Susceptibility Locus For Bipolar Disorder Research Articles

Genetic Pathways and Functional Subnetworks for the Complex Nature of Bipolar Disorder in Genome-Wide Association Study.

Bipolar disorder is a complex psychiatric trait that is also recognized as a high substantial heritability from a worldwide distribution. The success in identifying susceptibility loci for bipolar disorder (BPD) has been limited due to its complex genetic architecture. Growing evidence from association studies including genome-wide association (GWA) studies points to the need of improved analytic strategies to pinpoint the missing heritability for BPD. More importantly, many studies indicate that BPD has a strong association with dementia. We conducted advanced pathway analytics strategies to investigate synergistic effects of multilocus within biologically functional pathways, and further demonstrated functional effects among proteins in subnetworks to examine mechanisms underlying the complex nature of bipolarity using a GWA dataset for BPD. We allowed bipolar susceptible loci to play a role that takes larger weights in pathway-based analytic approaches. Having significantly informative genes identified from enriched pathways, we further built function-specific subnetworks of protein interactions using MetaCore. The gene-wise scores (i.e., minimum p-value) were corrected for the gene-length, and the results were corrected for multiple tests using Benjamini and Hochberg’s method. We found 87 enriched pathways that are significant for BPD; of which 36 pathways were reported. Most of them are involved with several metabolic processes, neural systems, immune system, molecular transport, cellular communication, and signal transduction. Three significant and function-related subnetworks with multiple hotspots were reported to link with several Gene Ontology processes for BPD. Our comprehensive pathway-network frameworks demonstrated that the use of prior knowledge is promising to facilitate our understanding between complex psychiatric disorders (e.g., BPD) and dementia for the access to the connection and clinical implications, along with the development and progression of dementia.

Fine-mapping scan of bipolar disorder susceptibility loci in Latino pedigrees.

We previously identified bipolar disorder (BD) susceptibility loci on 8q24, 14q32, and 2q12-14 in a genome-wide nonparametric linkage screen in a Latino cohort. We now perform a fine mapping analysis using a dense map of additional SNPs to identify BD susceptibility genes within these regions. One thousand nine hundred and thirty-eight individuals with Latino ancestry (880 individuals with BD Type I or Schizoaffective, Bipolar Type) from 416 Latino pedigrees from the United States, Mexico, Costa Rica, and Guatemala were genotyped with 3,074 SNPs to provide dense coverage of the 8q24 (11.5 cM), 14q32 (7.5 cM), and 2q12-14 (6.5 cM) chromosomal loci. Single-marker association tests in the presence of linkage were performed using the LAMP software. The top linkage peak (rs7834818; LOD = 5.08, p = 3.30E - 5) and associated single marker (rs2280915, p = 2.70E - 12) were located within FBXO32 on 8q24. On chromosome 2, the top linkage peak (rs6750326; LOD = 5.06, p = 3.50E - 5) and associated single marker (rs11887088, p = 2.90E - 6) were located in intragenic regions near ACTR3 and DPP10. None of the additional markers in the region around chromosome 14q32 met significance levels for linkage or association. We identified six SNPs on 2q12-q14 and one SNP in FBXO32 on 8q24 that were significantly associated with BD in this Latino cohort.

A genome-wide association study identifies two novel susceptibility loci and trans population polygenicity associated with bipolar disorder

Genome-wide association studies (GWASs) have identified several susceptibility loci for bipolar disorder (BD) and shown that the genetic architecture of BD can be explained by polygenicity, with numerous variants contributing to BD. In the present GWAS (Phase I/II), which included 2964 BD and 61 887 control subjects from the Japanese population, we detected a novel susceptibility locus at 11q12.2 (rs28456, P=6.4 × 10−9), a region known to contain regulatory genes for plasma lipid levels (FADS1/2/3). A subsequent meta-analysis of Phase I/II and the Psychiatric GWAS Consortium for BD (PGC-BD) identified another novel BD gene, NFIX (Pbest=5.8 × 10−10), and supported three regions previously implicated in BD susceptibility: MAD1L1 (Pbest=1.9 × 10−9), TRANK1 (Pbest=2.1 × 10−9) and ODZ4 (Pbest=3.3 × 10−9). Polygenicity of BD within Japanese and trans-European-Japanese populations was assessed with risk profile score analysis. We detected higher scores in BD cases both within (Phase I/II) and across populations (Phase I/II and PGC-BD). These were defined by (1) Phase II as discovery and Phase I as target, or vice versa (for ‘within Japanese comparisons’, Pbest~10−29, R2~2%), and (2) European PGC-BD as discovery and Japanese BD (Phase I/II) as target (for ‘trans-European-Japanese comparison,’ Pbest~10−13, R2~0.27%). This ‘trans population’ effect was supported by estimation of the genetic correlation using the effect size based on each population (liability estimates~0.7). These results indicate that (1) two novel and three previously implicated loci are significantly associated with BD and that (2) BD ‘risk’ effect are shared between Japanese and European populations.

T29 - GSK-3b 50 T/C Polymorphism And Lithium Maintenance Treatment In Bipolar Disorder

Background Bipolar Disorder is a chronic debilitating mental illness requiring long term medications. Bipolar disorder also has heritability of 80%, thus probably indicating an underlying genetic etiology. Glycogen Synthase Kinase (GSK) is a serine/threonine kinase. GSK3-b is an essential element of the Wnt/beta-catenin pathway. GSK-3B gene has been mapped to chromosome 3q13.3, a potential susceptibility locus for bipolar disorder. GSK-3B 50 T/C single nucleotide polymorphism (SNP) falls into the effective promoter region (nt − 171 to + 29) of the GSK-3B gene and the presence of T allele is noted to increase the transcriptional activity. GSK-3B is also directly inhibited by Lithium which is widely used in the prophylaxis of Bipolar Disorder. Earlier Studies have also found a positive correlation between Mutant C allele carriers of 50 T/C SNP and better response to Lithium. Methods 441 patients with Diagnosis of Bipolar Disorder according to DSM-IV were recruited from all patients attending Outpatient Services of National Institute of Mental Health and Neurological Sciences (NIMHANS). The diagnosis was confirmed using Clinical Interview and MINI 5.0.0. Genotype analysis for 189 patients selected was done for GSK-3B -50 T/C using PCR-RFLP method. Treatment response has been assessed using “Retrospective Criteria of Long Term Treatment Response in Research Subjects with Bipolar Disorder” for 95 patients for whom NIMH life charts were available Results Of all the 441 patients who were selected for the study, demographic analysis was done with the mean age at onset being 21.40 years (SD- 6.940). Lifetime psychotic symptoms were noted among 377 subjects. The genotype Frequencies for the GSK-3B 50 T/C polymorphism CC-25.9%, TC-47.6%, TT-26.5% for 189 patients, did not deviate significantly from Hardy-Weinberg equilibrium. Of the patients who were C allele carriers (N=78) there were 14 subjects who were poor responders (score less than or equal 3) and 64 subjects who were good responders (score >3).However this difference was not significant(p>0.05,Spearman’s correlation p>0.05). No statistically significant correlation was found between GSK-3B 50 T/C SNP and the clinical parameters that were studied including age at onset(n=186), and presence of psychotic symptoms(n=186) (all p>0.05) Discussion The study did not duplicate the favorable response to Lithium among patients who carry C allele in GSK-3B 50T/C SNP using a well validated scale to assess lithium response like “Retrospective Criteria of Long Term Treatment Response in Research Subjects with Bipolar Disorder” scale probably owing to difference in the allelic frequencies in the studied population. In a previous study by Benedetti et al,2008 among 60 Caucasian subjects had CC- 5%, TC-40%, TT-55% which significantly varies with the frequencies noted in the studied population. The limitation being that study was under-powered to assess the allelic association and a larger study is being completed currently. The study though did not find any positive association of GSK-3B 50 T/C with other clinical parameters that were studied. No other previous studies have looked into the association between the studied SNP and clinical parameters of Bipolar Disorder in this population. We are also in the process of doing gene expression analysis from cell lines (lymphoblastoid, induced pluripotent) derived from patients with this SNP to obtain further insights into the mechanism of Lithium in bipolar disorder.

A comprehensive analysis of NDST3 for schizophrenia and bipolar disorder in Han Chinese.

A novel susceptibility locus (rs11098403) for schizophrenia and bipolar disorder (BD) was identified in an Ashkenazi Jewish population by a recent large-scale genome-wide association study. The rs11098403 is located in the vicinity of the gene encoding N-deacetylase/N-sulfotransferase (heparan glucosaminyl) 3, (NDST3). This study aimed to replicate the results in a Han Chinese population and then potentially extend these findings. We performed a two-stage study to investigate the association of NDST3 with the schizophrenia and BD risk in the Han Chinese. In stage 1, a total of 632 patients with schizophrenia, 654 patients with BD and 684 healthy controls were recruited from the Shanghai region. In stage 2, 522 schizophrenia patients and 547 normal subjects were enrolled from the Hangzhou region. Then, we conducted a meta-analysis based on the present literature. In stage 1, the single nucleotide polymorphism (SNP) rs11098403 showed a significant association with schizophrenia (corrected P=0.005). The frequency of the rs11098403 G allele was significantly lower among schizophrenia patients than among the controls (odds ratio (OR)=0.68, 95% confidence interval (CI): 0.55−0.84, corrected P=0.002). No significant difference was observed in individual SNP marker genotypes or allele distributions between the BD and control groups. In stage 2, the association of rs11098403 with schizophrenia could be validated (genotypic P=0.001 and allelic P=0.0003). After pooling all data from 1861 patients with schizophrenia and 2081 controls, we observed a significant association of the rs11098403 G allele with schizophrenia (Z=5.56, P<0.001), with an OR=0.70 (95% CI: 0.61−0.79). Then, we performed an expression quantitative trait loci analysis to investigate the functional effect of rs11098403 on NDST3 expression in the brain. We observed a significant association of rs11098403 with NDST3 expression in the hippocampus (P=0.027), although the significance did not survive after multiple testing correction. Our findings provided preliminary evidence that rs11098403 might modify the genetic risk of schizophrenia in the Han Chinese. Further investigations are warranted to identify the precise mechanism regulating brain NDST3 expression in the Han Chinese. These results would help to explain the pathophysiological mechanism of schizophrenia.

A genome-wide linkage scan of bipolar disorder in Latino families identifies susceptibility loci at 8q24 and 14q32.

A genome-wide nonparametric linkage screen was performed to localize Bipolar Disorder (BP) susceptibility loci in a sample of 3757 individuals of Latino ancestry. The sample included 963 individuals with BP phenotype (704 relative pairs) from 686 families recruited from the US, Mexico, Costa Rica, and Guatemala. Non-parametric analyses were performed over a 5 cM grid with an average genetic coverage of 0.67 cM. Multipoint analyses were conducted across the genome using non-parametric Kong & Cox LOD scores along with Sall statistics for all relative pairs. Suggestive and significant genome-wide thresholds were calculated based on 1000 simulations. Single-marker association tests in the presence of linkage were performed assuming a multiplicative model with a population prevalence of 2%. We identified two genome-wide significant susceptibly loci for BP at 8q24 and 14q32, and a third suggestive locus at 2q13-q14. Within these three linkage regions, the top associated single marker (rs1847694, P = 2.40 × 10(-5)) is located 195 Kb upstream of DPP10 in Chromosome 2. DPP10 is prominently expressed in brain neuronal populations, where it has been shown to bind and regulate Kv4-mediated A-type potassium channels. Taken together, these results provide additional evidence that 8q24, 14q32, and 2q13-q14 are susceptibly loci for BP and these regions may be involved in the pathogenesis of BP in the Latino population.

A genome-wide supported variant in CACNA1C influences hippocampal activation during episodic memory encoding and retrieval

The alpha 1C subunit of the L-type voltage-gated calcium channel (CACNA1C) gene is one of the best replicated susceptibility loci for bipolar disorder, schizophrenia and major depression. It is involved in learning, memory and brain plasticity. Genetic studies using functional magnetic resonance imaging (fMRI) reported evidence of association with the CACNA1C single nucleotide polymorphism rs1006737 with functional correlates of episodic memory encoding and retrieval, especially activations in the hippocampus. These results, however, are inconsistent with regard to the magnitude and directionality of effect. In the present study, brain activation was measured with fMRI during an episodic memory encoding and retrieval task using neutral faces in two independent samples of 94 and 111 healthy subjects, respectively. Within whole brain analyses, a main effect of genotype emerged mainly in the right hippocampus during encoding as well as retrieval within the first sample: Carriers of the minor allele (A) exhibited lower activations compared to G/G allele carriers. This effect could be replicated within the second sample, however, only for the retrieval condition. The results strengthen findings that rs1006737 is associated with neural systems related to memory processes in hippocampal regions which are detectable in healthy subjects.

Association of rs1006737 in CACNA1C with alterations in prefrontal activation and fronto‐hippocampal connectivity

Genome-wide association studies have identified the rs1006737 single nucleotide polymorphism (SNP) in the CACNA1C gene as a susceptibility locus for schizophrenia and bipolar disorder. On the neural systems level this association is explained by altered functioning of the dorsolateral prefrontal cortex (DLPFC) and the hippocampal formation (HF), brain regions also affected by mental illness. In the present study we investigated the association of rs1006737 genotype with prefrontal activation and fronto-hippocampal connectivity. We used functional magnetic resonance imaging to measure neural activation during an n-back working memory task in 94 healthy subjects. All subjects were genotyped for the SNP rs1006737. We tested associations of the rs1006737 genotype with changes in working-memory-related DLPFC activation and functional integration using a seed region functional connectivity approach. Rs1006737 genotype was associated with altered right-hemispheric DLPFC activation. The homozygous A (risk) group showed decreased activation compared to G-allele carriers. Further, the functional connectivity analysis revealed a positive association of fronto-hippocampal connectivity with rs1006737 A alleles. We did not replicate the previous findings of increased right DLPFC activation in CACNA1C rs1006737 A homozygotes. In fact, we found the opposite effect, thus questioning prefrontal inefficiency as rs1006737 genotype-related intermediate phenotype. On the other hand, our results indicate that alterations in the functional coupling between the prefrontal cortex and the medial temporal lobe could represent a neural system phenotype that is mediated by CACNA1C rs1006737 and other genetic susceptibility loci for schizophrenia and bipolar disorder.

Identifying bipolar disorder susceptibility loci in a densely affected pedigree

Identifying bipolar disorder susceptibility loci in a densely affected pedigree

Assessment of relatedness between neurocan gene as bipolar disorder susceptibility locus and schizophrenia

Large scale genetic association meta-analyses showed that neurocan (NCAN) gene polymorphism rs1064395 is susceptibility locus for bipolar disorder. These studies also included patients with bipolar disorder originated from Bosnia and Herzegovina. Followed by theory of shared genetic elements between bipolar disorder and schizophrenia susceptibility, other studies explored several genetic factors with schizophrenia vulnerability as well. In this work, authors investigated the association between previously confirmed bipolar disorder genetic risk factor- neurocan with schizophrenia in a population sample of Bosnia and Herzegovina. Ethical aspects of this research were assessed by Ethics Committee of Clinical Center University of Sarajevo. Blood samples for DNA extraction were taken from the total of 86 patients and healthy individuals who previously signed informed consent. Genotyping for rs 1064395 was done using direct sequencing method. A case-control analysis of common genetic polymorphism within neurocan gene and schizophrenia status in a consecutively sampled patient cohort have been done using Fisher-exact test with odds-ratio calculation. No statistically significant allele and genotype association with disease status was found (p>0.05). Our finding supports the fact that large-scale genetic association studies approach need to be employed when detecting the variants with small additive effect in phenotypes with complex ethiology.

Tests of linkage and allelic association between markers in the 1p36 PRKCZ (Protein Kinase C Zeta) gene region and bipolar affective disorder

Three linkage studies of families with multiple cases of bipolar disorder and/or unipolar affective disorder have confirmed the involvement of the chromosome 1p36 region in the etiology of affective disorders with LOD scores of 2.7, 3.6, and 3.97. We investigated the protein kinase C zeta gene (PRKCZ) as a susceptibility locus for bipolar disorder because it is highly brain expressed and is localized close to the marker D1S243 which was linked to affective disorder in a single large UCL bipolar disorder family with a LOD of 3.1. PRKCZ encodes an unusual type of protein kinase which affects axonal differentiation through Wnt-signaling. We genotyped four microsatellite markers and nine single nucleotide polymorphism (SNP) markers within or near the PRKCZ gene in the UCL case-control sample of 600 bipolar disorder patients and up to 605 supernormal controls. Markers D1S243 and rs3128396 were significantly associated with bipolar disorder (empirical P = 0.037 and P = 0.040, respectively). We also included data from eight SNPs which were genotyped as part of our GWA study on bipolar disorder for association analysis. Tests of haplotypic association found that a haplotype block comprising markers rs3128296, rs2503706, and rs3128309 was associated with bipolar disorder (empirical P = 0.004). A previous linkage study had shown greater evidence for linkage within female cases compared to males. Therefore, to assess if the association was sex-specific, we performed a female-only allelic-association analysis, which resulted in SNPs rs3128296 and rs3128309 becoming associated with bipolar disorder (P = 0.004 and P = 0.016, respectively). PRKCZ may play a role in susceptibility to bipolar affective disorder.

The effect of genome-wide supported variants in CACNA1C and NRGN on functional correlates of episodic memory encoding and retrieval

Objective: Genetic studies implicated variation in NRGN and CACNA1C as a susceptibility locus for bipolar disorder, schizophrenia and major depression. Method: We investigated the influence of the CACNA1C single nucleotide polymorphism (SNP) rs1006737 and rs12807809 of NRGN on functional correlates of episodic memory encoding and retrieval. Brain activation was measured with functional magnetic resonance imaging (fMRI) during an episodic memory encoding and retrieval task in 94 healthy individuals who were genotyped for both variants. Results: In the fMRI experiment, while there were no differences in behavioral performance, neural activation-mainly in the superior frontal gyrus and inferior and middle temporal gyrus – was associated with CACNA1C genotype during encoding and retrieval. For NRGN, differential brain activation was evident in the anterior cingulate cortex for the encoding and posterior cingulate regions during retrieval. Conclusions: Our data suggest that both variants influence the neural systems related to memory processes: Brain activations during encoding and retrieval of new material might compensate for otherwise insufficient performance. These findings are in line with results of imaging studies in affective disorder and schizophrenia. It may explain some of the brain activation variation found in these disorders and healthy subjects.

Genome-Wide Searches for Bipolar Disorder Genes

Whole-genome linkage and association studies of bipolar disorder are beginning to provide some compelling evidence for the involvement of several chromosomal regions and susceptibility genes in the pathogenesis of bipolar disorder. Developments in genotyping technology and efforts to combine data from different studies have helped in identifying chromosomes 6q16-q25, 13q, and 16p12 as probable susceptibility loci for bipolar disorder and confirmed CACNA1C and ANK3 as susceptibility genes for bipolar disorder. However, a lack of replication is still apparent in the literature. New studies focusing on copy number variants as well as new analytical approaches utilizing pathway analysis offer a new direction in the study of the genetics of bipolar disorder.

Genetic variations in FOXO3A are associated with Bipolar Disorder without confering vulnerability for suicidal behavior

Genetic variation plays an important role in Bipolar Disorder (BD) and suicide susceptibility. However, little is known about the genetic influence on the risk of suicide, particularly in BD patients. Since FOXO3A plays a role in distinct mood-relevant behavioral processes, this gene could be a novel gene candidate for BD. Thus, we investigated whether FOXO3A polymorphisms are associated with BD and suicidal behavior in BD patients. TaqMan genotyping was used to detect FOXO3A SNPs in 273 BD patients and 264 control subjects. Three SNPs (rs1536057, rs2802292 and rs1935952) were associated with BD, but none was positively linked with suicidal behavior. A systematic evaluation within the whole FOXO3A gene and drug treatment in patients was not performed. These data suggest that FOXO3A is a novel susceptibility locus for BD, but not for suicidal behavior in BD patients. These results may contribute to a better understanding of the BD genetics.

Genome‐wide association analysis of age at onset and psychotic symptoms in bipolar disorder

Genome-wide association studies (GWAS) have identified several susceptibility loci for bipolar disorder (BP), most notably ANK3. However, most of the inherited risk for BP remains unexplained. One reason for the limited success may be the genetic heterogeneity of BP. Clinical sub-phenotypes of BP may identify more etiologically homogeneous subsets of patients, which can be studied with increased power to detect genetic variation. Here, we report on a mega-analysis of two widely studied sub-phenotypes of BP, age at onset and psychotic symptoms, which are familial and clinically significant. We combined data from three GWAS: NIMH Bipolar Disorder Genetic Association Information Network (GAIN-BP), NIMH Bipolar Disorder Genome Study (BiGS), and a German sample. The combined sample consisted of 2,836 BP cases with information on sub-phenotypes and 2,744 controls. Imputation was performed, resulting in 2.3 million SNPs available for analysis. No SNP reached genome-wide significance for either sub-phenotype. In addition, no SNP reached genome-wide significance in a meta-analysis with an independent replication sample. We had 80% power to detect associations with a common SNP at an OR of 1.6 for psychotic symptoms and a mean difference of 1.8 years in age at onset. Age at onset and psychotic symptoms in BP may be influenced by many genes of smaller effect sizes or other variants not measured well by SNP arrays, such as rare alleles.

Most genome-wide significant susceptibility loci for schizophrenia and bipolar disorder reported to date cross-traditional diagnostic boundaries

Recent findings from genetic epidemiology and from genome-wide association studies point strongly to a partial overlap in the genes that contribute susceptibility to schizophrenia and bipolar disorder (BD). Previous data have also directly implicated one of the best supported schizophrenia-associated loci, zinc finger binding protein 804A (ZNF804A), as showing trans-disorder effects, and the same is true for one of the best supported bipolar loci, calcium channel, voltage-dependent, L type, alpha 1C subunit (CACNA1C) which has also been associated with schizophrenia. We have undertaken a cross-phenotype study based upon the remaining variants that show genome-wide evidence for association in large schizophrenia and BD meta-analyses. These comprise in schizophrenia, SNPs in or in the vicinity of transcription factor 4 (TCF4), neurogranin (NRGN) and an extended region covering the MHC locus on chromosome 6. For BD, the strongly supported variants are in the vicinity of ankyrin 3, node of Ranvier (ANK3) and polybromo-1 (PBRM1). Using data sets entirely independent of their original discoveries, we observed strong evidence that the PBRM1 locus is also associated with schizophrenia (P = 0.00015) and nominally significant evidence (P < 0.05) that the NRGN and the extended MHC region are associated with BD. Moreover, considering this highly restricted set of loci as a group, the evidence for trans-disorder effects is compelling (P = 4.7 × 10(-5)). Including earlier reported data for trans-disorder effects for ZNF804A and CACNA1C, six out of eight of the most robustly associated loci for either disorder show trans-disorder effects.

A new susceptibility locus for bipolar affective disorder in PAR1 on Xp22.3/Yp11.3

We present the findings of a linkage study of bipolar affective disorder (BPAD) that involve the pseudoautosomal region 1 of the human sex chromosomes. We analyzed a substantial subset of pedigrees (89 families of German and Spanish origin; 661 participants; 298 affected individuals) from the large collection of BPAD-affected families with which a genomewide linkage analysis was previously performed and where the pseudoautosomal regions were poorly covered. Nonparametric linkage (Z(lr)) scores were calculated. The highest Z(lr) scores were obtained on Xp22.3/Yp11.3 in the Spanish subsample (DXS1071; Z(lr) = 3.54, P(empirical) = 0.0009 for the broad definition of affection sttuts; Z(lr) = 2.63, P(empirical) = 0.0129 for the medium definition of affection status; Z(lr) = 2.12, P(empirical) = 0.0429 for the narrow definition of affection status). Empirical P-values are adjusted using the Bonferroni correction to account for the testing of three affection status definitions. This region has not drawn much attention in previous linkage studies of BPAD. On the basis of these results, Xp22.3/Yp11.3 should now be considered a candidate region for BPAD.

Exacerbation of Darier Disease by Lithium Carbonate

Darier disease (DD) and Hailey-Hailey disease (HHD) are rare autosomal dominantly inherited genodermatoses with mutations in the respective genes, ATP2A2 and ATP2C1, that encode the respective calcium adenosine triphosphatases SERCA2 and PMRI/SPCA1. Lithium is an effective therapy used in psychiatry as prophylaxis against recurrent mania and to treat acute schizoaffective, impulsive, and alcoholic disorders. We discuss a patient with DD who claimed that her skin condition had flared after she was administered lithium therapy for bipolar disorder. DD may flare after lithium therapy, an association that has rarely been reported. Not uncommonly, DD has been observed to coexist with affective disorders, with reports of the bipolar disorder susceptibility locus cosegregating with a separate DD gene. A mechanism by which lithium worsens disease has recently been studied in rats. DD's coexistence with affective disorders and the mechanisms by which lithium may cause exacerbation of DD and HHD are reviewed.

Meta-analysis of genome-wide association data identifies a risk locus for major mood disorders on 3p21.1

The major mood disorders, which include bipolar disorder (BD) and major depressive disorder (MDD), are substantially heritable, but few risk loci have been identified. We performed a meta-analysis of 5 major mood disorder case-control samples, including over 13,600 unique individuals genotyped with approximately 500,000 to 1 million single nucleotide polymorphism (SNP) markers on high-density arrays. Allele-wise association results were meta-analyzed with a method that weights results by sample size. We found genome-wide significant evidence that SNPs in a region of chromosome 3p21.1were associated with major mood disorders. The SNP rs2251219 returned the smallest meta-analysis p-value, 3.63 × 10−8, with a pooled odds ratio of 0.87. Supportive results were observed in 2 out of 3 independent samples tested in a replication study. These results implicate one or more genes in this region in the etiology of major mood disorders and suggest that BD and MDD share genetic risk factors.

Association between the serotonin 2A receptor gene and bipolar affective disorder in an Australian cohort

The serotonin 2A receptor gene (HTR2A) is involved in serotonergic neurotransmission, and has been targeted as a functional candidate for mood disorders because of the extensive support for the involvement of serotonin in mood regulation. We previously reported linkage evidence for a bipolar affective disorder susceptibility locus on chromosome 13q, which harbours HTR2A, thus making the gene both a positional and functional candidate. We assessed HTR2A for association in an Australian bipolar disorder case-control cohort. Single nucleotide polymorphisms (SNPs) were selected across HTR2A exons and introns, and were investigated for association in an Australian cohort of 218 cases and 166 healthy controls. SNP haplotypes were also examined for association. Significant association of rs2224721 (P = 0.02) and borderline significance of rs1923886 (P = 0.05) were observed. The former remained significant after multiple testing corrections using the rough False Discovery Rate method, but did not exceed the more conservative Bonferroni's correction threshold. Haplotype association analysis suggests that the haplotype CCGCA (at SNPs rs3125, rs6314, rs1923886, rs2224721 and rs2770296) is protective against bipolar disorder (P = 0.021, odds ratio 0.63) and the rarer haplotype CCACG confers risk to the disorder (P = 0.0065, odds ratio 3.08). We found that HTR2A is associated with bipolar disorder. The HTR2A gene should not be excluded as a potential susceptibility gene for bipolar disorder despite a number of conflicting association results.