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Kozlova AA, Rubets E, Vareltzoglou MR, Jarzebska N, Ragavan VN, Chen Y, Martens-Lobenhoffer J, Bode-Böger SM, Gainetdinov RR, Rodionov RN, Bernhardt N. Knock-out of the critical nitric oxide synthase regulator DDAH1 in mice impacts amphetamine sensitivity and dopamine metabolism. J Neural Transm (Vienna) 2023; 130:1097-1112. [PMID: 36792833 PMCID: PMC10460711 DOI: 10.1007/s00702-023-02597-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 01/28/2023] [Indexed: 02/17/2023]
Abstract
The enzyme dimethylarginine dimethylaminohydrolase 1 (DDAH1) plays a pivotal role in the regulation of nitric oxide levels by degrading the main endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA). Growing evidence highlight the potential implication of DDAH/ADMA axis in the etiopathogenesis of several neuropsychiatric and neurological disorders, yet the underlying molecular mechanisms remain elusive. In this study, we sought to investigate the role of DDAH1 in behavioral endophenotypes with neuropsychiatric relevance. To achieve this, a global DDAH1 knock-out (DDAH1-ko) mouse strain was employed. Behavioral testing and brain region-specific neurotransmitter profiling have been conducted to assess the effect of both genotype and sex. DDAH1-ko mice exhibited increased exploratory behavior toward novel objects, altered amphetamine response kinetics and decreased dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) level in the piriform cortex and striatum. Females of both genotypes showed the most robust amphetamine response. These results support the potential implication of the DDAH/ADMA pathway in central nervous system processes shaping the behavioral outcome. Yet, further experiments are required to complement the picture and define the specific brain-regions and mechanisms involved.
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Affiliation(s)
- Alena A Kozlova
- Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307, Dresden, Germany
| | - Elena Rubets
- Division of Angiology, Department of Internal Medicine III, University Center for Vascular Medicine, Technische Universität Dresden, 01307, Dresden, Germany
| | - Magdalini R Vareltzoglou
- Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307, Dresden, Germany
| | - Natalia Jarzebska
- Division of Angiology, Department of Internal Medicine III, University Center for Vascular Medicine, Technische Universität Dresden, 01307, Dresden, Germany
| | - Vinitha N Ragavan
- Division of Angiology, Department of Internal Medicine III, University Center for Vascular Medicine, Technische Universität Dresden, 01307, Dresden, Germany
| | - Yingjie Chen
- Department of Physiology & Biophysics, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | | | - Stefanie M Bode-Böger
- Institute of Clinical Pharmacology, Otto-Von-Guericke University, Magdeburg, Germany
| | - Raul R Gainetdinov
- Institute of Translational Biomedicine and Saint-Petersburg University Hospital, Saint-Petersburg State University, 199034, Saint-Petersburg, Russia
| | - Roman N Rodionov
- Division of Angiology, Department of Internal Medicine III, University Center for Vascular Medicine, Technische Universität Dresden, 01307, Dresden, Germany
| | - Nadine Bernhardt
- Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307, Dresden, Germany.
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2
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Greenwood TA. Genetic Influences on Cognitive Dysfunction in Schizophrenia. Curr Top Behav Neurosci 2022; 63:291-314. [PMID: 36029459 DOI: 10.1007/7854_2022_388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Schizophrenia is a severe and debilitating psychotic disorder that is highly heritable and relatively common in the population. The clinical heterogeneity associated with schizophrenia is substantial, with patients exhibiting a broad range of deficits and symptom severity. Large-scale genomic studies employing a case-control design have begun to provide some biological insight. However, this strategy combines individuals with clinically diverse symptoms and ignores the genetic risk that is carried by many clinically unaffected individuals. Consequently, the majority of the genetic architecture underlying schizophrenia remains unexplained, and the pathways by which the implicated variants contribute to the clinically observable signs and symptoms are still largely unknown. Parsing the complex, clinical phenotype of schizophrenia into biologically relevant components may have utility in research aimed at understanding the genetic basis of liability. Cognitive dysfunction is a hallmark symptom of schizophrenia that is associated with impaired quality of life and poor functional outcome. Here, we examine the value of quantitative measures of cognitive dysfunction to objectively target the underlying neurobiological pathways and identify genetic variants and gene networks contributing to schizophrenia risk. For a complex disorder, quantitative measures are also more efficient than diagnosis, allowing for the identification of associated genetic variants with fewer subjects. Such a strategy supplements traditional analyses of schizophrenia diagnosis, providing the necessary biological insight to help translate genetic findings into actionable treatment targets. Understanding the genetic basis of cognitive dysfunction in schizophrenia may thus facilitate the development of novel pharmacological and procognitive interventions to improve real-world functioning.
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Affiliation(s)
- Tiffany A Greenwood
- Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
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3
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Faraone SV, Larsson H. Genetics of attention deficit hyperactivity disorder. Mol Psychiatry 2019; 24:562-575. [PMID: 29892054 PMCID: PMC6477889 DOI: 10.1038/s41380-018-0070-0] [Citation(s) in RCA: 565] [Impact Index Per Article: 94.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Revised: 01/31/2018] [Accepted: 02/19/2018] [Indexed: 02/07/2023]
Abstract
Decades of research show that genes play an vital role in the etiology of attention deficit hyperactivity disorder (ADHD) and its comorbidity with other disorders. Family, twin, and adoption studies show that ADHD runs in families. ADHD's high heritability of 74% motivated the search for ADHD susceptibility genes. Genetic linkage studies show that the effects of DNA risk variants on ADHD must, individually, be very small. Genome-wide association studies (GWAS) have implicated several genetic loci at the genome-wide level of statistical significance. These studies also show that about a third of ADHD's heritability is due to a polygenic component comprising many common variants each having small effects. From studies of copy number variants we have also learned that the rare insertions or deletions account for part of ADHD's heritability. These findings have implicated new biological pathways that may eventually have implications for treatment development.
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Affiliation(s)
- Stephen V Faraone
- Departments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, 13210, USA.
| | - Henrik Larsson
- School of Medical Sciences, Örebro University, Örebro, Sweden
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
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Abstract
Schizophrenia (SZ) is a severe psychotic disorder that is highly heritable and common in the general population. The genetic heterogeneity of SZ is substantial, with contributions from common, rare, and de novo variants, in addition to environmental factors. Large genome-wide association studies have detected many variants that are associated with SZ, yet the pathways by which these variants influence risk remain largely unknown. SZ is also clinically heterogeneous, with patients exhibiting a broad range of deficits and symptom severity that vary over the course of illness and treatment, which has complicated efforts to identify risk variants. However, the underlying brain dysfunction forms a more stable trait marker that quantitative neurocognitive and neurophysiological endophenotypes may be able to objectively measure. These endophenotypes are less likely to be heterogeneous than the disorder and provide a neurobiological context to detect risk variants and underlying pathways among genes associated with SZ diagnosis. Furthermore, many endophenotypes are translational into animal model systems, allowing for direct evaluation of the neural circuit dysfunctions and neurobiological substrates. We review a selection of the most promising SZ endophenotypes, including prepulse inhibition, mismatch negativity, oculomotor antisaccade, letter-number sequencing, and continuous performance tests. We also highlight recent findings from large consortia that suggest the potential role of genes, particularly in the neuregulin and glutamate pathways, in several of these endophenotypes. Although endophenotypes require additional time and effort to assess, the insight into the underlying neurobiology that they provide may ultimately reveal the underlying genetic architecture for SZ and suggest novel treatment targets.
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Sakamoto K, Crowley JJ. A comprehensive review of the genetic and biological evidence supports a role for MicroRNA-137 in the etiology of schizophrenia. Am J Med Genet B Neuropsychiatr Genet 2018; 177:242-256. [PMID: 29442441 PMCID: PMC5815396 DOI: 10.1002/ajmg.b.32554] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Accepted: 05/05/2017] [Indexed: 01/06/2023]
Abstract
Since it was first associated with schizophrenia (SCZ) in a 2011 genome-wide association study (GWAS), there have been over 100 publications focused on MIR137, the gene encoding microRNA-137. These studies have examined everything from its fundamental role in the development of mice, flies, and fish to the intriguing enrichment of its target gene network in SCZ. Indeed, much of the excitement surrounding MIR137 is due to the distinct possibility that it could regulate a gene network involved in SCZ etiology, a disease which we now recognize is highly polygenic. Here we comprehensively review, to the best of our ability, all published genetic and biological evidence that could support or refute a role for MIR137 in the etiology of SCZ. Through a careful consideration of the literature, we conclude that the data gathered to date continues to strongly support the involvement of MIR137 and its target gene network in neuropsychiatric traits, including SCZ risk. There remain, however, more unanswered than answered questions regarding the mechanisms linking MIR137 genetic variation with behavior. These questions need answers before we can determine whether there are opportunities for diagnostic or therapeutic interventions based on MIR137. We conclude with a number of suggestions for future research on MIR137 that could help to provide answers and hope for a greater understanding of this devastating disorder.
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Affiliation(s)
- Kensuke Sakamoto
- Department of Genetics, University of North Carolina at Chapel Hill, NC, USA
| | - James J. Crowley
- Department of Genetics, University of North Carolina at Chapel Hill, NC, USA
- Department of Psychiatry, University of North Carolina at Chapel Hill, NC, USA
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
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6
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Genome-Wide Association Study of Loneliness Demonstrates a Role for Common Variation. Neuropsychopharmacology 2017; 42:811-821. [PMID: 27629369 PMCID: PMC5312064 DOI: 10.1038/npp.2016.197] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Revised: 08/29/2016] [Accepted: 09/02/2016] [Indexed: 01/28/2023]
Abstract
Loneliness is a complex biological trait that has been associated with numerous negative health outcomes. The measurement and environmental determinants of loneliness are well understood, but its genetic basis is not. Previous studies have estimated the heritability of loneliness between 37 and 55% using twins and family-based approaches, and have explored the role of specific candidate genes. We used genotypic and phenotypic data from 10 760 individuals aged ⩾50 years that were collected by the Health and Retirement Study (HRS) to perform the first genome-wide association study of loneliness. No associations reached genome-wide significance (p>5 × 10-8). Furthermore, none of the previously published associations between variants within candidate genes (BDNF, OXTR, RORA, GRM8, CHRNA4, IL-1A, CRHR1, MTHFR, DRD2, APOE) and loneliness were replicated (p>0.05), despite our much larger sample size. We estimated the chip heritability of loneliness and examined coheritability between loneliness and several personality and psychiatric traits. Our estimates of chip heritability (14-27%) support a role for common genetic variation. We identified strong genetic correlations between loneliness, neuroticism, and a scale of 'depressive symptoms.' We also identified weaker evidence for coheritability with extraversion, schizophrenia, bipolar disorder, and major depressive disorder. We conclude that loneliness, as defined in this study, is a modestly heritable trait that has a highly polygenic genetic architecture. The coheritability between loneliness and neuroticism may reflect the role of negative affectivity that is common to both traits. Our results also reflect the value of studies that probe the common genetic basis of salutary social bonds and clinically defined psychiatric disorders.
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7
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Wheeler HE, Gamazon ER, Frisina RD, Perez-Cervantes C, El Charif O, Mapes B, Fossa SD, Feldman DR, Hamilton RJ, Vaughn DJ, Beard CJ, Fung C, Kollmannsberger C, Kim J, Mushiroda T, Kubo M, Ardeshir-Rouhani-Fard S, Einhorn LH, Cox NJ, Dolan ME, Travis LB. Variants in WFS1 and Other Mendelian Deafness Genes Are Associated with Cisplatin-Associated Ototoxicity. Clin Cancer Res 2016; 23:3325-3333. [PMID: 28039263 DOI: 10.1158/1078-0432.ccr-16-2809] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Revised: 12/09/2016] [Accepted: 12/13/2016] [Indexed: 01/22/2023]
Abstract
Purpose: Cisplatin is one of the most commonly used chemotherapy drugs worldwide and one of the most ototoxic. We sought to identify genetic variants that modulate cisplatin-associated ototoxicity (CAO).Experimental Design: We performed a genome-wide association study (GWAS) of CAO using quantitative audiometry (4-12 kHz) in 511 testicular cancer survivors of European genetic ancestry. We performed polygenic modeling and functional analyses using a variety of publicly available databases. We used an electronic health record cohort to replicate our top mechanistic finding.Results: One SNP, rs62283056, in the first intron of Mendelian deafness gene WFS1 (wolframin ER transmembrane glycoprotein) and an expression quantitative trait locus (eQTL) for WFS1 met genome-wide significance for association with CAO (P = 1.4 × 10-8). A significant interaction between cumulative cisplatin dose and rs62283056 genotype was evident, indicating that higher cisplatin doses exacerbate hearing loss in patients with the minor allele (P = 0.035). The association between decreased WFS1 expression and hearing loss was replicated in an independent BioVU cohort (n = 18,620 patients, Bonferroni adjusted P < 0.05). Beyond this top signal, we show CAO is a polygenic trait and that SNPs in and near 84 known Mendelian deafness genes are significantly enriched for low P values in the GWAS (P = 0.048).Conclusions: We show for the first time the role of WFS1 in CAO and document a statistically significant interaction between increasing cumulative cisplatin dose and rs62283056 genotype. Our clinical translational results demonstrate that pretherapy patient genotyping to minimize ototoxicity could be useful when deciding between cisplatin-based chemotherapy regimens of comparable efficacy with different cumulative doses. Clin Cancer Res; 23(13); 3325-33. ©2016 AACR.
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Affiliation(s)
- Heather E Wheeler
- Department of Biology, Loyola University Chicago, Chicago, Illinois.,Department of Computer Science, Loyola University Chicago, Chicago, Illinois
| | - Eric R Gamazon
- Division of Genetic Medicine, Vanderbilt University, Nashville, Tennessee.,Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | - Robert D Frisina
- Department of Chemical and Biomedical Engineering, University of South Florida, Tampa, Florida.,Department of Communication Sciences and Disorders, Global Center for Hearing and Speech Research, University of South Florida, Tampa, Florida
| | - Carlos Perez-Cervantes
- Department of Biology, Loyola University Chicago, Chicago, Illinois.,Department of Computer Science, Loyola University Chicago, Chicago, Illinois
| | - Omar El Charif
- Department of Medicine, University of Chicago, Chicago, Illinois
| | - Brandon Mapes
- Department of Medicine, University of Chicago, Chicago, Illinois
| | - Sophie D Fossa
- Department of Oncology, Oslo University Hospital, Radiumhospital, Oslo, Norway
| | - Darren R Feldman
- Department of Medical Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Robert J Hamilton
- Department of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
| | - David J Vaughn
- Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Clair J Beard
- Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Chunkit Fung
- J.P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York
| | | | - Jeri Kim
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | | | - Michiaki Kubo
- RIKEN Center for Integrative Medical Science, Yokohama, Japan
| | | | - Lawrence H Einhorn
- Department of Medical Oncology, Indiana University, Indianapolis, Indiana.
| | - Nancy J Cox
- Division of Genetic Medicine, Vanderbilt University, Nashville, Tennessee
| | - M Eileen Dolan
- Department of Medicine, University of Chicago, Chicago, Illinois
| | - Lois B Travis
- Department of Medical Oncology, Indiana University, Indianapolis, Indiana
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8
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Shahani N, Swarnkar S, Giovinazzo V, Morgenweck J, Bohn LM, Scharager-Tapia C, Pascal B, Martinez-Acedo P, Khare K, Subramaniam S. RasGRP1 promotes amphetamine-induced motor behavior through a Rhes interaction network ("Rhesactome") in the striatum. Sci Signal 2016; 9:ra111. [PMID: 27902448 PMCID: PMC5142824 DOI: 10.1126/scisignal.aaf6670] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The striatum of the brain coordinates motor function. Dopamine-related drugs may be therapeutic to patients with striatal neurodegeneration, such as Huntington's disease (HD) and Parkinson's disease (PD), but these drugs have unwanted side effects. In addition to stimulating the release of norepinephrine, amphetamines, which are used for narcolepsy and attention-deficit/hyperactivity disorder (ADHD), trigger dopamine release in the striatum. The guanosine triphosphatase Ras homolog enriched in the striatum (Rhes) inhibits dopaminergic signaling in the striatum, is implicated in HD and L-dopa-induced dyskinesia, and has a role in striatal motor control. We found that the guanine nucleotide exchange factor RasGRP1 inhibited Rhes-mediated control of striatal motor activity in mice. RasGRP1 stabilized Rhes, increasing its synaptic accumulation in the striatum. Whereas partially Rhes-deficient (Rhes+/-) mice had an enhanced locomotor response to amphetamine, this phenotype was attenuated by coincident depletion of RasGRP1. By proteomic analysis of striatal lysates from Rhes-heterozygous mice with wild-type or partial or complete knockout of Rasgrp1, we identified a diverse set of Rhes-interacting proteins, the "Rhesactome," and determined that RasGRP1 affected the composition of the amphetamine-induced Rhesactome, which included PDE2A (phosphodiesterase 2A; a protein associated with major depressive disorder), LRRC7 (leucine-rich repeat-containing 7; a protein associated with bipolar disorder and ADHD), and DLG2 (discs large homolog 2; a protein associated with chronic pain). Thus, this Rhes network provides insight into striatal effects of amphetamine and may aid the development of strategies to treat various neurological and psychological disorders associated with the striatal dysfunction.
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Affiliation(s)
- Neelam Shahani
- Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA
| | - Supriya Swarnkar
- Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA
| | - Vincenzo Giovinazzo
- Harriet L. Wilkes Honors College, Florida Atlantic University, Jupiter, FL 33458, USA
| | - Jenny Morgenweck
- Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA
| | - Laura M Bohn
- Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA
| | | | - Bruce Pascal
- Informatics Core, The Scripps Research Institute, Jupiter, FL 33458, USA
| | | | - Kshitij Khare
- Department of Statistics, University of Florida, Gainesville, FL 32611, USA
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9
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Li Q, Chan SY, Wong KK, Wei R, Leung YO, Ding AY, Hui TCK, Cheung C, Chua SE, Sham PC, Wu EX, McAlonan GM. Tspyl2 Loss-of-Function Causes Neurodevelopmental Brain and Behavior Abnormalities in Mice. Behav Genet 2016; 46:529-37. [PMID: 26826030 PMCID: PMC4886156 DOI: 10.1007/s10519-015-9777-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Accepted: 12/09/2015] [Indexed: 01/04/2023]
Abstract
Testis specific protein, Y-encoded-like 2 (TSPYL2) regulates the expression of genes encoding glutamate receptors. Glutamate pathology is implicated in neurodevelopmental conditions such as autism spectrum disorder, attention deficit hyperactivity disorder (ADHD) and schizophrenia. In line with this, a microduplication incorporating the TSPYL2 locus has been reported in people with ADHD. However, the role of Tspyl2 remains unclear. Therefore here we used a Tspyl2 loss-of-function mouse model to directly examine how this gene impacts upon behavior and brain anatomy. We hypothesized that Tspyl2 knockout (KO) would precipitate a phenotype relevant to neurodevelopmental conditions. In line with this prediction, we found that Tspyl2 KO mice were marginally more active, had significantly impaired prepulse inhibition, and were significantly more 'sensitive' to the dopamine agonist amphetamine. In addition, the lateral ventricles were significantly smaller in KO mice. These findings suggest that disrupting Tspyl2 gene expression leads to behavioral and brain morphological alterations that mirror a number of neurodevelopmental psychiatric traits.
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Affiliation(s)
- Qi Li
- Department of Psychiatry, The University of Hong Kong, Hong Kong SAR, China
- State Key Laboratory for Cognitive and Brain Sciences, The University of Hong Kong, Hong Kong SAR, China
- HKU-SIRI, The University of Hong Kong, Hong Kong SAR, China
| | - Siu Yuen Chan
- Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong SAR, China.
| | - Kwun K Wong
- Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Ran Wei
- Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, China
| | - Yu On Leung
- Department of Psychiatry, The University of Hong Kong, Hong Kong SAR, China
| | - Abby Y Ding
- Medical Physics and Research Department, Hong Kong Sanatorium and Hospital, The University of Hong Kong, Hong Kong SAR, China
| | - Tomy C K Hui
- Department of Psychiatry, The University of Hong Kong, Hong Kong SAR, China
| | - Charlton Cheung
- Department of Psychiatry, The University of Hong Kong, Hong Kong SAR, China
| | - Siew E Chua
- Department of Psychiatry, The University of Hong Kong, Hong Kong SAR, China
| | - Pak C Sham
- Department of Psychiatry, The University of Hong Kong, Hong Kong SAR, China
- State Key Laboratory for Cognitive and Brain Sciences, The University of Hong Kong, Hong Kong SAR, China
- Genome Research Centre, The University of Hong Kong, Hong Kong SAR, China
| | - Ed X Wu
- Laboratory of Biomedical Imaging and Signal Processing, The University of Hong Kong, Hong Kong SAR, China
- Department of Electrical and Electronic Engineering, The University of Hong Kong, Hong Kong SAR, China
| | - Grainne M McAlonan
- Department of Forensic and Neurodevelopmental Science, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, UK.
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10
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Smith CT, Weafer J, Cowan RL, Kessler RM, Palmer AA, de Wit H, Zald DH. Individual differences in timing of peak positive subjective responses to d-amphetamine: Relationship to pharmacokinetics and physiology. J Psychopharmacol 2016; 30:330-43. [PMID: 26880226 PMCID: PMC5049703 DOI: 10.1177/0269881116631650] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Rate of delivery of psychostimulants has been associated with their positive euphoric effects and potential addiction liability. However, information on individual differences in onset of d-amphetamine's effects remains scarce. We examined individual differences in the time to peak subjective and physiological effects and the pharmacokinetics/pharmacodynamics of oral d-amphetamine. We considered two independent studies that used different dosing regimens where subjects completed the drug effects questionnaire at multiple time points post d-amphetamine. Based on the observation of distinct individual differences in time course of drug effects questionnaire "feel", "high", and "like" ratings (DEQH+L+F) in Study 1, subjects in both studies were categorized as early peak responders (peak within 60 minutes), late peak responders (peak > 60 minutes) or nonresponders; 20-25% of participants were categorized as early peak responders, 50-55% as late peak responders and 20-30% as nonresponders. Physiological (both studies) and plasma d-amphetamine (Study 1) were compared among these groups. Early peak responders exhibited an earlier rise in plasma d-amphetamine levels and more sustained elevation in heart rate compared to late peak responders. The present data illustrate the presence of significant individual differences in the temporal pattern of responses to oral d-amphetamine, which may contribute to heightened abuse potential.
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Affiliation(s)
- Christopher T. Smith
- Department of Psychology, PMB 407817, Vanderbilt University, 2301 Vanderbilt Place, Nashville, TN 37240-7817
| | - Jessica Weafer
- Department of Psychiatry and Behavioral Neuroscience, MC3077, University of Chicago, 5821 S. Maryland Avenue, Chicago, IL 60637
| | - Ronald L. Cowan
- Department of Psychology, PMB 407817, Vanderbilt University, 2301 Vanderbilt Place, Nashville, TN 37240-7817,Department of Psychiatry, Vanderbilt University School of Medicine, 1601 23 Ave South, Suite 3057, Nashville, TN, 37212
| | | | - Abraham A. Palmer
- Department of Psychiatry and Behavioral Neuroscience, MC3077, University of Chicago, 5821 S. Maryland Avenue, Chicago, IL 60637,Department of Human Genetics, University of Chicago, 920 E 58 St., CLSC-507G, Chicago, IL 60637
| | - Harriet de Wit
- Department of Psychiatry and Behavioral Neuroscience, MC3077, University of Chicago, 5821 S. Maryland Avenue, Chicago, IL 60637
| | - David H. Zald
- Department of Psychology, PMB 407817, Vanderbilt University, 2301 Vanderbilt Place, Nashville, TN 37240-7817,Department of Psychiatry, Vanderbilt University School of Medicine, 1601 23 Ave South, Suite 3057, Nashville, TN, 37212
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11
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Hnrnph1 Is A Quantitative Trait Gene for Methamphetamine Sensitivity. PLoS Genet 2015; 11:e1005713. [PMID: 26658939 PMCID: PMC4675533 DOI: 10.1371/journal.pgen.1005713] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Accepted: 11/09/2015] [Indexed: 11/19/2022] Open
Abstract
Psychostimulant addiction is a heritable substance use disorder; however its genetic basis is almost entirely unknown. Quantitative trait locus (QTL) mapping in mice offers a complementary approach to human genome-wide association studies and can facilitate environment control, statistical power, novel gene discovery, and neurobiological mechanisms. We used interval-specific congenic mouse lines carrying various segments of chromosome 11 from the DBA/2J strain on an isogenic C57BL/6J background to positionally clone a 206 kb QTL (50,185,512–50,391,845 bp) that was causally associated with a reduction in the locomotor stimulant response to methamphetamine (2 mg/kg, i.p.; DBA/2J < C57BL/6J)—a non-contingent, drug-induced behavior that is associated with stimulation of the dopaminergic reward circuitry. This chromosomal region contained only two protein coding genes—heterogeneous nuclear ribonucleoprotein, H1 (Hnrnph1) and RUN and FYVE domain-containing 1 (Rufy1). Transcriptome analysis via mRNA sequencing in the striatum implicated a neurobiological mechanism involving a reduction in mesolimbic innervation and striatal neurotransmission. For instance, Nr4a2 (nuclear receptor subfamily 4, group A, member 2), a transcription factor crucial for midbrain dopaminergic neuron development, exhibited a 2.1-fold decrease in expression (DBA/2J < C57BL/6J; p 4.2 x 10−15). Transcription activator-like effector nucleases (TALENs)-mediated introduction of frameshift deletions in the first coding exon of Hnrnph1, but not Rufy1, recapitulated the reduced methamphetamine behavioral response, thus identifying Hnrnph1 as a quantitative trait gene for methamphetamine sensitivity. These results define a novel contribution of Hnrnph1 to neurobehavioral dysfunction associated with dopaminergic neurotransmission. These findings could have implications for understanding the genetic basis of methamphetamine addiction in humans and the development of novel therapeutics for prevention and treatment of substance abuse and possibly other psychiatric disorders. Both genetic and environmental factors can powerfully modulate susceptibility to substance use disorders. Quantitative trait locus (QTL) mapping is an unbiased discovery-based approach that is used to identify novel genetic factors and provide new mechanistic insight into phenotypic variation associated with disease. In this study, we focused on the genetic basis of variation in sensitivity to the acute locomotor stimulant response to methamphetamine which is a behavioral phenotype in rodents that is associated with stimulated dopamine release and activation of the brain reward circuitry involved in addiction. Using brute force monitoring of recombination events associated with changes in behavior, we fortuitously narrowed the genotype-phenotype association down to just two genes that we subsequently targeted using a contemporary genome editing approach. The gene that we validated–Hnrnph1 –is an RNA binding protein that did not have any previously known function in psychostimulant behavior or psychostimulant addiction. Our behavioral data combined with our gene expression results provide a compelling rationale for a new line of investigation regarding Hnrnph1 and its role in neural development and plasticity associated with the addictions and perhaps other dopamine-dependent psychiatric disorders.
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Gamazon ER, Wheeler HE, Shah KP, Mozaffari SV, Aquino-Michaels K, Carroll RJ, Eyler AE, Denny JC, Nicolae DL, Cox NJ, Kyung Im H. A gene-based association method for mapping traits using reference transcriptome data. Nat Genet 2015; 47:1091-8. [PMID: 26258848 PMCID: PMC4552594 DOI: 10.1038/ng.3367] [Citation(s) in RCA: 1188] [Impact Index Per Article: 118.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Accepted: 07/06/2015] [Indexed: 12/14/2022]
Abstract
Genome-wide association studies (GWAS) have identified thousands of variants robustly associated with complex traits. However, the biological mechanisms underlying these associations are, in general, not well understood. We propose a gene-based association method called PrediXcan that directly tests the molecular mechanisms through which genetic variation affects phenotype. The approach estimates the component of gene expression determined by an individual's genetic profile and correlates 'imputed' gene expression with the phenotype under investigation to identify genes involved in the etiology of the phenotype. Genetically regulated gene expression is estimated using whole-genome tissue-dependent prediction models trained with reference transcriptome data sets. PrediXcan enjoys the benefits of gene-based approaches such as reduced multiple-testing burden and a principled approach to the design of follow-up experiments. Our results demonstrate that PrediXcan can detect known and new genes associated with disease traits and provide insights into the mechanism of these associations.
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Affiliation(s)
- Eric R. Gamazon
- Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL
- Division of Genetic Medicine, Vanderbilt University, Nashville, TN
| | - Heather E. Wheeler
- Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL
| | - Kaanan P. Shah
- Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL
| | | | | | - Robert J. Carroll
- Department of Biomedical Informatics, Vanderbilt University, Nashville, TN
| | - Anne E. Eyler
- Department of Medicine, Vanderbilt University, Nashville, TN
| | - Joshua C. Denny
- Department of Biomedical Informatics, Vanderbilt University, Nashville, TN
| | - GTEx Consortium
- A full list of members and affiliations appears in the Supplementary Note
| | - Dan L. Nicolae
- Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL
- Department of Human Genetics, University of Chicago, Chicago, IL
- Department of Statistics, University of Chicago, Chicago, IL
| | - Nancy J. Cox
- Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL
- Division of Genetic Medicine, Vanderbilt University, Nashville, TN
- Department of Human Genetics, University of Chicago, Chicago, IL
| | - Hae Kyung Im
- Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL
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Pallanti S, Salerno L. Raising attention to attention deficit hyperactivity disorder in schizophrenia. World J Psychiatry 2015; 5:47-55. [PMID: 25815254 PMCID: PMC4369549 DOI: 10.5498/wjp.v5.i1.47] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2014] [Revised: 11/20/2014] [Accepted: 12/31/2014] [Indexed: 02/05/2023] Open
Abstract
Schizophrenia and attention deficit hyperactivity disorder (ADHD) are two psychiatric disorders with a negative impact on quality of life of individuals affected. Although they are classified into distinct disorders categories, attentional dysfunction is considered as a core feature in both conditions, either at the clinical then pathophysiological level. Beyond the obvious clinical overlap between these disorders, the Research Domain Criteria approach might offer an interesting perspective for disentangling common circuits underpinning both disorders. Hence, we review evidences regarding the overlap between schizophrenia and ADHD, at the clinical level, and at the level of underlying brain mechanisms. The evidence regarding the influence of environmental risk factors in the emergence of both disorders, and their developmental trajectories is also reviewed. Among these, we will try to elucidate the complex relationship between stimulants use and psychotic symptoms, discussing the potential role of ADHD medication in inducing psychosis or in exacerbating it. We aim that, taken together, these findings may promote further investigation with important implications both for clinicians and research. In fact, considering the amounting evidence on the overlap between schizophrenia and ADHD, the delineation of their boundaries might help in the decision for diagnosis and treatment. Moreover, it may help to promote interventions focused on the prevention of both schizophrenia and ADHD, by the reduction of recognized environmental risk factors.
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Rutter JL, Volkow ND. Re-defininG AddiC(CH3)Tion: genomics and epigenomics on substance use disorders. Mol Genet Genomic Med 2014; 2:273-9. [PMID: 25077169 PMCID: PMC4113267 DOI: 10.1002/mgg3.93] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2014] [Accepted: 05/23/2014] [Indexed: 11/17/2022] Open
Affiliation(s)
- Joni L Rutter
- National Institute on Drug Abuse, National Institutes of Health Bethesda, Maryland, 20892
| | - Nora D Volkow
- National Institute on Drug Abuse, National Institutes of Health Bethesda, Maryland, 20892
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