroenterologic disorders such irritable bowel syndrome (IBS) and eating disorders as well as comorbid psychiatric conditions. 5-HT3 receptor antagonists are established treatments for emesis and IBS and are beneficial in the treatment of psychiatric diseases. Several case-control and pharmacogenetic studies have demonstrated an association between HTR3 variants and psychiatric and neurogastroenterologic phenotypes. Recently, their potential as predictors of nausea and vomiting and treatment of psychiatric disorders became evident. This information is now available in the serotonin receptor 3 HTR3 gene allelic variant database (www.htr3.uni-hd.de), which contains five sub-databases, one for each of the five different serotonin receptor genes HTR3A-E. Information on HTR3 variants, their functional relevance, associated phenotypes, and pharmacogenetic data such as drug response and side effects are available. This central information pool should help clinicians as well as scientists to evaluate their findings and to use the relevant information for subsequent genotype-phenotype correlation studies and pharmacogenetic approaches.
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Affiliation(s)
- Jacopo Celli
- Center of Human and Clinical Genetics, Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands
| | - Gudrun Rappold
- Department of Human Molecular Genetics, University of Heidelberg, Heidelberg, Germany
| | - Beate Niesler
- Department of Human Molecular Genetics, University of Heidelberg, Heidelberg, Germany
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14
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Correia SS, Goosens KA. Input-specific contributions to valence processing in the amygdala. ACTA ACUST UNITED AC 2016; 23:534-43. [PMID: 27634144 PMCID: PMC5026206 DOI: 10.1101/lm.037887.114] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Accepted: 04/26/2016] [Indexed: 10/25/2022]
Abstract
Reward and punishment are often thought of as opposing processes: rewards and the environmental cues that predict them elicit approach and consummatory behaviors, while punishments drive aversion and avoidance behaviors. This framework suggests that there may be segregated brain circuits for these valenced behaviors. The basolateral amygdala (BLA) is one brain region that contributes to both types of motivated behavior. Individual neurons in the BLA can favor positive over negative valence, or vice versa, but these neurons are intermingled, showing no anatomical segregation. The amygdala receives inputs from many brain areas and current theories posit that encoding of positive versus negative valence by BLA neurons is determined by the wiring of each neuron. Specifically, many projections from other brain areas that respond to positive and negative valence stimuli and predictive cues project strongly to the BLA and likely contribute to valence processing within the BLA. Here we review three of these areas, the basal forebrain, the dorsal raphe nucleus and the ventral tegmental area, and discuss how these may promote encoding of positive and negative valence within the BLA.
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Affiliation(s)
- Susana S Correia
- McGovern Institute for Brain Research and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
| | - Ki A Goosens
- McGovern Institute for Brain Research and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
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15
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Kim HW, Kang JI, Lee SH, An SK, Sohn SY, Hwang EH, Lee SY, Kim SJ. Common variants of HTR3 genes are associated with obsessive-compulsive disorder and its phenotypic expression. Sci Rep 2016; 6:32564. [PMID: 27616601 PMCID: PMC5018838 DOI: 10.1038/srep32564] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Accepted: 08/09/2016] [Indexed: 12/24/2022] Open
Abstract
Evidence from literature supports the existence of associations between serotonin-related genetic variants and obsessive-compulsive disorder (OCD), but few studies have explored the involvement of serotonin receptor type 3 genes (HTR3) in OCD. To identify whether HTR3 variability affects an individual’s susceptibility to OCD, we examined 10 HTR3 variants in 596 individuals with OCD and 599 controls. A significant difference existed in the genotypic distribution of the HTR3B variant rs1176744 between individuals with OCD and controls (odds ratio [OR] = 0.74, 95% confidence interval [CI] = 0.60–0.91, P = 0.0043). A protective haplotype in HTR3B was also associated with OCD (OR = 0.77, CI = 0.63–0.95, permutated P = 0.0179). Analyses of OCD sub-phenotypes demonstrated significant associations between rs3758987 and early onset OCD in male subjects (OR = 0.49, CI = 0.31–0.79, P = 0.0031) and among rs6766410, rs6443930, and the cleaning dimension in female subjects (OR = 0.36, CI = 0.18–0.69, P = 0.0016 and OR = 0.47, CI = 0.29–0.79, P = 0.0030, respectively). Additionally, rs6766410 was related to contamination-based disgust in OCD (P = 0.0044). These results support that common HTR3 variants are involved in OCD and some of its clinical phenotypes.
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Affiliation(s)
- Hae Won Kim
- Department of Psychiatry, Yonsei University College of Medicine, Seoul, Republic of Korea.,Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jee In Kang
- Department of Psychiatry, Yonsei University College of Medicine, Seoul, Republic of Korea.,Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sang-Hyuk Lee
- Department of Psychiatry, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Suk Kyoon An
- Department of Psychiatry, Yonsei University College of Medicine, Seoul, Republic of Korea.,Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sung Yun Sohn
- Department of Psychiatry, Yonsei University College of Medicine, Seoul, Republic of Korea.,Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Eun Hee Hwang
- Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Su Young Lee
- Department of Psychiatry, Cheil General Hospital &Women's Healthcare Center, Dankook University College of Medicine, Seoul, Republic of Korea
| | - Se Joo Kim
- Department of Psychiatry, Yonsei University College of Medicine, Seoul, Republic of Korea.,Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
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16
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Smoller JW, Gardner-Schuster E, Misiaszek M. Genetics of anxiety: would the genome recognize the DSM? Depress Anxiety 2016; 25:368-77. [PMID: 18412063 DOI: 10.1002/da.20492] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
The nosology of anxiety disorders has undergone substantial evolution over the past several decades. The modern classification of these disorders dates to the publication of Diagnostic and Statistical Manual-III (DSM-III) in 1980, but the validity of the current diagnostic categories has been the subject of controversy. Genetic research can help clarify the boundaries of diagnostic categories by examining the etiologic relationships among them. The question posed in the title of this article asks to what degree the DSM-IV definitions of the anxiety disorders are supported by the evolving body of research on the genetic basis of pathologic anxiety. With DSM-V on the horizon, there is a renewed imperative to examine the structure of these disorders. In this article, we address this issue by, first, providing a brief update about the current status of genetic research on anxiety disorders and then considering whether the evidence suggests that genetic influences conform to or transcend DSM definitions. Finally, we discuss future directions for the genetic dissection of anxiety disorders.
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Affiliation(s)
- Jordan W Smoller
- Department of Psychiatry, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
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Gupta D, Prabhakar V, Radhakrishnan M. 5HT3 receptors: Target for new antidepressant drugs. Neurosci Biobehav Rev 2016; 64:311-25. [PMID: 26976353 DOI: 10.1016/j.neubiorev.2016.03.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2015] [Revised: 02/29/2016] [Accepted: 03/01/2016] [Indexed: 12/31/2022]
Abstract
5HT3 receptors (5HT3Rs) have long been identified as a potential target for antidepressants. Several studies have reported that antagonism of 5HT3Rs produces antidepressant-like effects. However, the exact role of 5HT3Rs and the mode of antidepressant action of 5HT3R antagonists still remain a mystery. Here, we provide a comprehensive overview of 5HT3Rs: (a) regional and subcellular distribution of 5HT3Rs in discrete brain regions, (b) preclinical and clinical evidence supporting the antidepressant effect of 5HT3R antagonists, and (c) neurochemical, biological and neurocellular signaling pathways associated with the antidepressant action of 5HT3R antagonists. 5HT3Rs located on the serotonergic and other neurotransmitter interneuronal projections control their release and affect mood and emotional behavior; however, new evidence suggests that apart from modulating the neurotransmitter functions, 5HT3R antagonists have protective effects in the pathogenic events including hypothalamic-pituitary-adrenal-axis hyperactivity, brain oxidative stress and impaired neuronal plasticity, pointing to hereby unknown and novel mechanisms of their antidepressant action. Nonetheless, further investigations are warranted to establish the exact role of 5HT3Rs in depression and antidepressant action of 5HT3R antagonists.
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Affiliation(s)
- Deepali Gupta
- Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Rajasthan 333031, India.
| | - Visakh Prabhakar
- Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Rajasthan 333031, India.
| | - Mahesh Radhakrishnan
- Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Rajasthan 333031, India.
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Abstract
IBS is the most prevalent functional gastrointestinal disorder and phenotypically characterized by chronic abdominal discomfort, pain and altered defecation patterns. The pathophysiology of IBS is multifactorial, albeit with a substantial genetic component. To date, studies using various methodologies, ranging from family and twin studies to candidate gene approaches and genome-wide association studies, have identified several genetic variants in the context of IBS. Yet, despite enlarged sample sizes, increased statistical power and meta-analyses in the past 7 years, positive associations are still scarce and/or have not been reproduced. In addition, epigenetic and pharmacogenetic approaches remain in their infancy. A major hurdle is the lack of large homogenized case-control cohorts recruited according to standardized and harmonized criteria. The COST Action BM1106 GENIEUR (GENes in Irritable Bowel Syndrome Research Network EURope) has been established to address these obstacles. In this Review, the (epi)genetic working group of GENIEUR reports on the current state-of-the-art in the field, highlights fundamental flaws and pitfalls in current IBS (epi)genetic research and provides a vision on how to address and improve (epi)genetic approaches in this complex disorder in the future.
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19
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Jang KI, Lee SH, Huh HJ, Chae JH. Influence of the 5-HT3A Receptor Gene Polymorphism and Childhood Sexual Trauma on Central Serotonin Activity. PLoS One 2015; 10:e0145269. [PMID: 26701104 PMCID: PMC4689356 DOI: 10.1371/journal.pone.0145269] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Accepted: 12/02/2015] [Indexed: 01/21/2023] Open
Abstract
Background Gene-environment interactions are important for understanding alterations in human brain function. The loudness dependence of auditory evoked potential (LDAEP) is known to reflect central serotonergic activity. Single nucleotide polymorphisms (SNPs) in the 5-HT3A serotonin receptor gene are associated with psychiatric disorders. This study aimed to investigate the effect between 5-HT3A receptor gene polymorphisms and childhood sexual trauma on the LDAEP as an electrophysiological marker in healthy subjects. Methods A total of 206 healthy subjects were recruited and evaluated using the childhood trauma questionnaire (CTQ) and hospital anxiety and depression scale (HADS). Peak-to-peak N1/P2 was measured at five stimulus intensities, and the LDAEP was calculated as the linear-regression slope. In addition, the rs1062613 SNPs of 5-HT3A (CC, CT, and TT) were analyzed in healthy subjects. Results There was a significant interaction between scores on the CTQ-sexual abuse subscale and 5-HT3A genotype on the LDAEP. Subjects with the CC polymorphism had a significantly higher LDEAP than T carriers in the sexually abused group. In addition, CC genotype subjects in the sexually abused group showed a significantly higher LDAEP compared with CC genotype subjects in the non-sexually abused group. Conclusions Our findings suggest that people with the CC polymorphism of the 5-HT3A gene have a greater risk of developing mental health problems if they have experienced childhood sexual abuse, possibly due to low central serotonin activity. Conversely, the T polymorphism may be protective against any central serotonergic changes following childhood sexual trauma.
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Affiliation(s)
- Kuk-In Jang
- Department of Biomedicine & Health Sciences, The Catholic University of Korea, College of Medicine, Seoul, Korea
- Clinical Emotion and Cognition Research Laboratory, Inje University, Goyang, Korea
| | - Seung-Hwan Lee
- Department of Psychiatry, Inje University College of Medicine, Ilsan Paik Hospital, Goyang, Korea
- Clinical Emotion and Cognition Research Laboratory, Inje University, Goyang, Korea
| | - Hyu Jung Huh
- Department of Psychiatry, Seoul St. Mary's Hospital, The Catholic University of Korea, College of Medicine, Seoul, Korea
| | - Jeong-Ho Chae
- Department of Biomedicine & Health Sciences, The Catholic University of Korea, College of Medicine, Seoul, Korea
- Department of Psychiatry, Seoul St. Mary's Hospital, The Catholic University of Korea, College of Medicine, Seoul, Korea
- * E-mail:
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Abstract
Aggression and violence represent a significant public health concern and a clinical challenge for the mental healthcare provider. A great deal has been revealed regarding the neurobiology of violence and aggression, and an integration of this body of knowledge will ultimately serve to advance clinical diagnostics and therapeutic interventions. We will review here the latest findings regarding the neurobiology of aggression and violence. First, we will introduce the construct of aggression, with a focus on issues related to its heterogeneity, as well as the importance of refining the aggression phenotype in order to reduce pathophysiologic variability. Next we will examine the neuroanatomy of aggression and violence, focusing on regional volumes, functional studies, and interregional connectivity. Significant emphasis will be on the amygdala, as well as amygdala-frontal circuitry. Then we will turn our attention to the neurochemistry and molecular genetics of aggression and violence, examining the extensive findings on the serotonergic system, as well as the growing literature on the dopaminergic and vasopressinergic systems. We will also address the contribution of steroid hormones, namely, cortisol and testosterone. Finally, we will summarize these findings with a focus on reconciling inconsistencies and potential clinical implications; and, then we will suggest areas of focus for future directions in the field.
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Gu QY, Zhang J, Feng YC, Dai GR, Du WP. Association of genetic polymorphisms in HTR3A and HTR3E with diarrhea predominant irritable bowel syndrome. Int J Clin Exp Med 2015; 8:4581-4585. [PMID: 26064388 PMCID: PMC4443222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2014] [Accepted: 01/30/2015] [Indexed: 06/04/2023]
Abstract
OBJECTIVE The present study aims to investigate the relationship between genetic polymorphisms in HTR3A and HTR3E and diarrhea predominant irritable bowel syndrome (D-IBS) in a Chinese population. METHODS We enrolled 500 D-IBS patients and 500 age- and sex-matched healthy control subjects to detect the genotypes in HTR3A and HTR3B gene by using of PCR-RFLP method. RESULTS There were significant difference between the D-IBS patients and the health control subjects in the distribution of genotype and allele of rs1062613 in HTR3A gene. As regarding rs62625044 in HTR3E gene, we found there was a significant different between the case and the control group in the distribution of GA genotype and A allele in female but not in male. CONCLUSION The present study suggested that there are associations of D-IBS risk with genetic polymorphisms in HTR3A and HTR3E.
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Affiliation(s)
- Qiao-Yan Gu
- Department of Gastroenterology, Second Affiliated Hospital of Xi’an Jiaotong UniversityXi’an 710004, Shaanxi Province, P. R. China
- Department of Gastroenterology, Affiliated Hospital of Yan’an UniversityYan’an 716000, Shaanxi Province, P. R. China
| | - Jun Zhang
- Department of Gastroenterology, Second Affiliated Hospital of Xi’an Jiaotong UniversityXi’an 710004, Shaanxi Province, P. R. China
| | - Yi-Chao Feng
- Department of Gastroenterology, Affiliated Hospital of Yan’an UniversityYan’an 716000, Shaanxi Province, P. R. China
| | - Guang-Rong Dai
- Department of Gastroenterology, Affiliated Hospital of Yan’an UniversityYan’an 716000, Shaanxi Province, P. R. China
| | - Wei-Ping Du
- Department of Gastroenterology, Affiliated Hospital of Yan’an UniversityYan’an 716000, Shaanxi Province, P. R. China
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22
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Jajodia A, Singh KD, Singhal A, Vig S, Datta M, Singh Y, Karthikeyan M, Kukreti R. Methylation of a HTR3A promoter variant alters the binding of transcription factor CTCF. RSC Adv 2015. [DOI: 10.1039/c5ra04455c] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Genetic studies pertaining to effector molecules have been pivotal in schizophrenia research.
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Affiliation(s)
- Ajay Jajodia
- Genomics and Molecular Medicine
- CSIR-Institute of Genomics and Integrative Biology
- Delhi-110007
- India
| | | | - Anshika Singhal
- Genomics and Molecular Medicine
- CSIR-Institute of Genomics and Integrative Biology
- Delhi-110007
- India
| | - Saurabh Vig
- Genomics and Molecular Medicine
- CSIR-Institute of Genomics and Integrative Biology
- Delhi-110007
- India
| | - Malabika Datta
- Genomics and Molecular Medicine
- CSIR-Institute of Genomics and Integrative Biology
- Delhi-110007
- India
| | - Yogendra Singh
- Genomics and Molecular Medicine
- CSIR-Institute of Genomics and Integrative Biology
- Delhi-110007
- India
| | | | - Ritushree Kukreti
- Genomics and Molecular Medicine
- CSIR-Institute of Genomics and Integrative Biology
- Delhi-110007
- India
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23
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Effects of L-theanine on posttraumatic stress disorder induced changes in rat brain gene expression. ScientificWorldJournal 2014; 2014:419032. [PMID: 25165739 PMCID: PMC4137547 DOI: 10.1155/2014/419032] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2014] [Revised: 04/11/2014] [Accepted: 05/13/2014] [Indexed: 01/02/2023] Open
Abstract
Posttraumatic stress disorder (PTSD) is characterized by the occurrence of a traumatic event that is beyond the normal range of human experience. The future of PTSD treatment may specifically target the molecular mechanisms of PTSD. In the US, approximately 20% of adults report taking herbal products to treat medical illnesses. L-theanine is the amino acid in green tea primarily responsible for relaxation effects. No studies have evaluated the potential therapeutic properties of herbal medications on gene expression in PTSD. We evaluated gene expression in PTSD-induced changes in the amygdala and hippocampus of Sprague-Dawley rats. The rats were assigned to PTSD-stressed and nonstressed groups that received either saline, midazolam, L-theanine, or L-theanine + midazolam. Amygdala and hippocampus tissue samples were analyzed for changes in gene expression. One-way ANOVA was used to detect significant difference between groups in the amygdala and hippocampus. Of 88 genes examined, 17 had a large effect size greater than 0.138. Of these, 3 genes in the hippocampus and 5 genes in the amygdala were considered significant (P < 0.05) between the groups. RT-PCR analysis revealed significant changes between groups in several genes implicated in a variety of disorders ranging from PTSD, anxiety, mood disorders, and substance dependence.
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Hansson C, Alvarez-Crespo M, Taube M, Skibicka KP, Schmidt L, Karlsson-Lindahl L, Egecioglu E, Nissbrandt H, Dickson SL. Influence of ghrelin on the central serotonergic signaling system in mice. Neuropharmacology 2014; 79:498-505. [DOI: 10.1016/j.neuropharm.2013.12.012] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2013] [Revised: 11/22/2013] [Accepted: 12/14/2013] [Indexed: 02/09/2023]
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Seneviratne C, Franklin J, Beckett K, Ma JZ, Ait-Daoud N, Payne TJ, Johnson BA, Li MD. Association, interaction, and replication analysis of genes encoding serotonin transporter and 5-HT3 receptor subunits A and B in alcohol dependence. Hum Genet 2013; 132:1165-76. [PMID: 23757001 PMCID: PMC3775919 DOI: 10.1007/s00439-013-1319-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2013] [Accepted: 05/26/2013] [Indexed: 12/12/2022]
Abstract
On the basis of the converging evidence showing regulation of drinking behavior by 5-HT3AB receptors and the serotonin transporter, we hypothesized that the interactive effects of genetic variations in the genes HTR3A, HTR3B, and SLC6A4 confer greater susceptibility to alcohol dependence (AD) than do their effects individually. We examined the associations of AD with 22 SNPs across HTR3A, HTR3B, and two functional variants in SLC6A4 in 500 AD and 280 healthy control individuals of European descent. We found that the alleles of the low-frequency SNPs rs33940208:T in HTR3A and rs2276305:A in HTR3B were inversely and nominally significantly associated with AD with odds ratio (OR) and 95 % confidence interval of 0.212 and 0.073, 0.616 (P = 0.004) and 0.261 and 0.088, 0.777 (P = 0.016), respectively. Further, our gene-by-gene interaction analysis revealed that two four-variant models that differed by only one SNP carried a risk for AD (empirical P < 1 × 10(-6) for prediction accuracy of the two models based on 10(6) permutations). Subsequent analysis of these two interaction models revealed an OR of 2.71 and 2.80, respectively, for AD (P < 0.001) in carriers of genotype combinations 5'-HTTLPR:LL/LS(SLC6A4)-rs1042173:TT/TG(SLC6A4)-rs1176744:AC(HTR3B)-rs3782025:AG(HTR3B) and 5'-HTTLPR:LL/LS(SLC6A4)-rs10160548:GT/TT(HTR3A)-rs1176744:AC(HTR3B)-rs3782025:AG(HTR3B). Combining all five genotypes resulted in an OR of 3.095 (P = 2.0 × 10(-4)) for AD. Inspired by these findings, we conducted the analysis in an independent sample, OZ-ALC-GWAS (N = 6699), obtained from the NIH dbGAP database, which confirmed the findings, not only for all three risk genotype combinations (Z = 4.384, P = 1.0 × 10(-5); Z = 3.155, P = 1.6 × 10(-3); and Z = 3.389, P = 7.0 × 10(-4), respectively), but also protective effects for rs33940208:T (χ (2) = 3.316, P = 0.0686) and rs2276305:A (χ (2) = 7.224, P = 0.007). These findings reveal significant interactive effects among variants in SLC6A4-HTR3A-HTR3B affecting AD. Further studies are needed to confirm these findings and characterize the molecular mechanisms underlying these effects.
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Affiliation(s)
- Chamindi Seneviratne
- Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, 1670 Discovery Drive, Charlottesville, VA 22911, USA
| | - Jason Franklin
- Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, 1670 Discovery Drive, Charlottesville, VA 22911, USA
| | - Katherine Beckett
- Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, 1670 Discovery Drive, Charlottesville, VA 22911, USA:
| | - Jennie Z. Ma
- Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA
| | - Nassima Ait-Daoud
- Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, 1670 Discovery Drive, Charlottesville, VA 22911, USA
| | - Thomas J. Payne
- ACT Center for Tobacco Treatment, Education and Research, Department of Otolaryngology, University of Mississippi Medical Center, Jackson, USA
| | - Bankole A. Johnson
- Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, 1670 Discovery Drive, Charlottesville, VA 22911, USA
| | - Ming D. Li
- Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, 1670 Discovery Drive, Charlottesville, VA 22911, USA
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Yildirim BO, Derksen JJ. Systematic review, structural analysis, and new theoretical perspectives on the role of serotonin and associated genes in the etiology of psychopathy and sociopathy. Neurosci Biobehav Rev 2013; 37:1254-96. [DOI: 10.1016/j.neubiorev.2013.04.009] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2012] [Revised: 04/09/2013] [Accepted: 04/17/2013] [Indexed: 12/18/2022]
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Engel M, Smidt MP, van Hooft JA. The serotonin 5-HT3 receptor: a novel neurodevelopmental target. Front Cell Neurosci 2013; 7:76. [PMID: 23761731 PMCID: PMC3669892 DOI: 10.3389/fncel.2013.00076] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2013] [Accepted: 05/06/2013] [Indexed: 01/28/2023] Open
Abstract
Serotonin (5-hydroxytryptamine, 5-HT), next to being an important neurotransmitter, recently gained attention as a key-regulator of pre- and postnatal development in the mammalian central nervous system (CNS). Several receptors for 5-HT are expressed in the developing brain including a ligand-gated ion channel, the 5-HT3 receptor. Over the past years, evidence has been accumulating that 5-HT3 receptors are involved in the regulation of neurodevelopment by serotonin. Here, we review the spatial and temporal expression patterns of 5-HT3 receptors in the pre- and early postnatal rodent brain and its functional implications. First, 5-HT3 receptors are expressed on GABAergic interneurons in neocortex and limbic structures derived from the caudal ganglionic eminence. Mature inhibitory GABAergic interneurons fine-tune neuronal excitability and thus are crucial for the physiological function of the brain. Second, 5-HT3 receptors are expressed on specific glutamatergic neurons, Cajal-Retzius cells in the cortex and granule cells in the cerebellum, where they regulate morphology, positioning, and connectivity of the local microcircuitry. Taken together, the 5-HT3 receptor emerges as a potential key-regulator of network formation and function in the CNS, which could have a major impact on our understanding of neurodevelopmental disorders in which 5-HT plays a role.
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Affiliation(s)
- Mareen Engel
- Center for NeuroScience, Swammerdam Institute for Life Sciences, University of AmsterdamAmsterdam, Netherlands
- Max Planck Institute of PsychiatryMunich, Germany
| | - Marten P. Smidt
- Center for NeuroScience, Swammerdam Institute for Life Sciences, University of AmsterdamAmsterdam, Netherlands
| | - Johannes A. van Hooft
- Center for NeuroScience, Swammerdam Institute for Life Sciences, University of AmsterdamAmsterdam, Netherlands
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28
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Neuro-genetics of persistent pain. Curr Opin Neurobiol 2013; 23:127-32. [DOI: 10.1016/j.conb.2012.11.007] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2012] [Revised: 11/14/2012] [Accepted: 11/19/2012] [Indexed: 11/20/2022]
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Rajkumar AP, Poonkuzhali B, Kuruvilla A, Srivastava A, Jacob M, Jacob KS. Outcome definitions and clinical predictors influence pharmacogenetic associations between HTR3A gene polymorphisms and response to clozapine in patients with schizophrenia. Psychopharmacology (Berl) 2012; 224:441-9. [PMID: 22700043 DOI: 10.1007/s00213-012-2773-2] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2012] [Accepted: 06/02/2012] [Indexed: 11/29/2022]
Abstract
RATIONALE Pharmacogenetics of schizophrenia has not yet delivered anticipated clinical dividends. Clinical heterogeneity of schizophrenia contributes to the poor replication of the findings of pharmacogenetic association studies. Functionally important HTR3A gene single-nucleotide polymorphisms (SNPs) were reported to be associated with response to clozapine. OBJECTIVE The aim of this study was to investigate how the association between HTR3A gene SNP and response to clozapine is influenced by various clinical predictors and by differing outcome definitions in patients with treatment-resistant schizophrenia (TRS). METHODS We recruited 101 consecutive patients with TRS, on stable doses of clozapine, and evaluated their HTR3A gene SNP (rs1062613 and rs2276302), psychopathology, and serum clozapine levels. We assessed their socio-demographic and clinical profiles, premorbid adjustment, traumatic events, cognition, and disability using standard assessment schedules. We evaluated their response to clozapine, by employing six differing outcome definitions. We employed appropriate multivariate statistics to calculate allelic and genotypic association, accounting for the effects of various clinical variables. RESULTS T allele of rs1062613 and G allele of rs2276302 were significantly associated with good clinical response to clozapine (p = 0.02). However, varying outcome definitions make these associations inconsistent. rs1062613 and rs2276302 could explain only 13.8 % variability in the responses to clozapine, while combined clinical predictors and HTR3A pharmacogenetic association model could explain 38 % variability. CONCLUSIONS We demonstrated that the results of pharmacogenetic studies in schizophrenia depend heavily on their outcome definitions and that combined clinical and pharmacogenetic models have better predictive values. Future pharmacogenetic studies should employ multiple outcome definitions and should evaluate associated clinical variables.
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Affiliation(s)
- A P Rajkumar
- Department of Psychiatry, Christian Medical College, Vellore 632002, India
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Wieser MJ, Brosch T. Faces in context: a review and systematization of contextual influences on affective face processing. Front Psychol 2012; 3:471. [PMID: 23130011 PMCID: PMC3487423 DOI: 10.3389/fpsyg.2012.00471] [Citation(s) in RCA: 213] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2012] [Accepted: 10/15/2012] [Indexed: 12/16/2022] Open
Abstract
Facial expressions are of eminent importance for social interaction as they convey information about other individuals’ emotions and social intentions. According to the predominant “basic emotion” approach, the perception of emotion in faces is based on the rapid, automatic categorization of prototypical, universal expressions. Consequently, the perception of facial expressions has typically been investigated using isolated, de-contextualized, static pictures of facial expressions that maximize the distinction between categories. However, in everyday life, an individual’s face is not perceived in isolation, but almost always appears within a situational context, which may arise from other people, the physical environment surrounding the face, as well as multichannel information from the sender. Furthermore, situational context may be provided by the perceiver, including already present social information gained from affective learning and implicit processing biases such as race bias. Thus, the perception of facial expressions is presumably always influenced by contextual variables. In this comprehensive review, we aim at (1) systematizing the contextual variables that may influence the perception of facial expressions and (2) summarizing experimental paradigms and findings that have been used to investigate these influences. The studies reviewed here demonstrate that perception and neural processing of facial expressions are substantially modified by contextual information, including verbal, visual, and auditory information presented together with the face as well as knowledge or processing biases already present in the observer. These findings further challenge the assumption of automatic, hardwired categorical emotion extraction mechanisms predicted by basic emotion theories. Taking into account a recent model on face processing, we discuss where and when these different contextual influences may take place, thus outlining potential avenues in future research.
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Lin MT, Huang KH, Huang CL, Huang YJ, Tsai GE, Lane HY. MET and AKT genetic influence on facial emotion perception. PLoS One 2012; 7:e36143. [PMID: 22558359 PMCID: PMC3338598 DOI: 10.1371/journal.pone.0036143] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2011] [Accepted: 03/26/2012] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Facial emotion perception is a major social skill, but its molecular signal pathway remains unclear. The MET/AKT cascade affects neurodevelopment in general populations and face recognition in patients with autism. This study explores the possible role of MET/AKT cascade in facial emotion perception. METHODS One hundred and eighty two unrelated healthy volunteers (82 men and 100 women) were recruited. Four single nucleotide polymorphisms (SNP) of MET (rs2237717, rs41735, rs42336, and rs1858830) and AKT rs1130233 were genotyped and tested for their effects on facial emotion perception. Facial emotion perception was assessed by the face task of Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT). Thorough neurocognitive functions were also assessed. RESULTS Regarding MET rs2237717, individuals with the CT genotype performed better in facial emotion perception than those with TT (p = 0.016 by ANOVA, 0.018 by general linear regression model [GLM] to control for age, gender, and education duration), and showed no difference with those with CC. Carriers with the most common MET CGA haplotype (frequency = 50.5%) performed better than non-carriers of CGA in facial emotion perception (p = 0.018, df = 1, F = 5.69, p = 0.009 by GLM). In MET rs2237717/AKT rs1130233 interaction, the C carrier/G carrier group showed better facial emotion perception than those with the TT/AA genotype (p = 0.035 by ANOVA, 0.015 by GLM), even when neurocognitive functions were controlled (p = 0.046 by GLM). CONCLUSIONS To our knowledge, this is the first study to suggest that genetic factors can affect performance of facial emotion perception. The findings indicate that MET variances and MET/AKT interaction may affect facial emotion perception, implicating that the MET/AKT cascade plays a significant role in facial emotion perception. Further replication studies are needed.
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Affiliation(s)
- Ming-Teng Lin
- Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan
- Department of Psychiatry, Zhudong Veterans Hospital, Hsinchu, Taiwan
| | - Kuo-Hao Huang
- Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan
- Department of Psychiatry, China Medical University Hospital, Taichung, Taiwan
| | - Chieh-Liang Huang
- Department of Psychiatry, China Medical University Hospital, Taichung, Taiwan
| | - Yu-Jhen Huang
- Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan
- Department of Psychiatry, China Medical University Hospital, Taichung, Taiwan
| | - Guochuan E. Tsai
- Department of Psychiatry, Harbor-UCLA Medical Center, Los Angeles Biomedical Research Institute, Torrance, California, United States of America
| | - Hsien-Yuan Lane
- Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan
- Department of Psychiatry, China Medical University Hospital, Taichung, Taiwan
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32
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Watanabe N, Wada M, Irukayama-Tomobe Y, Ogata Y, Tsujino N, Suzuki M, Furutani N, Sakurai T, Yamamoto M. A single nucleotide polymorphism of the neuropeptide B/W receptor-1 gene influences the evaluation of facial expressions. PLoS One 2012; 7:e35390. [PMID: 22545105 PMCID: PMC3335863 DOI: 10.1371/journal.pone.0035390] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2011] [Accepted: 03/15/2012] [Indexed: 11/21/2022] Open
Abstract
Neuropeptide B/W receptor-1 (NPBWR1) is expressed in discrete brain regions in rodents and humans, with particularly strong expression in the limbic system, including the central nucleus of the amygdala. Recently, Nagata-Kuroiwa et al. reported that Npbwr1(-/-) mice showed changes in social behavior, suggesting that NPBWR1 plays important roles in the emotional responses of social interactions.The human NPBWR1 gene has a single nucleotide polymorphism at nucleotide 404 (404A>T; SNP rs33977775). This polymorphism results in an amino acid change, Y135F. The results of an in vitro experiment demonstrated that this change alters receptor function. We investigated the effect of this variation on emotional responses to stimuli of showing human faces with four categories of emotional expressions (anger, fear, happiness, and neutral). Subjects' emotional levels on seeing these faces were rated on scales of hedonic valence, emotional arousal, and dominance (V-A-D). A significant genotype difference was observed in valence evaluation; the 404AT group perceived facial expressions more pleasantly than did the 404AA group, regardless of the category of facial expression. Statistical analysis of each combination of [V-A-D and facial expression] also showed that the 404AT group tended to feel less submissive to an angry face than did the 404AA group. Thus, a single nucleotide polymorphism of NPBWR1 seems to affect human behavior in a social context.
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Affiliation(s)
- Noriya Watanabe
- Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
- Japan Society for the Promotion of Science, Tokyo, Japan
- Graduate School of Engineering, Tamagawa University, Machida, Tokyo, Japan
| | - Mari Wada
- Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Yoko Irukayama-Tomobe
- Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
- University of Tsukuba Center for Behavioral Molecular Genetics (FIRST Program), Tokyo, Japan
| | - Yousuke Ogata
- Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
- Japan Society for the Promotion of Science, Tokyo, Japan
| | - Natsuko Tsujino
- Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Mika Suzuki
- Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Naoki Furutani
- Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Takeshi Sakurai
- Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan
- Exploratory Research for Advanced Technology Yanagisawa Orphan Receptor Project, Japan Science and Technology Agency, Tokyo, Japan
| | - Miyuki Yamamoto
- Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
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Replication of functional serotonin receptor type 3A and B variants in bipolar affective disorder: a European multicenter study. Transl Psychiatry 2012; 2:e103. [PMID: 22832903 PMCID: PMC3337070 DOI: 10.1038/tp.2012.30] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Serotonin type 3 receptors (5-HT(3)) are involved in learning, cognition and emotion, and have been implicated in various psychiatric phenotypes. However, their contribution to the pathomechanism of these disorders remains elusive. Three single nucleotide polymorphisms (SNPs) in the HTR3A and HTR3B genes (rs1062613, rs1176744 and rs3831455) have been associated with bipolar affective disorder (BPAD) in pilot studies, and all of them are of functional relevance. We performed a European multicenter study to confirm previous results and provide further evidence for the relevance of these SNPs to the etiology of neuropsychiatric disorders. This involved analysis of the distribution of the three SNPs among 1804 BPAD cases and 2407 healthy controls. A meta-analysis revealed a pooled odds ratio of 0.881 (P = 0.009, 95% confidence intervals = 0.802-0.968) for the non-synonymous functional SNP HTR3B p.Y129S (rs1176744), thereby confirming previous findings. In line with this, the three genome-wide association study samples BOMA (Bonn-Mannheim)-BPAD, WTCCC (Wellcome Trust Case Control Consortium)-BPAD and GAIN (Genetic Association Information Network)-BPAD, including >3500 patients and 5200 controls in total, showed an overrepresentation of the p.Y129 in patients. Remarkably, the meta-analysis revealed a P-value of 0.048 (OR = 0.934, fixed effect model). We also performed expression analyses to gain further insights into the distribution of HTR3A and HTR3B mRNA in the human brain. HTR3A and HTR3B were detected in all investigated brain tissues with the exception of the cerebellum, and large differences in the A:B subunit ratio were observed. Interestingly, expression of the B subunit was most prominent in the brain stem, amygdalae and frontal cortex, regions of relevance to psychiatric disorders. In conclusion, the present study provides further evidence for the presence of impaired 5-HT(3) receptor function in BPAD.
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Mujakovic S, ter Linde JJ, de Wit NJ, van Marrewijk CJ, Fransen GA, Onland-Moret NC, Laheij RJ, Muris JW, Grobbee DE, Samsom M, Jansen JB, Knottnerus A, Numans ME. Serotonin receptor 3A polymorphism c.-42C > T is associated with severe dyspepsia. BMC MEDICAL GENETICS 2011; 12:140. [PMID: 22014438 PMCID: PMC3213216 DOI: 10.1186/1471-2350-12-140] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/10/2011] [Accepted: 10/20/2011] [Indexed: 12/16/2022]
Abstract
BACKGROUND The association between anxiety and depression related traits and dyspepsia may reflect a common genetic predisposition. Furthermore, genetic factors may contribute to the risk of having increased visceral sensitivity, which has been implicated in dyspeptic symptom generation. Serotonin (5-HT) modulates visceral sensitivity by its action on 5-HT3 receptors. Interestingly, a functional polymorphism in HTR3A, encoding the 5-HT3 receptor A subunit, has been reported to be associated with depression and anxiety related traits. A functional polymorphism in the serotonin transporter (5-HTT), which terminates serotonergic signalling, was also found associated with these psychiatric comorbidities and increased visceral sensitivity in irritable bowel syndrome, which coexistence is associated with higher dyspeptic symptom severity. We investigated the association between these functional polymorphisms and dyspeptic symptom severity. METHODS Data from 592 unrelated, Caucasian, primary care patients with dyspepsia participating in a randomised clinical trial comparing step-up and step-down antacid drug treatment (The DIAMOND trial) were analysed. Patients were genotyped for HTR3A c.-42C > T SNP and the 44 bp insertion/deletion polymorphism in the 5-HTT promoter (5-HTTLPR). Intensity of 8 dyspeptic symptoms at baseline was assessed using a validated questionnaire (0 = none; 6 = very severe). Sum score ≥20 was defined severe dyspepsia. RESULTS HTR3A c.-42T allele carriers were more prevalent in patients with severe dyspepsia (OR 1.50, 95% CI 1.06-2.20). This association appeared to be stronger in females (OR 2.05, 95% CI 1.25-3.39) and patients homozygous for the long (L) variant of the 5-HTTLPR genotype (OR 2.00, 95% CI 1.01-3.94). Females with 5-HTTLPR LL genotype showed the strongest association (OR = 3.50, 95% CI = 1.37-8.90). CONCLUSIONS The HTR3A c.-42T allele is associated with severe dyspeptic symptoms. The stronger association among patients carrying the 5-HTTLPR L allele suggests an additive effect of the two polymorphisms. These results support the hypothesis that diminished 5-HT3 mediated antinociception predisposes to increased visceral sensitivity of the gastrointestinal tract. Moreover, the HTR3A c.-42C > T and 5-HTTLPR polymorphisms likely represent predisposing genetic variants in common to psychiatric morbidity and dyspepsia.
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Affiliation(s)
- Suhreta Mujakovic
- University Medical Centre Utrecht, Department of Gastroenterology & Hepatology, the Netherlands
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Kilpatrick LA, Labus JS, Coveleskie K, Hammer C, Rappold G, Tillisch K, Bueller JA, Suyenobu B, Jarcho JM, McRoberts JA, Niesler B, Mayer EA. The HTR3A polymorphism c. -42C>T is associated with amygdala responsiveness in patients with irritable bowel syndrome. Gastroenterology 2011; 140:1943-51. [PMID: 21420406 PMCID: PMC3757951 DOI: 10.1053/j.gastro.2011.03.011] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2010] [Revised: 02/02/2011] [Accepted: 03/07/2011] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS 5-Hydroxytryptamine (5-HT)3 receptor (5-HT3R) antagonists are effective in treating patients with irritable bowel syndrome (IBS) and have anxiolytic effects. Their therapeutic effects are related, in part, to reducing amygdala engagement during expected visceral pain. A single nucleotide polymorphism in HTR3A, c.-42C>T;(C178T; rs1062613), is associated with altered reactivity of the amygdala during emotional face processing in healthy subjects (controls). We evaluated the influence of this single nucleotide polymorphism on amygdala reactivity to emotional faces and nonemotional stimuli in female patients with IBS and controls. METHODS We measured brain responses during an affect-matching paradigm in 54 women (26 with IBS, 29 controls) using functional magnetic resonance imaging. We examined associations between HTR3A c.-42C>T genotype (C/C vs T carrier) and responses in amygdala and other regions of brain that expressed high levels of 5-HT3R. RESULTS The C/C genotype was associated with greater anxiety symptoms in patients with IBS and controls and increased activation of the amygdala under emotional and nonemotional conditions. Among patients with IBS, C/C genotype was associated with greater symptom ratings. A subset of IBS patients with the C/C genotype had increased amygdala responses to nonemotional stimuli, compared with other subjects with C/C genotype. CONCLUSIONS Regardless of diagnosis, the C/C genotype of the c.-42C>T polymorphism in HTR3A, compared with T carrier status, is associated with increased anxiety and amygdala responsiveness during emotional and nonemotional tasks. This polymorphism was associated with severity of IBS symptoms. Although this genotype is not sufficient for diagnosis of IBS, it is associated with severity of symptoms.
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Affiliation(s)
- LA Kilpatrick
- Center for Neurobiology of Stress, Ahmanson-Lovelace Brain Mapping Center, UCLA, Department of Medicine, Ahmanson-Lovelace Brain Mapping Center, UCLA
| | - JS Labus
- Center for Neurobiology of Stress, Ahmanson-Lovelace Brain Mapping Center, UCLA, Department of Psychiatry & Biobehavioral Sciences, Ahmanson-Lovelace Brain Mapping Center, UCLA, Brain Research Institute, David Geffen School of Medicine, UCLA
| | - K Coveleskie
- Center for Neurobiology of Stress, Ahmanson-Lovelace Brain Mapping Center, UCLA
| | - C Hammer
- Department of Human Molecular Genetics, University of Heidelberg, Germany
| | - G Rappold
- Department of Human Molecular Genetics, University of Heidelberg, Germany
| | - K Tillisch
- Center for Neurobiology of Stress, Ahmanson-Lovelace Brain Mapping Center, UCLA, Department of Medicine, Ahmanson-Lovelace Brain Mapping Center, UCLA
| | - JA Bueller
- Center for Neurobiology of Stress, Ahmanson-Lovelace Brain Mapping Center, UCLA, Department of Medicine, Ahmanson-Lovelace Brain Mapping Center, UCLA
| | - B Suyenobu
- Center for Neurobiology of Stress, Ahmanson-Lovelace Brain Mapping Center, UCLA, Department of Medicine, Ahmanson-Lovelace Brain Mapping Center, UCLA
| | - JM Jarcho
- Center for Neurobiology of Stress, Ahmanson-Lovelace Brain Mapping Center, UCLA, Department of Medicine, Ahmanson-Lovelace Brain Mapping Center, UCLA
| | - JA McRoberts
- Center for Neurobiology of Stress, Ahmanson-Lovelace Brain Mapping Center, UCLA, Department of Medicine, Ahmanson-Lovelace Brain Mapping Center, UCLA
| | - B Niesler
- Department of Human Molecular Genetics, University of Heidelberg, Germany
| | - EA Mayer
- Center for Neurobiology of Stress, Ahmanson-Lovelace Brain Mapping Center, UCLA, Department of Medicine, Ahmanson-Lovelace Brain Mapping Center, UCLA, Department of Psychiatry & Biobehavioral Sciences, Ahmanson-Lovelace Brain Mapping Center, UCLA, Brain Research Institute, David Geffen School of Medicine, UCLA
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Niesler B. 5-HT(3) receptors: potential of individual isoforms for personalised therapy. Curr Opin Pharmacol 2011; 11:81-6. [PMID: 21345729 DOI: 10.1016/j.coph.2011.01.011] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2010] [Revised: 01/29/2011] [Accepted: 01/31/2011] [Indexed: 01/28/2023]
Abstract
Serotonin type 3 (5-HT(3)) receptors are ligand-gated ion channels built by five subunits of diverse composition. In humans, five subunits exist (5-HT3A-E) which are encoded by the genes HTR3A-E and are expressed in various isoforms. Recently, the importance of factors influencing receptor expression became clear, such as chaperones and microRNAs. Owing to their expression profile and physiological functions, 5-HT(3) receptors have been implicated in irritable bowel syndrome (IBS) and psychiatric disorders. Interestingly, HTR3 variants have now been shown to be associated with these conditions. This underlines the potential of 5-HT(3) receptors as therapeutic targets and may enable personalised therapies in the future.
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Affiliation(s)
- Beate Niesler
- Institute of Human Genetics, Department of Human Molecular Genetics, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
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Scharinger C, Rabl U, Sitte HH, Pezawas L. Imaging genetics of mood disorders. Neuroimage 2010; 53:810-21. [PMID: 20156570 PMCID: PMC4502568 DOI: 10.1016/j.neuroimage.2010.02.019] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2009] [Revised: 01/17/2010] [Accepted: 02/09/2010] [Indexed: 12/15/2022] Open
Abstract
Mood disorders are highly heritable and have been linked to brain regions of emotion processing. Over the past few years, an enormous amount of imaging genetics studies has demonstrated the impact of risk genes on brain regions and systems of emotion processing in vivo in healthy subjects as well as in mood disorder patients. While sufficient evidence already exists for several monaminergic genes as well as for a few non-monoaminergic genes, such as brain-derived neurotrophic factor (BDNF) in healthy subjects, many others only have been investigated in single studies so far. Apart from these studies, the present review also covers imaging genetics studies applying more complex genetic disease models of mood disorders, such as epistasis and gene-environment interactions, and their impact on brain systems of emotion processing. This review attempts to provide a comprehensive overview of the rapidly growing field of imaging genetics studies in mood disorder research.
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Affiliation(s)
- Christian Scharinger
- Division of Biological Psychiatry, Department of Psychiatry and Psychotherapy, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria
| | - Ulrich Rabl
- Division of Biological Psychiatry, Department of Psychiatry and Psychotherapy, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria
| | - Harald H. Sitte
- Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Austria
| | - Lukas Pezawas
- Division of Biological Psychiatry, Department of Psychiatry and Psychotherapy, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria
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Influence of 5-HT3 receptor subunit genes HTR3A, HTR3B, HTR3C, HTR3D and HTR3E on treatment response to antipsychotics in schizophrenia. Pharmacogenet Genomics 2010; 19:843-51. [PMID: 19794330 DOI: 10.1097/fpc.0b013e3283313296] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVES Among serotonin (5-HT) receptors, the 5-HT3 receptor is the only ligand-gated ion channel. 5-HT3 antagonists such as ondansetron and tropisetron may improve auditory gating and neurocognitive deficits in schizophrenic patients. Moreover, many antipsychotic drugs are antagonists at 5-HT3 receptors. However, the role of 5-HT3 receptor variants on response to antipsychotic drugs in schizophrenic patients is still unclear. METHODS In a prospective, randomized, double-blind study, we have assessed six functional and coding variants of the subunit genes HTR3A, HTR3B as well as the novel HTR3C, HTR3D, and HTR3E subunits in the response to haloperidol or risperidone. Seventy patients were treated for 4 weeks and positive symptoms, negative symptoms, and general psychopathology were measured by the Positive and Negative Syndrome Scale (PANSS). RESULTS HTR3E had an effect on the speed of response to antipsychotics. GG-allele carriers responded more quickly to treatment on the PANSS negative symptom subscale (P = 0.03) and on the total PANSS score (P = 0.04) irrespective of medication. In a second independent study of 144 schizophrenia patients treated with atypical antipsychotics, this effect could not be confirmed. CONCLUSION Our findings argue against a major effect of HTR3 variants in response to antipsychotics. Solely, the HTR3E and also the HTR3A variant could exert a weak effect on the speed of response to antipsychotics.
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Gatt JM, Williams LM, Schofield PR, Dobson-Stone C, Paul RH, Grieve SM, Clark CR, Gordon E, Nemeroff CB. Impact of the HTR3A gene with early life trauma on emotional brain networks and depressed mood. Depress Anxiety 2010; 27:752-9. [PMID: 20694966 DOI: 10.1002/da.20726] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The risk for mental illnesses such as depression is increasingly conceptualized as the product of gene-environment interactions and their impact on brain structure and function. The role of serotonin 3A receptor gene (HTR3A -42C>T polymorphism) and its interaction with early life stress (ELS) was investigated in view of the receptor's localization to brain regions central to emotion processing. METHODS Fronto-limbic grey matter (GM) loss was measured using magnetic resonance imaging and assessed using voxel-based morphometry analysis in 397 nonclinical individuals from the Brain Resource International Database. Negative mood symptoms were also assessed. RESULTS The HTR3A CC genotype group, compared to the T carriers, demonstrated comparative loss to GM in hippocampal structures, which extended to the frontal cortices for those CC genotype individuals also exposed to ELS. Elevations in depressed mood were also evident. CONCLUSIONS These findings suggest that the HTR3A CC genotype may be associated with alterations in brain structures central to emotion processing, particularly when exposed to stress, and further highlight the potential role of the serotonin system in the pathophysiology of affective disorders. In contrast, those individuals with the T allele, in particular the TT genotype, may be more protected from such alterations combined with minimal exposure to ELS events.
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Affiliation(s)
- Justine M Gatt
- The Brain Dynamics Center, Westmead Millennium Institute & Discipline of Psychiatry, University of Sydney at Westmead Hospital, New South Wales, Australia
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Walstab J, Rappold G, Niesler B. 5-HT(3) receptors: role in disease and target of drugs. Pharmacol Ther 2010; 128:146-69. [PMID: 20621123 DOI: 10.1016/j.pharmthera.2010.07.001] [Citation(s) in RCA: 151] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2010] [Accepted: 06/21/2010] [Indexed: 12/19/2022]
Abstract
Serotonin type 3 (5-HT(3)) receptors are pentameric ion channels belonging to the superfamily of Cys-loop receptors. Receptor activation either leads to fast excitatory responses or modulation of neurotransmitter release depending on their neuronal localisation. 5-HT(3) receptors are known to be expressed in the central nervous system in regions involved in the vomiting reflex, processing of pain, the reward system, cognition and anxiety control. In the periphery they are present on a variety of neurons and immune cells. 5-HT(3) receptors are known to be involved in emesis, pain disorders, drug addiction, psychiatric and GI disorders. Progress in molecular genetics gives direction to personalised medical strategies for treating complex diseases such as psychiatric and functional GI disorders and unravelling individual drug responses in pharmacogenetic approaches. Here we discuss the molecular basis of 5-HT(3) receptor diversity at the DNA and protein level, of which our knowledge has greatly extended in the last decade. We also evaluate their role in health and disease and describe specific case-control studies addressing the involvement of polymorphisms of 5-HT3 subunit genes in complex disorders and responses to drugs. Furthermore, we focus on the actual state of the pharmacological knowledge concerning not only classical 5-HT(3) antagonists--the setrons--but also compounds of various substance classes targeting 5-HT(3) receptors such as anaesthetics, opioids, cannabinoids, steroids, antidepressants and antipsychotics as well as natural compounds derived from plants. This shall point to alternative treatment options modulating the 5-HT(3) receptor system and open new possibilities for drug development in the future.
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Affiliation(s)
- Jutta Walstab
- Department of Human Molecular Genetics, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany
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Influence of serotonin 3A and 3B receptor genes on clozapine treatment response in schizophrenia. Pharmacogenet Genomics 2010; 20:274-6. [PMID: 20168265 DOI: 10.1097/fpc.0b013e328337ce3e] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Earlier results suggest a minor role of variants in the serotonin 3 receptor (HTR3) subunit genes on antipsychotic treatment outcome of schizophrenia patients. In this study, we further investigated the role of the subunits A and B of the HTR3 receptor using 140 schizophrenia patients taking clozapine for 6 months. We have found significant allelic association of clozapine response with three variants in the HTR3A receptor (rs2276302, rs1062613, rs1150226) although only rs1062613 association remained significant after permutations (permutated P=0.041). Moreover, rs2276302 and rs1062613 have shown nominally significant genotypic association. The two haplotypes composed of rs2276302-rs1062613-rs1150226 were also nominally significant. Taken together, our results suggest that variants in the HTR3A receptor gene can play a role in the treatment outcome of clozapine in schizophrenia patients that are refractory or intolerant of typical antipsychotic therapy. Further studies are necessary to confirm the reported associations.
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Lowry CA, Hale MW. Serotonin and the Neurobiology of Anxious States. HANDBOOK OF BEHAVIORAL NEUROSCIENCE 2010. [DOI: 10.1016/s1569-7339(10)70091-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Guimarães FS, Zangrossi H, Del Ben CM, Graeff FG. Serotonin in Panic and Anxiety Disorders. HANDBOOK OF BEHAVIORAL NEUROSCIENCE 2010. [DOI: 10.1016/s1569-7339(10)70105-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/12/2023]
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Functional variants of the serotonin receptor type 3A and B gene are associated with eating disorders. Pharmacogenet Genomics 2009; 19:790-9. [PMID: 19741568 DOI: 10.1097/fpc.0b013e32833132b3] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
OBJECTIVE As a key player in modulating both human physiological and behavioural functions including anxiety, perception and in particular appetite, serotonin (5-hydroxytryptamine, 5-HT) is likely to be involved in the aetiology of eating disorders. Studies showing serotonin receptor type 3 (5-HT3) receptors to mediate food intake depression (anorexic response) have triggered our interest in investigating the putative role of variants in the 5-HT3 receptor genes, HTR3A and HTR3B, in the susceptibility to anorexia nervosa (AN) and bulimia nervosa (BN). METHODS Two hundred and sixty-five patients with AN and 91 patients with BN as well as 191 healthy controls served as a pilot study group for mutational analysis by direct sequencing. Variants showing a significant association were subsequently genotyped in an independent Spanish cohort of 78 patients with AN and 119 patients with BN as well as 331 healthy controls for replication purposes. RESULTS In the pilot study, we found the coding HTR3B variant, p.Y129S, (rs1176744, P = 0.004, odds ratio = 2.06) to be associated with the restrictive subtype of AN. The association was confirmed in the Spanish study group (P = 0.034, odds ratio = 2.26). CONCLUSION Our study provides first evidence for an involvement of 5-HT3 variants in the aetiopathology of eating disorders in humans.
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Tottenham N, Tanaka JW, Leon AC, McCarry T, Nurse M, Hare TA, Marcus DJ, Westerlund A, Casey BJ, Nelson C. The NimStim set of facial expressions: judgments from untrained research participants. Psychiatry Res 2009; 168:242-9. [PMID: 19564050 PMCID: PMC3474329 DOI: 10.1016/j.psychres.2008.05.006] [Citation(s) in RCA: 2438] [Impact Index Per Article: 152.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2007] [Revised: 08/24/2007] [Accepted: 05/04/2008] [Indexed: 12/14/2022]
Abstract
A set of face stimuli called the NimStim Set of Facial Expressions is described. The goal in creating this set was to provide facial expressions that untrained individuals, characteristic of research participants, would recognize. This set is large in number, multiracial, and available to the scientific community online. The results of psychometric evaluations of these stimuli are presented. The results lend empirical support for the validity and reliability of this set of facial expressions as determined by accurate identification of expressions and high intra-participant agreement across two testing sessions, respectively.
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Affiliation(s)
- Nim Tottenham
- Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College, New York, NY 10021, USA.
| | - James W. Tanaka
- Department of Psychology, University of Victoria, Victoria, British Columbia, Canada
| | - Andrew C. Leon
- Department of Psychiatry, Weill Cornell Medical College, New York, NY, USA
| | - Thomas McCarry
- Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College, New York, NY, USA
| | - Marcella Nurse
- Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College, New York, NY, USA
| | - Todd A. Hare
- Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College, New York, NY, USA
| | | | - Alissa Westerlund
- Developmental Medicine Center, Children’s Hospital Boston/Harvard Medical School, Boston, MA, USA
| | - BJ Casey
- Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College, New York, NY, USA
| | - Charles Nelson
- Developmental Medicine Center, Children’s Hospital Boston/Harvard Medical School, Boston, MA, USA
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Rehnström K, Ylisaukko-oja T, Nummela I, Ellonen P, Kempas E, Vanhala R, von Wendt L, Järvelä I, Peltonen L. Allelic variants in HTR3C show association with autism. Am J Med Genet B Neuropsychiatr Genet 2009; 150B:741-6. [PMID: 19035560 PMCID: PMC2703778 DOI: 10.1002/ajmg.b.30882] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Autism spectrum disorders (ASDs) are severe neurodevelopmental disorders with a strong genetic component. Only a few predisposing genes have been identified so far. We have previously performed a genome-wide linkage screen for ASDs in Finnish families where the most significant linkage peak was identified at 3q25-27. Here, 11 positional and functionally relevant candidate genes at 3q25-27 were tested for association with autistic disorder. Genotypes of 125 single nucleotide polymorphisms (SNPs) were determined in 97 families with at least one individual affected with autistic disorder. The most significant association was observed using two non-synonymous SNPs in HTR3C, rs6766410 and rs6807362, both resulting in P = 0.0012 in family-based association analysis. In addition, the haplotype C-C corresponding to amino acids N163-A405 was overtransmitted to affected individuals (P = 0.006). Sequencing revealed no other variants in the coding region or splice sites of HTR3C. Based on the association analysis results in a previously identified linkage region, we propose that HTR3C represents a novel candidate locus for ASDs and should be tested in other populations.
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Affiliation(s)
- Karola Rehnström
- Department of Molecular Medicine, National Public Health Institute and Institute for Molecular Medicine Finland, Helsinki, Finland.
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Pantazatos SP, Li J, Pavlidis P, Lussier YA. Integration of Neuroimaging and Microarray Datasets through Mapping and Model-Theoretic Semantic Decomposition of Unstructured Phenotypes. Cancer Inform 2009; 8:75-94. [PMID: 20495688 PMCID: PMC2874327 DOI: 10.4137/cin.s1046] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
An approach towards heterogeneous neuroscience dataset integration is proposed that uses Natural Language Processing (NLP) and a knowledge-based phenotype organizer system (PhenOS) to link ontology-anchored terms to underlying data from each database, and then maps these terms based on a computable model of disease (SNOMED CT(R)). The approach was implemented using sample datasets from fMRIDC, GEO, The Whole Brain Atlas and Neuronames and allowed for complex queries such as "List all disorders with a finding site of brain region X, and then find the semantically related references in all participating databases based on the ontological model of the disease or its anatomical and morphological attributes". Precision of the NLP-derived coding of the unstructured phenotypes in each dataset was 88% (n=50), and precision of the semantic mapping between these terms across datasets was 98% (n=100). To our knowledge, this is the first example of the use of both semantic decomposition of disease relationships and hierarchical information found in ontologies to integrate heterogeneous phenotypes across clinical and molecular datasets.
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Affiliation(s)
- Spiro P. Pantazatos
- Department of Physiology and Cellular Biophysics, Columbia University, New York, NY U.S.A
- Department of Biomedical Informatics, Columbia University, New York, NY U.S.A
| | - Jianrong Li
- Center for Biomedical Informatics, Department of Medicine, University of Chicago, Chicago, IL U.S.A
| | - Paul Pavlidis
- Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada
| | - Yves A. Lussier
- Center for Biomedical Informatics, Department of Medicine, University of Chicago, Chicago, IL U.S.A
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3B but which 3B and that's just one of the questions: the heterogeneity of human 5-HT3 receptors. Trends Pharmacol Sci 2009; 29:437-44. [PMID: 18597859 DOI: 10.1016/j.tips.2008.06.001] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2008] [Revised: 04/14/2008] [Accepted: 06/15/2008] [Indexed: 01/19/2023]
Abstract
The 5-hydroxytryptamine 3 (5-HT3) receptor is expressed widely in the central and peripheral nervous systems, where it mediates or modulates a wide range of physiological processes. The receptor is targeted by drugs administered for nausea and/or emesis and irritable bowel syndrome and has been proposed as a potential drug target in various psychiatric disorders. The 5-HT3 receptor is a pentameric ligand-gated ion channel and belongs to the Cys-loop receptor family. In contrast to the immense heterogeneity characterizing other Cysloop receptors, native 5-HT3 receptors historically have been considered a much more homogenous receptor population. However, the recent discovery of additional 5-HT3 subunits and the dawning realization that central and peripheral 5-HT3 receptor populations might comprise several subtypes characterized by distinct functional properties has emphasized the complexity of human 5-HT3 receptor signaling. In this review potential implications of these findings and of the entirely new layer of interindividual diversity introduced to the 5-HT3 receptor system by genetic variations will be outlined.
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Barnes NM, Hales TG, Lummis SC, Peters JA. The 5-HT3 receptor--the relationship between structure and function. Neuropharmacology 2009; 56:273-84. [PMID: 18761359 PMCID: PMC6485434 DOI: 10.1016/j.neuropharm.2008.08.003] [Citation(s) in RCA: 181] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2008] [Revised: 07/31/2008] [Accepted: 08/01/2008] [Indexed: 12/15/2022]
Abstract
The 5-hydroxytryptamine type-3 (5-HT3) receptor is a cation-selective ion channel of the Cys-loop superfamily. 5-HT3 receptor activation in the central and peripheral nervous systems evokes neuronal excitation and neurotransmitter release. Here, we review the relationship between the structure and the function of the 5-HT3 receptor. 5-HT3A and 5-HT3B subunits are well established components of 5-HT3 receptors but additional HTR3C, HTR3D and HTR3E genes expand the potential for molecular diversity within the family. Studies upon the relationship between subunit structure and the ionic selectivity and single channel conductances of 5-HT3 receptors have identified a novel domain (the intracellular MA-stretch) that contributes to ion permeation and selectivity. Conventional and unnatural amino acid mutagenesis of the extracellular domain of the receptor has revealed residues, within the principle (A-C) and complementary (D-F) loops, which are crucial to ligand binding. An area requiring much further investigation is the subunit composition of 5-HT3 receptors that are endogenous to neurones, and their regional expression within the central nervous system. We conclude by describing recent studies that have identified numerous HTR3A and HTR3B gene polymorphisms that impact upon 5-HT3 receptor function, or expression, and consider their relevance to (patho)physiology.
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Affiliation(s)
- Nicholas M. Barnes
- Cellular and Molecular Neuropharmacology Research Group, Department of Pharmacology, Division of Neuroscience, The Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
| | - Tim G. Hales
- Department of Pharmacology and Physiology, The George Washington University, Washington, DC 20037, USA
| | - Sarah C.R. Lummis
- Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW, UK
| | - John A. Peters
- Neurosciences Institute, Division of Pathology and Neuroscience, Ninewells Hospital and Medical School, The University of Dundee, Dundee DD1 9SY, UK
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