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


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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    • "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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    ABSTRACT: Depression, type 2 diabetes (T2D), and metabolic syndrome (MetS) are often comorbid. Depression per se increases the risk for T2D by 60%. This risk is not accounted for by the use of antidepressant therapy. Stress causes hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis, by triggering the hypothalamic corticotropin-releasing hormone (CRH) secretion, which stimulates the anterior pituitary to release the adrenocorticotropin hormone (ACTH), which causes the adrenal secretion of cortisol. Depression is associated with an increased level of cortisol, and CRH and ACTH at inappropriately "normal" levels, that is too high compared to their expected lower levels due to cortisol negative feedback. T2D and MetS are also associated with hypercortisolism. High levels of cortisol can impair mood as well as cause hyperglycemia and insulin resistance and other traits typical of T2D and MetS. We hypothesize that HPA axis hyperactivation may be due to variants in the genes of the CRH receptors (CRHR1, CRHR2), corticotropin receptors (or melanocortin receptors, MC1R-MC5R), glucocorticoid receptor (NR3C1), mineralocorticoid receptor (NR3C2), and of the FK506 binding protein 51 (FKBP5), and that these variants may be partially responsible for the clinical association of depression, T2D and MetS. In this review, we will focus on the correlation of stress, HPA axis hyperactivation, and the possible genetic role of the CRHR1, CRHR2, MCR1-5, NR3C1, and NR3C2 receptors and FKBP5 in the susceptibility to the comorbidity of depression, T2D, and MetS. New studies are needed to confirm the hypothesized role of these genes in the clinical association of depression, T2D, and MetS.
    The Application of Clinical Genetics 04/2014; 7:43-53. DOI:10.2147/TACG.S39993
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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.
    PLoS ONE 11/2013; 8(11):e80206. DOI:10.1371/journal.pone.0080206 · 3.23 Impact Factor
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    • "Family and epidemiological studies have demonstrated a strong genetic contribution to the risk for BP (Smoller and Finn 2003), suggesting that studying the gene(s) in patients with BP may help researchers and clinicians not only understand the pathophysiology of BP but also the mechanism of pharmacological treatments. However, specific genes for BP have yet to be identified (Farmer et al. 2007; Hayden and Nurnberger 2006). As with other complex disorders, the difficulty of identifying BP-specific gene(s) stems from the etiological heterogeneity of BP and small phenotypic effect resulting from individual genetic variants (Kremeyer et al. 2006). "
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    ABSTRACT: There is increasing evidence supporting the relationship between bipolar disorder (BP) and neurotrophin. The present study investigated the relationship between neurotrophic tyrosine kinase receptor type 2 (NTRK2) gene polymorphisms and bipolar I disorder (BP I) susceptibility and treatment response to mood stabilizers (lithium or valproate). Two-hundred eighty-four patients who met the DSM-IV criteria for BP I and 295 matched healthy controls were enrolled into this study. TaqMan® SNP genotyping assays were applied to genotype three NTRK2 gene polymorphisms (rs2769605, rs1565445, rs1387923). Our study showed a significant allelic association between NTRK2 gene polymorphism rs2769605 and treatment response to mood stabilizers in BP I patients (t = -2.53, P = 0.01). However, no significant association between NTRK2 gene polymorphisms and BP I susceptibility was observed after correcting for multiple comparisons. The results suggest that the NTRK2 gene polymorphism likely plays an essential role in treatment response to mood stabilizers in Han Chinese BP I patients.
    Journal of Molecular Neuroscience 01/2013; 50(2). DOI:10.1007/s12031-013-9956-0 · 2.34 Impact Factor
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