Article

Molecular genetics of bipolar disorder

Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202-4887, USA.
Genes Brain and Behavior (Impact Factor: 3.66). 03/2006; 5(1):85-95. DOI: 10.1111/j.1601-183X.2005.00138.x
Source: PubMed

ABSTRACT

Bipolar disorder (BPD) is an often devastating illness characterized by extreme mood dysregulation. Although family, twin and adoption studies consistently indicate a strong genetic component, specific genes that contribute to the illness remain unclear. This study gives an overview of linkage studies of BPD, concluding that the regions with the best evidence for linkage include areas on chromosomes 2p, 4p, 4q, 6q, 8q, 11p, 12q, 13q, 16p, 16q, 18p, 18q, 21q, 22q and Xq. Association studies are summarized, which support a possible role for numerous candidate genes in BPD including COMT, DAT, HTR4, DRD4, DRD2, HTR2A, 5-HTT, the G72/G30 complex, DISC1, P2RX7, MAOA and BDNF. Animal models related to bipolar illness are also reviewed, with special attention paid to those with clear genetic implications. We conclude with suggestions for strategies that may help clarify the genetic bases of this complex illness.

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    • "Several dysfunctions of the serotonin pathway occurring at the molecular-signaling-neuronal firing level in several brain regions have been correlated with both diseases. Furthermore, several genome wide association studies and/or copy number variation studies have investigated correlations between individual genes and psycho-pathogenesis and provided strong support for shared genetic risk across the diseases (Hayden and Nurnberger, 2006; Craddock and Sklar, 2013; Giusti-Rodríguez and Sullivan, 2013). The dysfunction of serotonin pathway was potentially linked with SZ phenotype, when lysergic acid diethylamide (LSD), mescalin and psilocybin were observed that could cause various symptoms resembling SZ (such as hallucinations, altered cognition, delusions, paranoia) in sequences and the single nucleotide polymorphisms, SNPs). "
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    ABSTRACT: Serotonin is a neurotransmitter that plays a predominant role in mood regulation. The importance of the serotonin pathway in controlling behavior and mental status is well recognized. All the serotonin elements - serotonin receptors, serotonin transporter, tryptophan hydroxylase and monoamine oxidase proteins - can show alterations in terms of mRNA or protein levels and protein sequence, in schizophrenia and bipolar disorder. Additionally, when examining the genes sequences of all serotonin elements, several single nucleotide polymorphisms (SNPs) have been found to be more prevalent in schizophrenic or bipolar patients than in healthy individuals. Several of these alterations have been associated either with different phenotypes between patients and healthy individuals or with the response of psychiatric patients to the treatment with atypical antipsychotics. The complex pattern of genetic diversity within the serotonin pathway hampers efforts to identify the key variations contributing to an individual's susceptibility to the disease. In this review article, we summarize all genetic alterations found across the serotonin pathway, we provide information on whether and how they affect schizophrenia or bipolar disorder phenotypes, and, on the contribution of familial relationships on their detection frequencies. Furthermore, we provide evidence on whether and how specific gene polymorphisms affect the outcome of schizophrenic or bipolar patients of different ethnic groups, in response to treatment with atypical antipsychotics. All data are discussed thoroughly, providing prospective for future studies.
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    • "However, there are no studies in human genetics of T2D or MetS. The MC1R genetic locus 16q24 is linked to bipolar disorder,61,62 T2D nephropathy,63 and left ventricular thickness in the setting of MetS.64 "
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    • "The gene thus had been proposed to be implicated in anxiety and cognitive function [54]. Several studies have shown that HTR4 polymorphisms could predispose to attention deficit hyperactivity disorder (ADHD) and bipolar disorder [55], [56], while AUD was strongly associated with both ADHD and bipolar disorder [57], [58], [59], [60]. Because the 5-HT4 receptor can modulate release of neurotransmitters (acetylcholine, dopamine, serotonin, and GABA) [61], [62], it is possible that the genetic polymorphism of HTR4 influences the interaction of neurotransmitters in the pathogenesis of AUD, which result in the association of AUD with polymorphisms of HTR4. "
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    ABSTRACT: Studies of linkage and association in various ethnic populations have revealed many predisposing genes of multiple neurotransmitter systems for alcohol use disorders (AUD). However, evidence often is contradictory regarding the contribution of most candidate genes to the susceptibility of AUD. We, therefore, performed a case-control study to investigate the possible associations of genes selected from multiple neurotransmitter systems with AUD in a homogeneous Tibetan community population in China. AUD cases (N = 281) with an alcohol use disorder identification test (AUDIT) score ≥10, as well as healthy controls (N = 277) with an AUDIT score ≤5, were recruited. All participants were genotyped for 366 single nucleotide polymorphisms (SNPs) of 34 genes selected from those involved in neurotransmitter systems. Association analyses were performed using PLINK version 1.07 software. Allelic analyses before adjustment for multiple tests showed that 15 polymorphisms within seven genes were associated with AUD (p<0.05). After adjustment for the number of SNPs genotyped within each gene, only the association of a single marker (rs10044881) in HTR4 remained statistically significant. Haplotype analysis for two SNPs in HTR4 (rs17777298 and rs10044881) showed that the haplotype AG was significantly associated with the protective effect for AUD. In conclusion, the present study discovered that the HTR4 gene may play a marked role in the pathogenesis of AUD. In addition, this Tibetan population sample marginally replicated previous evidence regarding the associations of six genes in AUD.
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