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Abstract
Linkage studies have defined at least five bipolar (BP) disorder susceptibility loci that meet suggested guidelines for initial identification and subsequent confirmation. These loci, found on 18p11, 18q22, 21q21, 4p16, and Xq26, are targets for BP candidate gene investigations. Molecular dissection of expressed sequences for these regions is likely to yield specific BP susceptibility alleles in most cases, in all probability, these BP susceptibility alleles will be common in the general population, and, individually, will be neither necessary nor sufficient for manifestation syndrome. Additive or multiplicative oligogenic models involving several susceptibility loci appear most reasonable at present, it is hoped thai these BP susceptibility genes will increase understanding of many mysteries surrounding these disorders, including drug response, cycling patterns, age-of-onset, and modes of transmission.
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Affiliation(s)
- W H Berrettini
- The department of Psychiatry and the Center for Neurobiology and Behavior, University of Pennsylvania, USA
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Seifuddin F, Mahon PB, Judy J, Pirooznia M, Jancic D, Taylor J, Goes FS, Potash JB, Zandi PP. Meta-analysis of genetic association studies on bipolar disorder. Am J Med Genet B Neuropsychiatr Genet 2012; 159B:508-18. [PMID: 22573399 PMCID: PMC3582382 DOI: 10.1002/ajmg.b.32057] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2011] [Accepted: 04/10/2012] [Indexed: 01/05/2023]
Abstract
Numerous candidate gene association studies of bipolar disorder (BP) have been carried out, but the results have been inconsistent. Individual studies are typically underpowered to detect associations with genes of small effect sizes. We conducted a meta-analysis of published candidate gene studies to evaluate the cumulative evidence. We systematically searched for all published candidate gene association studies of BP. We then carried out a random-effects meta-analysis on all polymorphisms that were reported on by three or more case-control studies. The results from meta-analyses of these genes were compared with the findings from a recent mega-analysis of eleven genome-wide association studies (GWAS) in BP performed by the Psychiatric GWAS Consortium (PGC). A total of 487 articles were included in our review. Among these, 33 polymorphisms in 18 genes were reported on by three or more case-control studies and included in the random-effects meta-analysis. Polymorphisms in BDNF, DRD4, DAOA, and TPH1, were found to be nominally significant with a P-value < 0.05. However, none of the findings were significant after correction for multiple testing. Moreover, none of these polymorphisms were nominally significant in the PGC-BP GWAS. A number of plausible candidate genes have been previously associated with BP. However, the lack of robust findings in our review of these candidate genes highlights the need for more atheoretical approaches to study the genetics of BP afforded by GWAS. The results of this meta-analysis and from other on-going genomic experiments in BP are available online at Metamoodics (http://metamoodics.igm.jhmi.edu).
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Affiliation(s)
- Fayaz Seifuddin
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Pamela Belmonte Mahon
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Jennifer Judy
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Mehdi Pirooznia
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Dubravka Jancic
- Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa
| | - Jacob Taylor
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Fernando S. Goes
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - James B. Potash
- Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa
| | - Peter P. Zandi
- Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
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Zou YF, Wang F, Feng XL, Li WF, Tian YH, Tao JH, Pan FM, Huang F. Association of DRD2 gene polymorphisms with mood disorders: a meta-analysis. J Affect Disord 2012; 136:229-237. [PMID: 21130502 DOI: 10.1016/j.jad.2010.11.012] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2010] [Revised: 11/05/2010] [Accepted: 11/09/2010] [Indexed: 11/29/2022]
Abstract
BACKGROUND In the past few decades, a number of studies have investigated the association of dopamine D2 receptor (DRD2) gene polymorphisms with mood disorders, but the findings are not always consistent. The aim of our study was to assess the association between DRD2 gene polymorphisms and mood disorders by using a meta-analysis. METHODS Data were collected from the following electronic databases: PubMed, Elsevier Science Direct, Cochrane Library, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, and Wanfang, with the last report up to June 2010. Meta-analysis was performed in a fixed/random effect model by using the software Review Manager 4.2. RESULTS We identified 19 separate studies using search, but only 14 separate studies (2157 cases and 3272 controls) were included in the current study. Meta-analysis was performed for three DRD2 gene polymorphisms (-141Cins/del, Ser311/Cys311, and TaqI A1). We performed meta-analysis in overall, Caucasian, and Asian populations. We also performed disease-specific meta-analysis in unipolar disorder and bipolar disorder. We found no association between DRD2 gene -141Cins/del polymorphism and mood disorders in overall and Caucasian populations (P>0.05). We also found no association between DRD2 gene Ser311/Cys311 polymorphism and mood disorders in overall, Caucasian, and Asian populations (P>0.05). An association of DRD2 gene TaqI A1 polymorphism with mood disorders was found in overall population, and the individuals with A1A1 genotype were more susceptible to mood disorders in comparison to those with A2A1 and A2A2 genotypes (OR=1.84, 95% CI=1.07-3.17, P=0.03). LIMITATION Meta-analysis is retrospective research that is subject to the methodological deficiencies of the included studies. CONCLUSION This meta-analysis suggests that mood disorders may be associated with DRD2 gene TaqI A1 polymorphism, but not -141Cins/del and Ser311/Cys311.
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Affiliation(s)
- Yan-Feng Zou
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, and Department of Oncology, The first affiliated Hospital of Anhui Medical University, Hefei, China
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4
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Walderhaug E, Varga M, Pedro MS, Hu J, Neumeister A. The role of the aminergic systems in the pathophysiology of bipolar disorder. Curr Top Behav Neurosci 2011; 5:107-126. [PMID: 25236552 DOI: 10.1007/7854_2010_72] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
Bipolar disorder (BPD) is a major medical and social burden, but little is known about the specific pathophysiology of BPD. The key biogenic amines in the aminergic system include serotonin (5-HT), norepinephrine (NE), dopamine (DA), and acetylcholine (ACh). By analyzing these neurotransmitters, this chapter highlights three hypotheses in the pathophysiology of BPD: the biogenic amine hypothesis, the cholinergic-aminergic balance hypothesis, and the permissive hypothesis. Evidence from select studies of cerebrospinal fluid, postmortem subjects, neuroimaging, genetic factors, and pharmacological agents will be used to reconcile these hypotheses. Possible explanations for discrepancies in these hypotheses are given, and directions for future studies are suggested.
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Affiliation(s)
- Espen Walderhaug
- Department of Psychology, University of Oslo, 1094, Blindern, 0317, Oslo, Norway,
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5
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Abstract
OBJECTIVE Despite effective pharmacological treatments for bipolar disorder, we still lack a comprehensive pathophysiological model of the illness. Recent neurobiological research has implicated a number of key brain regions and neuronal components in the behavioural and cognitive manifestations of bipolar disorder. Dopamine has previously been investigated in some depth in bipolar disorder, but of late has not been a primary focus of attention. This article examines the role of dopamine in bipolar disorder, incorporating recent advances into established models where possible. METHODS A critical evaluation of the literature was undertaken, including a review of behavioural, neurochemical, receptor, and imaging studies, as well as genetic studies focusing on dopamine receptors and related metabolic pathways. In addition, pharmacologic manipulation of the central dopaminergic pathways and comparisons with other disease states such as schizophrenia were considered, principally as a means of exploring the hypothesised models. RESULTS Multiple lines of evidence, including data from pharmacological interventions and structural and functional magnetic resonance imaging studies, suggest that the dopaminergic system may play a central role in bipolar disorder. CONCLUSION Future research into the pathophysiological mechanisms of bipolar disorder and the development of new treatments for bipolar disorder should focus on the dopaminergic system.
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Affiliation(s)
- David A Cousins
- Newcastle Magnetic Resonance Centre, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, UK.
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Gershon AA, Vishne T, Grunhaus L. Dopamine D2-like receptors and the antidepressant response. Biol Psychiatry 2007; 61:145-53. [PMID: 16934770 DOI: 10.1016/j.biopsych.2006.05.031] [Citation(s) in RCA: 112] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2006] [Revised: 05/12/2006] [Accepted: 05/16/2006] [Indexed: 01/11/2023]
Abstract
Converging lines of evidence suggest a role for the mesolimbic dopamine system in the response to somatic antidepressant therapies. Here, we review evidence suggesting that antidepressant treatments of different types share the effect of increasing the sensitivity of dopamine D2-like receptors in the nucleus accumbens, clinical studies suggesting that activation of these receptors has antidepressant efficacy, as well as relevant imaging and genetic data on the role of this system in the antidepressant response. We then attempt to reconcile this data with evidence of a common target of antidepressant drugs in the cyclic adenosine monophosphate (cAMP) response element binding protein-brain-derived neurotrophic factor (CREB-BDNF) pathway in a model that suggests potential directions for future inquiry.
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Affiliation(s)
- Ari A Gershon
- Division of Psychiatry, Chaim Sheba Medical Center, Tel Hashomer, Israel.
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Fallin MD, Lasseter VK, Avramopoulos D, Nicodemus KK, Wolyniec PS, McGrath JA, Steel G, Nestadt G, Liang KY, Huganir RL, Valle D, Pulver AE. Bipolar I disorder and schizophrenia: a 440-single-nucleotide polymorphism screen of 64 candidate genes among Ashkenazi Jewish case-parent trios. Am J Hum Genet 2005; 77:918-36. [PMID: 16380905 PMCID: PMC1285177 DOI: 10.1086/497703] [Citation(s) in RCA: 310] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2005] [Accepted: 08/25/2005] [Indexed: 12/11/2022] Open
Abstract
Bipolar, schizophrenia, and schizoaffective disorders are common, highly heritable psychiatric disorders, for which familial coaggregation, as well as epidemiological and genetic evidence, suggests overlapping etiologies. No definitive susceptibility genes have yet been identified for any of these disorders. Genetic heterogeneity, combined with phenotypic imprecision and poor marker coverage, has contributed to the difficulty in defining risk variants. We focused on families of Ashkenazi Jewish descent, to reduce genetic heterogeneity, and, as a precursor to genomewide association studies, we undertook a single-nucleotide polymorphism (SNP) genotyping screen of 64 candidate genes (440 SNPs) chosen on the basis of previous linkage or of association and/or biological relevance. We genotyped an average of 6.9 SNPs per gene, with an average density of 1 SNP per 11.9 kb in 323 bipolar I disorder and 274 schizophrenia or schizoaffective Ashkenazi case-parent trios. Using single-SNP and haplotype-based transmission/disequilibrium tests, we ranked genes on the basis of strength of association (P<.01). Six genes (DAO, GRM3, GRM4, GRIN2B, IL2RB, and TUBA8) met this criterion for bipolar I disorder; only DAO has been previously associated with bipolar disorder. Six genes (RGS4, SCA1, GRM4, DPYSL2, NOS1, and GRID1) met this criterion for schizophrenia or schizoaffective disorder; five replicate previous associations, and one, GRID1, shows a novel association with schizophrenia. In addition, six genes (DPYSL2, DTNBP1, G30/G72, GRID1, GRM4, and NOS1) showed overlapping suggestive evidence of association in both disorders. These results may help to prioritize candidate genes for future study from among the many suspected/proposed for schizophrenia and bipolar disorders. They provide further support for shared genetic susceptibility between these two disorders that involve glutamate-signaling pathways.
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Affiliation(s)
- M Daniele Fallin
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21231, USA
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Oswald P, Souery D, Mendlewicz J. Molecular genetics of affective disorders. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28:865-77. [PMID: 15363609 DOI: 10.1016/j.pnpbp.2004.05.028] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/10/2004] [Indexed: 11/16/2022]
Abstract
Evidence for familial aggregation in Affective Disorders (AD) has been provided in classical studies. Linkage and association genetic studies have been proposed to detect genetic factors implicated in AD. However, findings from molecular genetic studies remain inconclusive. Nevertheless, current research is focusing on the phenotypes, both sub- and endophenotypes. In addition, recent advances in technology, such as microarrays, provide new tools in psychiatric genetics. These different approaches offer a new optimism era in the search of genetic factors in AD.
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Affiliation(s)
- Pierre Oswald
- Department of Psychiatry, Erasme Hospital, Free University of Brussels, 808 route de Lennik, B-1070, Brussels, Belgium.
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Anney RJL, Olsson CA, Lotfi-Miri M, Patton GC, Williamson R. Nicotine dependence in a prospective population-based study of adolescents. ACTA ACUST UNITED AC 2004; 14:73-81. [PMID: 15077008 DOI: 10.1097/00008571-200402000-00001] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Dopamine is a key neurotransmitter of the mesolimbic reward pathway in the human brain, and tyrosine hydroxylase (TH) is the rate-limiting enzyme in dopamine biosynthesis. Consequently, the gene encoding TH is a strong candidate for involvement in the genetic component of addiction. The importance of this gene in nicotine dependence is supported by many studies showing a link between nicotine administration and TH expression. A functional tetranucleotide repeat polymorphism within intron 1 of the TH gene (HUMTH01-VNTR) has been shown to modify tobacco use in two independent Caucasian samples from the USA and Australia. Using information drawn from an eight-wave Australian population-based longitudinal study of adolescent health, we tested the effect of the HUMTH01-VNTR on nicotine dependence. Comparisons were made between dependent smokers and non-dependent smokers. These data provide further support for a protective association between the K4 allele and dependent smoking (odds ratio 0.54, 95% confidence interval 0.28-1.0). No associations were observed at any of three other common TH polymorphisms (rs6356, rs6357 and HUMTH01-PstI). Including these data, three independent studies, two of which use identical phenotypes, have now identified a protective relationship between the K4 allele of the functional HUMTH01-VNTR polymorphism and high-level smoking.
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Affiliation(s)
- Richard J L Anney
- Behavioural Genetics Laboratory, Murdoch Childrens Research Institute, Royal Children's Hospital,University of Melbourne, Parkville, Melbourne, Australia.
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Li JZ, Chen X, Yang H, Wang SL, Gong XL, Feng H, Guo BY, Yu L, Wang ZG, Fu JL. Establishment of transgenic mice carrying gene encoding human zinc finger protein 191. World J Gastroenterol 2004; 10:264-7. [PMID: 14716836 PMCID: PMC4717017 DOI: 10.3748/wjg.v10.i2.264] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: Human zinc finger protein 191 (ZNF191) was cloned and characterized as a Krüppel-like transcription factor, which might be relevant to many diseases such as liver cancer, neuropsychiatric and cardiovascular diseases. Although progress has been made recently, the biological function of ZNF191 remains largely unidentified. The aim of this study was to establish a ZNF 191 transgenic mouse model, which would promote the functional study of ZNF191.
METHODS: Transgene fragments were microinjected into fertilized eggs of mice. The manipulated embryos were transferred into the oviducts of pseudo-pregnant female mice. The offsprings were identified by PCR and Southern blot analysis. ZNF 191 gene expression was analyzed by RT-PCR. Transgenic founder mice were used to establish transgenic mouse lineages. The first generation (F1) and the second generation (F2) mice were identified by PCR analysis. Ten-week transgenic mice were used for pathological examination.
RESULTS: Four mice were identified as carrying copies of ZNF191 gene. The results of RT-PCR showed that ZNF 191 gene was expressed in the liver, testis and brain in one of the transgenic mouse lineages. Genetic analysis of transgenic mice demonstrated that ZNF 191 gene was integrated into the chromosome at a single site and could be transmitted stably. Pathological analysis showed that the expression of ZNF 191 did not cause obvious pathological changes in multiple tissues of transgenic mice.
CONCLUSION: ZNF 191 transgenic mouse model would facilitate the investigation of biological functions of ZNF191 in vivo.
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Affiliation(s)
- Jian-Zhong Li
- Department of Medical Genetics, Second Military Medical University, Shanghai 200433, China
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11
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Abstract
This article presents a conceptual review of the genetic underpinnings of psychotic mood disorders. Both unipolar and bipolar forms of mood disorder sometimes feature psychotic symptoms. Some evidence from epidemiological research suggests that psychotic forms of mood disorder specifically might be heritable. Linkage studies of mood disorders in general have also provided some support for that notion, as have associated studies involving serotonin and dopamine genes and psychotic mood disorder. Some research suggests there might be a genetic connection between schizophrenia and bipolar disorder, undermining the Kraepelinian dichotomous classification of the psychoses. Future research should continue to examine psychotic forms of mood disorder using both epidemiological and molecular approaches.
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Affiliation(s)
- Ming T Tsuang
- Harvard Medical School Department of Psychiatry at the Massachusetts Mental Health Center, 74 Fenwood Road, Boston, MA, USA.
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Meloni R, Biguet NF, Mallet J. Post-genomic era and gene discovery for psychiatric diseases: there is a new art of the trade? The example of the HUMTH01 microsatellite in the Tyrosine Hydroxylase gene. Mol Neurobiol 2002; 26:389-403. [PMID: 12428766 DOI: 10.1385/mn:26:2-3:389] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The microsatellite HUMTH01, located in the first intron of the Tyrosine Hydroxylase (TH) gene (encoding the rate-limiting enzyme in the synthesis of catecholamines), is characterized by a TCAT repeated motif and has been used in genetic studies of neuropsychiatric and other complex diseases, in which catecholaminergic neurotransmission is implicated. After reporting a positive association between HUMTH01 and bipolar disorder as well as schizophrenia, the authors established that HUMTH01 alleles display the features of regulatory elements. Thereafter, they cloned two proteins (ZNF191 and HBP1), specifically binding to HUMTH01, and demonstrated that allelic variations of HUMTH01 have a quantitative silencing effect on TH gene expression in vitro, and correlate with quantitative and qualitative changes in the binding by ZNF191. The authors aim to characterize the transduction pathway impinging on the HUMTH01 microsatellite and establish its relevance for TH gene regulation in vivo. Since the TCAT repeated sequence is widespread throughout the genome, their approach may lead to the dissection of the mechanisms underlying the quantitative expression of several genes implicated in complex genetic traits, both normal and pathological. Thus, these investigations on the possible contribution and potential role of the HUMTH01 microsatellite in neuro-pathological conditions may represent an example of the different approaches needed to validate genetic targets in the "post-genomic era."
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Affiliation(s)
- Rolando Meloni
- Laboratoire de Génétique de la Neurotransmissionet des Processus Neurodégénératifs (LGN), CNRS UMR 7091, Bât CERVI Hĵpital de la Pitié Salpêtrière, Paris, France.
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Cusin C, Serretti A, Lattuada E, Lilli R, Lorenzi C, Smeraldi E. Association study of MAO-A, COMT, 5-HT2A, DRD2, and DRD4 polymorphisms with illness time course in mood disorders. AMERICAN JOURNAL OF MEDICAL GENETICS 2002; 114:380-90. [PMID: 11992560 DOI: 10.1002/ajmg.10358] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
The aim of our study was to investigate a possible influence of monoamine oxydase A (MAO-A), catechol-O-methyltransferase (COMT), serotonin receptor 2A (5-HT2A), dopamine receptor D2 (DRD2), and dopamine receptor D4 (DRD4) gene variants on timing of recurrence in mood disorders. Gene variants were determined using PCR-based techniques in 550 inpatients affected by recurrent mood disorders (major depressives: n = 212; bipolars: n = 338), rapid cycling mood disorder (n = 81), and 663 controls. We investigated possible genetic influences by comparing illness time course of subjects subdivided according to genotype using multivariate analysis of variance (MANOVA). We could not observe a significantly different time course. No demographic and clinical variables such as sex, age or polarity of onset, presence of psychotic features, genetic loading, or education level influenced the observed results. Our results suggest that MAO-A, COMT, 5-HT2A, DRD2, and DRD4 gene variants are not involved in susceptibility toward different time courses in mood disorders.
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Affiliation(s)
- Cristina Cusin
- Department of Psychiatry, Vita-Salute University, Fondazione Centro San Raffaele del Monte Tabor, Milan, Italy
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15
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Massat I, Souery D, Del-Favero J, Van Gestel S, Serretti A, Macciardi F, Smeraldi E, Kaneva R, Adolfsson R, Nylander PO, Blackwood D, Muir W, Papadimitriou GN, Dikeos D, Oru? L, Segman RH, Ivezi? S, Aschauer H, Ackenheil M, Fuchshuber S, Dam H, Jakovljevi? M, Peltonen L, Hilger C, Hentges F, Staner L, Milanova V, Jazin E, Lerer B, Van Broeckhoven C, Mendlewicz J. Positive association of dopamine D2 receptor polymorphism with bipolar affective disorder in a European multicenter association study of affective disorders. ACTA ACUST UNITED AC 2002. [DOI: 10.1002/ajmg.10118] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Serretti A, Zanardi R, Cusin C, Rossini D, Lilli R, Lorenzi C, Lattuada E, Smeraldi E. No association between dopamine D(2) and D(4) receptor gene variants and antidepressant activity of two selective serotonin reuptake inhibitors. Psychiatry Res 2001; 104:195-203. [PMID: 11728608 DOI: 10.1016/s0165-1781(01)00324-9] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The possible association of the dopamine receptor D(2) (Ser 311Cys) and D(4) exon 3 (48 base pair repeat) gene variants with the antidepressant activity of selective serotonin reuptake inhibitors (SSRIs) was investigated in a sample of 364 inpatients affected by a major depressive episode treated with fluvoxamine, 300 mg/day (n=266), or paroxetine, 20-40 mg/day (n=98). The severity of depressive symptoms was assessed weekly with the Hamilton Rating Scale for Depression. Dopamine receptor D(2) (DRD2) and dopamine receptor D(4) (DRD4) allelic variants were determined in each subject by polymerase chain reaction. We observed that DRD2 and DRD4 variants were not associated with response to SSRI treatment. Possible stratification factors, such as sex, diagnosis, presence of psychotic features, depressive symptoms at baseline, paroxetine and fluvoxamine plasma levels, and pindolol augmentation did not significantly influence the observed results. The investigated DRD2 and DRD4 gene variants therefore do not seem to play a major role in the antidepressant activity of SSRIs, at least in the present sample.
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Affiliation(s)
- A Serretti
- Department of Psychiatry, Istituto Scientifico H San Raffaele, Vita-Salute University, Via Stamira D'Ancona 20, 20127 Milan, Italy.
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Abstract
The TaqIA D2 dopamine receptor (DRD2) minor (A1) allele was first associated with severe alcoholism a decade ago. Since then, studies both confirming and not confirmnning this finding were reported. However, a meta-analysis of a large number of Caucasian alcoholics (both more severe and less severe) and controls (both assessed and unassessed for substance use disorders) revealed a significantly higher frequency (p < 10(-6)) and prevalence (p < 10(-8)) of the DRD2 A1 allele in the alcoholics. Further analysis showed that the more severe alcoholics had a 3-fold higher prevalence of the DRD2 A1 allele than the assessed controls (p < 10(-10)), whereas no difference was found between the less severe alcoholics and the unassessed controls. DRD2 exonic or promoter mutations have not yet been associated with alcoholism, although two intronic variants at the TaqIB and intron 6 sites, which are in linkage disequilibrium with the TaqIA site, were associated with this disorder. Variants of the DRD2 gene have also been associated with cocaine, nicotine and opioid dependence, obesity and gambling. It is hypothesised that the DRD2 is a reinforcement or reward gene. Although less intensively studied than substance use disorders, the DRD2 gene has been implicated in Tourette's syndrome (TS), post-traumatic stress disorder (PTSD) and certain symptoms associated with affective disorders and schizophrenia. Further, DRD2 variants have been implicated in Parkinson's disease (PD) and in iatrogenically-induced movement disorders, as well as in certain migraineurs. Phenotypic differences have been associated with DRD2 variants. These include reduced D2 dopamine receptor numbers and diminished glucose metabolism in the brain of subjects who carry the DRD2 A1 allele. In addition, phenotypic differences have been found in neurocognitive and personality characteristics, and in treatment outcome of DRD2 variants. The involvement of the DRD2 gene in certain neuropsychiatric disorders opens up the potential of a targeted pharmacogenomic approach to the prevention and treatment of these disorders.
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Affiliation(s)
- E P Noble
- Alcohol Research Center, Department of Psychiatry and Biobehavioral Sciences and the Brain Research Institute, University of California, Los Angeles 90024, USA.
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Persson ML, Wasserman D, Jönsson EG, Bergman H, Terenius L, Gyllander A, Neiman J, Geijer T. Search for the influence of the tyrosine hydroxylase (TCAT)(n) repeat polymorphism on personality traits. Psychiatry Res 2000; 95:1-8. [PMID: 10904118 DOI: 10.1016/s0165-1781(00)00160-8] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
A putatively functional tetranucleotide repeat polymorphism in the tyrosine hydroxylase gene (TH) has been investigated with regard to different aspects of psychopathology. We investigated whether reported associations of this TH polymorphism may reflect associations with common personality traits. Personality was assessed by the NEO Personality Inventory-Revised version (NEO PI-R), in 205 healthy Caucasian volunteers. Tendencies for higher scores in the neuroticism (N) facets, Angry hostility (P=0.008) and Vulnerability (P=0.021), were observed among carriers of one of the alleles (T8). Healthy women with the T6/T10 genotype had significantly higher scores (P=0.001) in the Deliberation and Dutifulness facets (P=0.031) (the Conscientiousness dimension, C) and lower scores (P=0.031) in the Feelings facet (the Openness dimension, O). We concluded that: (1) higher mean scores in the Neuroticism facets among T8 allele carriers are consistent with previous data and warrants further research; (2) the T6/T10 genotype may influence personality among women; (3) these data should be cautiously interpreted in the absence of corroborating data.
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Affiliation(s)
- M L Persson
- Swedish National and Stockholm County Center for Suicide Research and Prevention, National Institute for Psychosocial Factors and Health, Department of Public Health Sciences, Karolinska Institutet, Stockholm, Sweden.
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Serretti A, Lattuada E, Lorenzi C, Lilli R, Smeraldi E. Dopamine receptor D2 Ser/Cys 311 variant is associated with delusion and disorganization symptomatology in major psychoses. Mol Psychiatry 2000; 5:270-4. [PMID: 10889529 DOI: 10.1038/sj.mp.4000726] [Citation(s) in RCA: 47] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The D2 receptor (DRD2) is a binding site of many psychoactive drugs and it has been proposed as a genetic risk factor for psychiatric disorders. The aim of this investigation was to study the DRD2 S311C variant in major psychoses. We studied 1182 inpatients with diagnoses of bipolar disorder (n = 480), major depressive disorder (n = 269), schizophrenia (n = 366), delusional disorder (n = 44), psychotic disorder not otherwise specified (n = 23) and 267 healthy controls. Eight hundred and eighty-seven subjects were also scored for their lifetime symptomatology using the the Operational Criteria checklist for psychotic illness (OPCRIT). DRD2 variants were not associated with affected subjects even when possible confounders like gender and onset were considered. When we considered the 887 subjects with the symptomatologic analysis, we observed a significant association of the DRD2 S311C variant with both delusion and disorganization features. The association was present independently from diagnoses. Our results do not show that coding variants of the DRD2 S311C play a major role in conferring susceptibility to major psychoses, but they may be connected with disorganized and delusional symptomatology independently from diagnoses.
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Affiliation(s)
- A Serretti
- Istituto Scientifico Ospedale San Raffaele, Department of Neuropsychiatric Sciences, University of Milan School of Medicine, Italy.
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Serretti A, Macciardi F, Cusin C, Lattuada E, Souery D, Lipp O, Mahieu B, Van Broeckhoven C, Blackwood D, Muir W, Aschauer HN, Heiden AM, Ackenheil M, Fuchshuber S, Raeymaekers P, Verheyen G, Kaneva R, Jablensky A, Papadimitriou GN, Dikeos DG, Stefanis CN, Smeraldi E, Mendlewicz J. Linkage of mood disorders with D2, D3 and TH genes: a multicenter study. J Affect Disord 2000; 58:51-61. [PMID: 10760558 DOI: 10.1016/s0165-0327(99)00112-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
BACKGROUND It has been suggested that the dopaminergic system is involved in the pathophysiology of mood disorders. We conducted a multicenter study of families with mood disorders, to investigate a possible linkage with genes coding for dopamine receptor D2, dopamine receptor D3 and tyrosine hydroxylase (TH). METHODS Twenty three mood disorder pedigrees collected within the framework of the European Collaborative Project on Affective Disorders were analyzed with parametric and non-parametric linkage methods. Various potential phenotypes were considered, from a narrow (only bipolar as affected) to a broad (bipolar+major depressive+schizoaffective disorders) definition of affection status. RESULTS Parametric analyses excluded linkage for all the candidate genes, even though small positive LOD (Limit of Detection) scores were observed for TH in three families. Non-parametric analyses yielded negative results for all markers. CONCLUSION The D2 and D3 dopamine receptors were, therefore, not a major liability factor for mood disorders in our sample, whereas TH may play a role in a subgroup of patients.
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Affiliation(s)
- A Serretti
- Istituto Scientifico Ospedale San Raffaele, Department of Neuropsychiatric Sciences, University of Milan School of Medicine, Via Luigi Prinetti 29, 20127, Milan, Italy.
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Abstract
OBJECTIVES To review the methodologies and findings in the genetics of bipolar disorder (BPD), and to suggest future directions for research. METHODS Reports of family, twin, adoption, linkage, association, cytogenetic, and animal model studies, and segregation analyses in English, were identified from multiple MEDLINE searches. Hand searches were carried out in bibliographies from review articles. RESULTS Family, twin, and adoption studies have provided strong evidence for a genetic etiology in BPD. Early reports of linkage of BPD to DNA markers at several chromosomal sites have not proven robust, perhaps because of the complex nature of BPD inheritance. However, linkage findings in the 1990s, on chromosomes 18, 21q, 12q, and 4p, have provided leads that are being pursued through both genetic and physical mapping. No gene has yet been definitively implicated in BPD. CONCLUSIONS Strategies for increasing the power to detect BPD genes include: (1) dividing the phenotype into genetically meaningful subtypes to decrease heterogeneity: and (2) ascertaining a very large family sample--a multicenter study now in progress will collect 700 bipolar I sibling pairs. BPD may result from several genes acting in concert so that new multilocus statistical methods could enhance the capacity to detect loci involved. Family-based association studies using a very large number of newly identified single nucleotide polymorphisms (SNPs) may allow for more efficient screening of the genome. As the Human Genome Project approaches its goal of isolating all genes by 2003, the data generated is likely to speed identification of candidate BPD genes.
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Affiliation(s)
- J B Potash
- Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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Gorwood P, Bellivier F, Adès J, Leboyer M. The DRD2 gene and the risk for alcohol dependence in bipolar patients. Eur Psychiatry 2000; 15:103-8. [PMID: 10881206 DOI: 10.1016/s0924-9338(00)00205-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
The high co-morbidity between bipolar disorder and alcohol dependence may have different explanations, one of them being the existence of common genetic factors for the two disorders. Several candidate genes may be involved but the genes acting in the dopaminergic pathway may be more specifically involved. We have thus tested the role of the gene encoding the D2 dopamine receptor (TaqI A1 allele) in the potentially shared vulnerability to alcohol dependence and bipolar disorder. One hundred and twenty-two French (for at least two generations) patients were recruited on the basis of hospital or outpatient files and were interviewed with the DIGS. The A1 allele frequencies were compared between four groups, namely, with bipolar patients and co-morbid alcohol dependence (N = 21), with bipolar patients without alcohol morbidity (N = 31), with alcohol dependence without mood disorder (N = 35) and unaffected controls (N = 35). The Hardy Weinberg equilibrium for the DRD2 Taq1 A1 genotypes was respected for the sample as a whole, and for each subsample. We observed that 42.9% of control subjects have at least one A1 allele, a frequency which is not significantly different from the one observed in the affected sample as a whole (39.1%), neither from patients with alcohol dependence (37.1%), patients with bipolar disorder (48.4%) nor patients with alcohol dependence and bipolar disorder (28.6%). The regression analysis based on the three variables (bipolar disorder, alcohol dependence and interaction between these two disorders) does not explain the presence of the A1 allele of the DRD2 gene. We thus found no evidence for a significant role of the A1 allele of the D2 dopamine receptor gene in the specific association between bipolar disorder and alcohol dependence in our sample.
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Affiliation(s)
- P Gorwood
- Hospital Louis Mourier (Service de Psychiatrie adulte du Professeur Adès). Colombes 92700, France
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23
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Ho LW, Furlong RA, Rubinsztein JS, Walsh C, Paykel ES, Rubinsztein DC. Genetic associations with clinical characteristics in bipolar affective disorder and recurrent unipolar depressive disorder. ACTA ACUST UNITED AC 2000. [DOI: 10.1002/(sici)1096-8628(20000207)96:1<36::aid-ajmg8>3.0.co;2-6] [Citation(s) in RCA: 73] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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24
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Bocchetta A, Piccardi MP, Palmas MA, Chillotti C, Oi A, Del Zompo M. Family-based association study between bipolar disorder andDRD2, DRD4, DAT, andSERT in Sardinia. ACTA ACUST UNITED AC 1999. [DOI: 10.1002/(sici)1096-8628(19991015)88:5<522::aid-ajmg16>3.0.co;2-m] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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Serretti A, Lilli R, Lorenzi C, Franchini L, Di Bella D, Catalano M, Smeraldi E. Dopamine receptor D2 and D4 genes, GABA(A) alpha-1 subunit genes and response to lithium prophylaxis in mood disorders. Psychiatry Res 1999; 87:7-19. [PMID: 10512150 DOI: 10.1016/s0165-1781(99)00056-6] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Lithium is an effective prophylactic agent in mood disorders, and genetic factors are likely to modulate individual susceptibility to lithium treatment. The aim of this study is to investigate the influence of dopamine receptor D2 (DRD2), D4 exon 3 (DRD4), and gamma-aminobutyric acid type A (GABA(A)) receptor alpha-1 subunit (GABRA1) gene variants on the efficacy of lithium prophylaxis in mood disorders. Patients with mood disorders (N = 125: bipolar subtype, n = 100; major depressive disorder subtype, n = 25) were followed prospectively for an average of 53 months and were typed for DRD2 (Ser311/Cys311: n = 121, VNTR: n = 63), DRD4 (n = 125) and GABRA1 (n = 61) variants using polymerase chain reaction (PCR) techniques. DRD2, DRD4 and GABRA1 variants were not associated with response to lithium. A trend was observed toward a better outcome of DRD4* 2/4 subjects, but it was due to only two subjects. Consideration of possible stratification effects like gender, polarity, family history, age at onset and duration of lithium treatment did not reveal any association either. DRD2, DRD4 and GABRA1 variants therefore do not appear to be associated with the outcome of lithium prophylaxis in mood disorders.
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Affiliation(s)
- A Serretti
- Istituto Scientifico Ospedale San Raffaele, Department of Neuropsychiatric Sciences, University of Milan School of Medicine, Italy.
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27
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Berrettini WH. Molecular linkage studies of bipolar disorder. DIALOGUES IN CLINICAL NEUROSCIENCE 1999; 1:12-21. [PMID: 22033545 PMCID: PMC3181563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 03/23/2024]
Abstract
Linkage studies have defined at least five bipolar (BP) disorder susceptibility loci that meet suggested guidelines for initial identification and subsequent confirmation. These loci, found on 18p11, 18q22, 21q21, 4p16, and Xq26, are targets for BP candidate gene investigations. Molecular dissection of expressed sequences for these regions is likely to yield specific BP susceptibility alleles in most cases, in all probability, these BP susceptibility alleles will be common in the general population, and, individually, will be neither necessary nor sufficient for manifestation syndrome. Additive or multiplicative oligogenic models involving several susceptibility loci appear most reasonable at present, it is hoped thai these BP susceptibility genes will increase understanding of many mysteries surrounding these disorders, including drug response, cycling patterns, age-of-onset, and modes of transmission.
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Affiliation(s)
- Wade H. Berrettini
- The department of Psychiatry and the Center for Neurobiology and Behavior, University of Pennsylvania, USA
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28
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Furlong RA, Rubinsztein JS, Ho L, Walsh C, Coleman TA, Muir WJ, Paykel ES, Blackwood DH, Rubinsztein DC. Analysis and metaanalysis of two polymorphisms within the tyrosine hydroxylase gene in bipolar and unipolar affective disorders. AMERICAN JOURNAL OF MEDICAL GENETICS 1999; 88:88-94. [PMID: 10050974 DOI: 10.1002/(sici)1096-8628(19990205)88:1<88::aid-ajmg16>3.0.co;2-j] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the synthesis of dopamine and noradrenaline. While positive associations between TH and bipolar affective disorder have been found in several studies, many studies have failed to reproduce these results. In order to clarify this situation, association studies of bipolar and unipolar affective disorder groups and metaanalyses of published data on the TH tetranucleotide repeat polymorphism were done. The association studies used the TH tetranucleotide repeat polymorphism in intron 1 and a PstI polymorphism at the 3' end of the gene. The study comprised 124 unrelated bipolar patients, 126 unipolar patients, and 242 controls. There was no significant association of either bipolar or unipolar affective disorder with the TH tetranucleotide repeat polymorphism. However, a weak association (chi2 = 3.946, 1 df, P = 0.047; odds ratio, allele 2 vs. allele 1 = 0.71 (95% CI, 0.51-0.996)) was observed in the unipolar sample with the TH-PstI polymorphism. Three metaanalyses of published data on the TH tetranucleotide repeat polymorphism in major affective disorder were performed: bipolar I + II vs. control using 583 cases and 745 controls; unipolar vs. control using 204 cases and 359 controls; and bipolar + unipolar vs. control using 846 cases and 823 controls. In each analysis there was no association of the TH tetranucleotide repeat polymorphism and affective disorder. These results do not support the tyrosine hydroxylase gene having a major role in the etiology of bipolar affective disorder. However, our data suggest that this locus should be examined in larger samples of unipolar affective disorder.
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Affiliation(s)
- R A Furlong
- Department of Medical Genetics, University of Cambridge, Addenbrooke's Hospital, UK
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29
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Savoye C, Laurent C, Amadeo S, Gheysen F, Leboyer M, Lejeune J, Zarifian E, Mallet J. No association between dopamine D1, D2, and D3 receptor genes and manic-depressive illness. Biol Psychiatry 1998; 44:644-7. [PMID: 9787891 DOI: 10.1016/s0006-3223(97)00441-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
BACKGROUND The dopaminergic receptor genes are candidate genes for manic-depressive illness (MDI). To test this putative involvement we used a case-control study on samples from the native population of the northwest part of France. METHODS Fifty patients for D1 and D2, 61 patients for D3, and 86-223 controls were tested. RESULTS No significant association was found between allelic frequencies or genotype counts and MDI, even when the data were pooled with those from published studies. CONCLUSIONS Single mutations of either of the studied receptor genes are not major determinants of MDI.
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Affiliation(s)
- C Savoye
- Service de Pédopsychiatrie, C.H.R.U. Clémenceau, Caen, France
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30
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Furlong RA, Coleman TA, Ho L, Rubinsztein JS, Walsh C, Paykel ES, Rubinsztein DC. No association of a functional polymorphism in the dopamine D2 receptor promoter region with bipolar or unipolar affective disorders. ACTA ACUST UNITED AC 1998. [DOI: 10.1002/(sici)1096-8628(19980907)81:5<385::aid-ajmg6>3.0.co;2-s] [Citation(s) in RCA: 25] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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31
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Bellivier F, Schürhoff F, Nosten-Bertrand M, Mallet J, Feingold J, Leboyer M. Methodological problems in meta-analysis of association studies between bipolar affective disorders and the tyrosine hydroxylase gene. AMERICAN JOURNAL OF MEDICAL GENETICS 1998; 81:349-52. [PMID: 9674984 DOI: 10.1002/(sici)1096-8628(19980710)81:4<349::aid-ajmg15>3.0.co;2-l] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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32
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Rossing MA. Genetic influences on smoking: candidate genes. ENVIRONMENTAL HEALTH PERSPECTIVES 1998; 106:231-238. [PMID: 9647893 PMCID: PMC1533105 DOI: 10.1289/ehp.98106231] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 05/22/2023]
Abstract
Twin studies consistently indicate important genetic influences on multiple aspects of smoking behavior, including both initiation and cessation; however, knowledge regarding the role of specific genes is extremely limited. Habit-forming actions of nicotine appear to be triggered primarily at nicotinic receptors on the cell bodies of dopaminergic neurons in the mesolimbic "reward" system of the brain, a region implicated in addiction to other substances including cocaine, opiates, and alcohol. Important aspects of the dopaminergic pathway include synthesis of dopamine in dopaminergic neurons, release of dopamine by presynaptic neurons, receptor activation of postsynaptic neurons, dopamine re-uptake by presynaptic neurons, and metabolism of released dopamine. Research examining the role of allelic variation in genes involved in these functions is being actively pursued with respect to addictive behavior as well as personality traits and psycho- and neuropathologic conditions and has implications for smoking research. In addition, genetic differences in nicotinic receptors or nicotine metabolism might reasonably be hypothesized to play a role in smoking addiction. A role of dopaminergic or other genes in smoking cessation is of particular potential importance, as research in this area may lead to the identification of subgroups of individuals for whom pharmacologic cessation aids may be most effective.
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Affiliation(s)
- M A Rossing
- Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle WA 98109, USA
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33
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Serretti A, Macciardi F, Verga M, Cusin C, Pedrini S, Smeraldi E. Tyrosine hydroxylase gene associated with depressive symptomatology in mood disorder. ACTA ACUST UNITED AC 1998. [DOI: 10.1002/(sici)1096-8628(19980328)81:2<127::aid-ajmg1>3.0.co;2-t] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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34
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Papadimitriou GN, Dikeos DG, Karadima G, Avramopoulos D, Daskalopoulou EG, Vassilopoulos D, Stefanis CN. Association between the GABAA receptor ?5 subunit gene locus (GABRA5) and bipolar affective disorder. ACTA ACUST UNITED AC 1998. [DOI: 10.1002/(sici)1096-8628(19980207)81:1<73::aid-ajmg14>3.0.co;2-t] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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35
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Malafosse A, Leboyer M, d'Amato T, Amadéo S, Abbar M, Campion D, Canseil O, Castelnau D, Gheysen F, Granger B, Henrikson B, Poirier MF, Sabaté O, Samolyk D, Feingold J, Mallet J. Manic depressive illness and tyrosine hydroxylase gene: linkage heterogeneity and association. Neurobiol Dis 1998; 4:337-49. [PMID: 9440122 DOI: 10.1006/nbdi.1997.0149] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Several studies have implicated the tyrosine hydroxylase (TH) locus within the 11p15 region in susceptibility to manic depressive illness (MDI). This possibility was further investigated by both parametric (lod score) and nonparametric (affected-pedigree-member and a case-control study) methods of analysis in 11 French MDI families and in a sample of 200 unrelated subjects. Both types of analyses corroborate the implication of this locus, and positive lod scores were obtained in two families, which most likely reflects genetic heterogeneity. Statistical analyses were also performed including available data from published reports. These analyses, which allowed for genetic heterogeneity, substantiated our findings. The combined maximum lod score for all the families studied was 3.68 at theta = 0.00 (number of families: 36) assuming heterogeneity (alpha = 15%, P = 0.01). Taken together these results converge to suggest that the risk factors for MDI lie in the 11p15 region with TH being the most likely candidate gene.
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Affiliation(s)
- A Malafosse
- CNRS UMR 9923, Hôpital Pitié Salpétrière, Paris, France
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36
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Turecki G, Rouleau GA, Mari J, Joober R, Morgan K. Lack of association between bipolar disorder and tyrosine hydroxylase: a meta-analysis. AMERICAN JOURNAL OF MEDICAL GENETICS 1997; 74:348-52. [PMID: 9259367 DOI: 10.1002/(sici)1096-8628(19970725)74:4<348::aid-ajmg2>3.0.co;2-l] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Tyrosine hydroxylase (TH) is a candidate gene extensively explored in several association studies of bipolar disorder (BD). However, because of conflicting results of independent studies and low statistical power of individual studies to detect small differences between cases and controls, reliable conclusions are difficult to formulate. A method to obtain more reliable conclusions about the involvement of the TH locus in the etiology of BD is meta-analysis. We undertook a meta-analysis of studies that investigated the association between BD and TH genetic markers. The studies were identified by means of computerized searches of several databases, and the scanning of review articles and the reference lists of the primary articles identified. More than 60 publications were reviewed, and 9 relevant articles were included in this meta-analysis, with an overall sample of 1,069 subjects (547 cases and 522 normal controls). The overall odds ratio (and confidence interval) based on combining the results of the studies was 1.02 (0.68-1.54). Test of the null hypothesis that the mean log odds ratio equals zero (chi2 = 0.11; 5 df; P > 0.05) indicated that there was no overall association between bipolar disorder and tyrosine hydroxylase.
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Affiliation(s)
- G Turecki
- Department of Neurology and Neuroscience, Centre for Research in Neuroscience, McGill University, Montreal, Canada.
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37
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Cavazzoni P, Alda M, Turecki G, Rouleau G, Grof E, Martin R, Duffy A, Grof P. Lithium-responsive affective disorders: no association with the tyrosine hydroxylase gene. Psychiatry Res 1996; 64:91-6. [PMID: 8912950 DOI: 10.1016/0165-1781(96)02888-0] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Family, adoption, and twin studies have demonstrated the involvement of genetic factors in the etiology of major affective disorders. In an attempt to identify the involved genes, several linkage and association studies have focused on the gene coding for tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis. The discrepant results to date could be explained by etiological heterogeneity, which may be substantially reduced by selecting patients according to lithium response. Therefore, we investigated 54 patients who had shown definite long-term response to lithium monotherapy in spite of a high risk of recurrence as indicated by the previous clinical course. All the subjects suffered from major affective disorder by Research Diagnostic Criteria (48 bipolar, 6 recurrent unipolar). They were compared to 94 population controls of similar ethnic background to test for association with a penta-allelic microsatellite marker found within the tyrosine hydroxylase gene. No significant differences in allele and genotype frequencies were observed between the two groups, providing further evidence against a major role for the tyrosine hydroxylase gene in the etiology of major affective disorders.
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Affiliation(s)
- P Cavazzoni
- Affective Disorders Service, University of Ottawa, Royal Ottawa Hospital, Canada
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