Candidate Gene For Bipolar Disorder Research Articles

Identification of the role of immune-related genes in the diagnosis of bipolar disorder with metabolic syndrome through machine learning and comprehensive bioinformatics analysis.

Bipolar disorder and metabolic syndrome are both associated with the expression of immune disorders. The current study aims to find the effective diagnostic candidate genes for bipolar affective disorder with metabolic syndrome. A validation data set of bipolar disorder and metabolic syndrome was provided by the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were found utilizing the Limma package, followed by weighted gene co-expression network analysis (WGCNA). Further analyses were performed to identify the key immune-related center genes through function enrichment analysis, followed by machine learning-based techniques for the construction of protein-protein interaction (PPI) network and identification of the Least Absolute Shrinkage and Selection Operator (LASSO) and Random Forest (RF). The receiver operating characteristic (ROC) curve was plotted to diagnose bipolar affective disorder with metabolic syndrome. To investigate the immune cell imbalance in bipolar disorder, the infiltration of the immune cells was developed. There were 2,289 DEGs in bipolar disorder, and 691 module genes in metabolic syndrome were identified. The DEGs of bipolar disorder and metabolic syndrome module genes crossed into 129 genes, so a total of 5 candidate genes were finally selected through machine learning. The ROC curve results-based assessment of the diagnostic value was done. These results suggest that these candidate genes have high diagnostic value. Potential candidate genes for bipolar disorder with metabolic syndrome were found in 5 candidate genes (AP1G2, C1orf54, DMAC2L, RABEPK and ZFAND5), all of which have diagnostic significance.

An integrative analysis of genome-wide association study and regulatory SNP annotation datasets identified candidate genes for bipolar disorder

BackgroundBipolar disorder (BD) is a complex mood disorder. The genetic mechanism of BD remains largely unknown.MethodsWe conducted an integrative analysis of genome-wide association study (GWAS) and regulatory SNP (rSNP) annotation datasets, including transcription factor binding regions (TFBRs), chromatin interactive regions (CIRs), mature microRNA regions (miRNAs), long non-coding RNA regions (lncRNAs), topologically associated domains (TADs) and circular RNAs (circRNAs). Firstly, GWAS dataset 1 of BD (including 20,352 cases and 31,358 controls) and GWAS dataset 2 of BD (including 7481 BD patients and 9250 controls) were integrated with rSNP annotation database to obtain BD associated SNP regulatory elements and SNP regulatory element-target gene (E–G) pairs, respectively. Secondly, a comparative analysis of the two datasets results was conducted to identify the common rSNPs and also their target genes. Then, gene sets enrichment analysis (FUMA GWAS) and HumanNet-XC analysis were conducted to explore the functional relevance of identified target genes with BD.ResultsAfter the integrative analysis, we identified 52 TFBRs target genes, 44 TADs target genes, 55 CIRs target genes and 21 lncRNAs target genes for BD, such as ITIH4 (Pdataset1 = 6.68 × 10−8, Pdataset2 = 6.64 × 10−7), ITIH3 (Pdataset1 = 1.09 × 10−8, Pdataset2 = 2.00 × 10−7), SYNE1 (Pdataset1 = 1.80 × 10−6, Pdataset2 = 4.33 × 10−9) and OPRM1 (Pdataset1 = 1.80 × 10−6, Pdataset2 = 4.33 × 10−9).ConclusionWe conducted a large-scale integrative analysis of GWAS and 6 common rSNP information datasets to explore the potential roles of rSNPs in the genetic mechanism of BD. We identified multiple candidate genes for BD, supporting the importance of rSNP in the development of BD.

Exome sequencing of a large family identifies potential candidate genes contributing risk to bipolar disorder

Bipolar disorder is a mental illness with lifetime prevalence of about 1%. Previous genetic studies have identified multiple chromosomal linkage regions and candidate genes that might be associated with bipolar disorder. The present study aimed to identify potential susceptibility variants for bipolar disorder using 6 related case samples from a four-generation family. A combination of exome sequencing and linkage analysis was performed to identify potential susceptibility variants for bipolar disorder. Our study identified a list of five potential candidate genes for bipolar disorder. Among these five genes, GRID1(Glutamate Receptor Delta-1 Subunit), which was previously reported to be associated with several psychiatric disorders and brain related traits, is particularly interesting. Variants with functional significance in this gene were identified from two cousins in our bipolar disorder pedigree. Our findings suggest a potential role for these genes and the related rare variants in the onset and development of bipolar disorder in this one family. Additional research is needed to replicate these findings and evaluate their patho-biological significance.

The COMT Val158Met Polymorphism Is Associated With Response to Add-on Dextromethorphan Treatment in Bipolar Disorder.

We previously conducted a randomized, double-blind, controlled, 12-week study evaluating the effect of add-on dextromethorphan (DM), a noncompetitive N-methyl-D-aspartate receptor antagonist, on patients with bipolar disorder (BD) treated using valproate (VPA), which showed negative clinical differences. The genetic variation between each individual may be responsible for interindividual differences. The catechol-O-methyltransferase (COMT) gene has been a candidate gene for BD. In the current study, we investigated whether the COMT Val158Met polymorphism predicts treatment response to VPA + add-on DM and to VPA + placebo. Patients with BD (n = 309) undergoing regular VPA treatments were randomly assigned to groups given either add-on DM (30 mg/d) (n = 102), DM (60 mg/d) (n = 101), or placebo (n = 106) for 12 weeks. The Hamilton Depression Rating Scale and Young Mania Rating Scale were used to evaluate clinical response during weeks 0, 1, 2, 4, 8, and 12. The genotypes of the COMT Val158Met polymorphism were determined using polymerase chain reaction plus restriction fragment length polymorphism analysis. To adjust for within-subject dependence over repeated assessments, multiple linear regression with generalized estimating equation methods was used. When stratified by the COMT Val158Met genotypes, significantly greater decreases in Hamilton Depression Rating Scale scores were found in the VPA + DM (30 mg/d) group in patients with the Val/Met genotype (P = 0.008). We conclude that the COMT Val158Met polymorphism may influence responses to DM (30 mg/d) by decreasing depressive symptoms in BD patients.

PS44. Funcional analysis of EHD1, a new candidate gene for bipolar disorder.

PS44. Funcional analysis of EHD1, a new candidate gene for bipolar disorder.

The ANK3 gene and facial affect processing: An ERP study.

ANK3 is one of the most promising candidate genes for bipolar disorder (BD). A polymorphism (rs10994336) within the ANK3 gene has been associated with BD in at least three genome-wide association studies of BD [McGuffin et al., 2003; Kieseppä, 2004; Edvardsen et al., 2008]. Because facial affect processing is disrupted in patients with BD, the current study aimed to explore whether the BD risk alleles are associated with the N170, an early event-related potential (ERP) component related to facial affect processing. We collected data from two independent samples of healthy individuals (Ns = 83 and 82, respectively) to test the association between rs10994336 and an early event-related potential (ERP) component (N170) that is sensitive to facial affect processing. Repeated-measures analysis of covariance in both samples consistently revealed significant main effects of rs10994336 genotype (Sample I: F (1, 72) = 7.24, P = 0.009; Sample II: F (1, 69) = 11.81, P = 0.001), but no significant interaction of genotype × electrodes (Ps > 0.05) or genotype × emotional conditions (Ps > 0.05). These results suggested that rs10994336 was linked to early ERP component reflecting facial structural encoding during facial affect processing. These results shed new light on the brain mechanism of this risk SNP and associated disorders such as BD. © 2016 Wiley Periodicals, Inc.

Investigation of manic and euthymic episodes identifies state- and trait-specific gene expression and STAB1 as a new candidate gene for bipolar disorder.

Bipolar disorder (BD) is a highly heritable psychiatric disease characterized by recurrent episodes of mania and depression. To identify new BD genes and pathways, the present study employed a three-step approach. First, gene-expression profiles of BD patients were assessed during both a manic and an euthymic phase. These profiles were compared intra-individually and with the gene-expression profiles of controls. Second, those differentially expressed genes that were considered potential trait markers of BD were validated using data from the Psychiatric Genomics Consortiums' genome-wide association study (GWAS) of BD. Third, the implicated molecular mechanisms were investigated using pathway analytical methods. In the present patients, this novel approach identified: (i) sets of differentially expressed genes specific to mania and euthymia; and (ii) a set of differentially expressed genes that were common to both mood states. In the GWAS data integration analysis, one gene (STAB1) remained significant (P=1.9 × 10−4) after adjustment for multiple testing. STAB1 is located in close proximity to PBMR1 and the NEK4-ITIH1-ITIH3-ITIH4 region, which are the top findings from GWAS meta-analyses of mood disorder, and a combined BD and schizophrenia data set. Pathway analyses in the mania versus control comparison revealed three distinct clusters of pathways tagging molecular mechanisms implicated in BD, for example, energy metabolism, inflammation and the ubiquitin proteasome system. The present findings suggest that STAB1 is a new and highly promising candidate gene in this region. The combining of gene expression and GWAS data may provide valuable insights into the biological mechanisms of BD.

Analysis of t(9;17)(q33.2;q25.3) chromosomal breakpoint regions and genetic association reveals novel candidate genes for bipolar disorder.

Breakpoints of chromosomal abnormalities facilitate identification of novel candidate genes for psychiatric disorders. Genome-wide significant evidence supports the linkage between chromosome 17q25.3 and bipolar disorder (BD). Co-segregation of translocation t(9;17)(q33.2;q25.3) with psychiatric disorders has been reported. We aimed to narrow down these chromosomal breakpoint regions and to investigate the associations between single nucleotide polymorphisms within these regions and BD as well as schizophrenia (SZ) in large genome-wide association study samples. We cross-linked Danish psychiatric and cytogenetic case registers to identify an individual with both t(9;17)(q33.2;q25.3) and BD. Fluorescent in situ hybridization was employed to map the chromosomal breakpoint regions of this proband. We accessed the Psychiatric Genomics Consortium BD (n=16,731) and SZ (n=21,856) data. Genetic associations between these disorders and single nucleotide polymorphisms within these breakpoint regions were analysed by BioQ, FORGE, and RegulomeDB programmes. Four protein-coding genes [coding for (endonuclease V (ENDOV), neuronal pentraxin I (NPTX1), ring finger protein 213 (RNF213), and regulatory-associated protein of mammalian target of rapamycin (mTOR) (RPTOR)] were found to be located within the 17q25.3 breakpoint region. NPTX1 was significantly associated with BD (p=0.004), while ENDOV was significantly associated with SZ (p=0.0075) after Bonferroni correction. Prior linkage evidence and our findings suggest NPTX1 as a novel candidate gene for BD.

Genetic risk prediction and neurobiological understanding of alcoholism.

We have used a translational Convergent Functional Genomics (CFG) approach to discover genes involved in alcoholism, by gene-level integration of genome-wide association study (GWAS) data from a German alcohol dependence cohort with other genetic and gene expression data, from human and animal model studies, similar to our previous work in bipolar disorder and schizophrenia. A panel of all the nominally significant P-value SNPs in the top candidate genes discovered by CFG (n=135 genes, 713 SNPs) was used to generate a genetic risk prediction score (GRPS), which showed a trend towards significance (P=0.053) in separating alcohol dependent individuals from controls in an independent German test cohort. We then validated and prioritized our top findings from this discovery work, and subsequently tested them in three independent cohorts, from two continents. In order to validate and prioritize the key genes that drive behavior without some of the pleiotropic environmental confounds present in humans, we used a stress-reactive animal model of alcoholism developed by our group, the D-box binding protein (DBP) knockout mouse, consistent with the surfeit of stress theory of addiction proposed by Koob and colleagues. A much smaller panel (n=11 genes, 66 SNPs) of the top CFG-discovered genes for alcoholism, cross-validated and prioritized by this stress-reactive animal model showed better predictive ability in the independent German test cohort (P=0.041). The top CFG scoring gene for alcoholism from the initial discovery step, synuclein alpha (SNCA) remained the top gene after the stress-reactive animal model cross-validation. We also tested this small panel of genes in two other independent test cohorts from the United States, one with alcohol dependence (P=0.00012) and one with alcohol abuse (a less severe form of alcoholism; P=0.0094). SNCA by itself was able to separate alcoholics from controls in the alcohol-dependent cohort (P=0.000013) and the alcohol abuse cohort (P=0.023). So did eight other genes from the panel of 11 genes taken individually, albeit to a lesser extent and/or less broadly across cohorts. SNCA, GRM3 and MBP survived strict Bonferroni correction for multiple comparisons. Taken together, these results suggest that our stress-reactive DBP animal model helped to validate and prioritize from the CFG-discovered genes some of the key behaviorally relevant genes for alcoholism. These genes fall into a series of biological pathways involved in signal transduction, transmission of nerve impulse (including myelination) and cocaine addiction. Overall, our work provides leads towards a better understanding of illness, diagnostics and therapeutics, including treatment with omega-3 fatty acids. We also examined the overlap between the top candidate genes for alcoholism from this work and the top candidate genes for bipolar disorder, schizophrenia, anxiety from previous CFG analyses conducted by us, as well as cross-tested genetic risk predictions. This revealed the significant genetic overlap with other major psychiatric disorder domains, providing a basis for comorbidity and dual diagnosis, and placing alcohol use in the broader context of modulating the mental landscape.

Association study of 83 candidate genes for bipolar disorder in chromosome 6q selected using an evidence‐based prioritization algorithm

Prior genome-scans of bipolar disorder have revealed chromosome 6q22 as a promising candidate region. However, linkage disequilibrium (LD) mapping studies have yet to identify replicated susceptibility loci. We analyzed 1,422 LD-tagging single nucleotide polymorphisms (SNPs) in 83 genes to test single-marker and locus-wide evidence of association with bipolar disorder in the NIMH Genetics Initiative bipolar pedigrees and the Portuguese Island Collection (PIC) (N = 1,093 in 528 informative pairs). Both studies previously demonstrated significant evidence of linkage to 6q. SNPs were genotyped using an Illumina iSelect genotyping array which employs the Infinium assay. Evidence of single-marker association was assessed using the generalized disequilibrium test (GDT). Empirical estimates of gene-wide significance were obtained by permutation (via 100,000 gene-dropping simulations) of Fisher's combined test of P-values for each locus. No single variant yielded significant experiment-wide evidence of association, for either the combined sample or in each subsample. Our gene-dropping simulations identified nominally significant gene-wide associations with multiple loci, of which NT5DC1 in the NIMH subsample and CCNC in the PIC were the strongest candidates. However, no one gene consistently exceeded empirical significance criteria in both independent samples or survived Bonferroni correction for the number of genes tested. Using a gene-based approach to family-based association, we identified gene-wide associations with several genes, though no single locus was significantly associated with bipolar disorder in both cohorts. This suggests that chromosome 6q may harbor multiple susceptibility loci or that complex patterns of LD in this region may confound approaches based on common SNPs. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.

The influence of dopamine‐related genes on perceptual stability

Bistable perception is the spontaneous and automatic alternation between two different perceptual states that occurs when sensory information is ambiguous. Perceptual alternation rates are robust within individuals but vary substantially between individuals. Slowed perceptual switching has been consistently reported in patients with bipolar disorder (BPD) and has been suggested as a trait marker for this disease. Although genetic factors have been implicated in both BPD and bistable perception, the underlying biological mechanisms that mediate the observed perceptual stability in BPD remain elusive. Here, we tested the effect of two variable number tandem repeat (VNTR) polymorphisms in DRD4 and DAT1 (SLC6A3), both candidate genes for BPD with functional impact on dopaminergic neurotransmission, on bistable perception in a cohort of 108 healthy human subjects. The BPD risk allele DRD4-2R was significantly associated with slow perceptual switching. There was no effect of DAT1 genotype on bistable perception. Our findings indicate that genetic differences in dopaminergic neurotransmission linked to BPD also account for interindividual variability in bistable perception, thus providing a genetic basis for perceptual stability as a trait marker of BPD.

Convergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk prediction.

We have used a translational convergent functional genomics (CFG) approach to identify and prioritize genes involved in schizophrenia, by gene-level integration of genome-wide association study data with other genetic and gene expression studies in humans and animal models. Using this polyevidence scoring and pathway analyses, we identify top genes (DISC1, TCF4, MBP, MOBP, NCAM1, NRCAM, NDUFV2, RAB18, as well as ADCYAP1, BDNF, CNR1, COMT, DRD2, DTNBP1, GAD1, GRIA1, GRIN2B, HTR2A, NRG1, RELN, SNAP-25, TNIK), brain development, myelination, cell adhesion, glutamate receptor signaling, G-protein–coupled receptor signaling and cAMP-mediated signaling as key to pathophysiology and as targets for therapeutic intervention. Overall, the data are consistent with a model of disrupted connectivity in schizophrenia, resulting from the effects of neurodevelopmental environmental stress on a background of genetic vulnerability. In addition, we show how the top candidate genes identified by CFG can be used to generate a genetic risk prediction score (GRPS) to aid schizophrenia diagnostics, with predictive ability in independent cohorts. The GRPS also differentiates classic age of onset schizophrenia from early onset and late-onset disease. We also show, in three independent cohorts, two European American and one African American, increasing overlap, reproducibility and consistency of findings from single-nucleotide polymorphisms to genes, then genes prioritized by CFG, and ultimately at the level of biological pathways and mechanisms. Finally, we compared our top candidate genes for schizophrenia from this analysis with top candidate genes for bipolar disorder and anxiety disorders from previous CFG analyses conducted by us, as well as findings from the fields of autism and Alzheimer. Overall, our work maps the genomic and biological landscape for schizophrenia, providing leads towards a better understanding of illness, diagnostics and therapeutics. It also reveals the significant genetic overlap with other major psychiatric disorder domains, suggesting the need for improved nosology.

Genome-wide association study meta-analysis of European and Asian-ancestry samples identifies three novel loci associated with bipolar disorder

Meta-analyses of bipolar disorder (BD) genome-wide association studies (GWAS) have identified several genome-wide significant signals in European-ancestry samples, but so far account for little of the inherited risk. We performed a meta-analysis of ∼750,000 high-quality genetic markers on a combined sample of ∼14,000 subjects of European and Asian-ancestry (phase I). The most significant findings were further tested in an extended sample of ∼17,700 cases and controls (phase II). The results suggest novel association findings near the genes TRANK1 (LBA1), LMAN2L and PTGFR. In phase I, the most significant single nucleotide polymorphism (SNP), rs9834970 near TRANK1, was significant at the P=2.4 × 10(-11) level, with no heterogeneity. Supportive evidence for prior association findings near ANK3 and a locus on chromosome 3p21.1 was also observed. The phase II results were similar, although the heterogeneity test became significant for several SNPs. On the basis of these results and other established risk loci, we used the method developed by Park et al. to estimate the number, and the effect size distribution, of BD risk loci that could still be found by GWAS methods. We estimate that >63,000 case-control samples would be needed to identify the ∼105 BD risk loci discoverable by GWAS, and that these will together explain <6% of the inherited risk. These results support previous GWAS findings and identify three new candidate genes for BD. Further studies are needed to replicate these findings and may potentially lead to identification of functional variants. Sample size will remain a limiting factor in the discovery of common alleles associated with BD.

Influence of the serotonin transporter gene polymorphism, cannabis and childhood sexual abuse on phenotype of bipolar disorder: A preliminary study

Objective The gene coding for the 5-HT transporter ( 5-HTT) is considered as a candidate gene for bipolar disorder, either as a “vulnerability” or as a “modifying the phenotype” gene. Psychotic symptoms occur at least once in one bipolar patient out of two, the relevant risk factors being insufficiently understood. The gene × environment interaction approach offers the opportunity to disentangle the latter, including childhood sexual abuse and cannabis abuse. Methods We investigated the 5-HTTLPR of the 5-HTT gene (G) and the presence of childhood sexual abuse and cannabis comorbidity (E) in 137 bipolar patients with (versus without) lifetime psychotic symptoms. Results The short allele and cannabis abuse were significantly more frequent among patients with psychotic symptoms than in those without ( p = 0.01 and p = 0.004, respectively), while childhood sexual abuse was not. Complex interactions were found between presence of the short allele, cannabis abuse or dependence and childhood sexual abuse. Conclusions The short allele of the 5-HTTLPR polymorphism of the 5-HTT gene was a risk factor for psychotic symptoms in bipolar disorder in the present sample, directly but also indirectly, through the presence of cannabis abuse or dependence, as an exacerbating factor heightening psychotic symptoms.

Lack of association of three GRIN2B polymorphisms with bipolar disorder

We investigated three polymorphisms in the NMDA receptor 2B subunit gene (GRIN2B), involved in glutamatergic neurotransmission, as a candidate gene for bipolar disorder. In the study we included 419 patients with bipolar disorder. Consensus diagnosis by at least two psychiatrists was made, according to DSM-IV criteria, using SCID. The control group consisted of 487 healthy subjects. Genotypes for − 200G/T, 366C/G and rs890G/T of GRIN2B polymorphisms were established by PCR-RFLP method. Linkage disequilibrium analysis was done with Haploview. Genotype distributions were in Hardy–Weinberg equilibrium for the three polymorphisms in the group of patients and control subjects. No association was found between the three polymorphisms and bipolar disorder. In linkage disequilibrium analysis we did not find linkage between the three polymorphisms of GRIN2B gene. The polymorphisms of GRIN2B gene analysed in this study are not likely to be associated with bipolar disorder.

Phenomic, Convergent Functional Genomic, and biomarker studies in a stress‐reactive genetic animal model of bipolar disorder and co‐morbid alcoholism

We had previously identified the clock gene D-box binding protein (Dbp) as a potential candidate gene for bipolar disorder and for alcoholism, using a Convergent Functional Genomics (CFG) approach. Here we report that mice with a homozygous deletion of DBP have lower locomotor activity, blunted responses to stimulants, and gain less weight over time. In response to a chronic stress paradigm, these mice exhibit a diametric switch in these phenotypes. DBP knockout mice are also activated by sleep deprivation, similar to bipolar patients, and that activation is prevented by treatment with the mood stabilizer drug valproate. Moreover, these mice show increased alcohol intake following exposure to stress. Microarray studies of brain and blood reveal a pattern of gene expression changes that may explain the observed phenotypes. CFG analysis of the gene expression changes identified a series of novel candidate genes and blood biomarkers for bipolar disorder, alcoholism, and stress reactivity.

Stage II follow-up on a linkage scan for bipolar disorder in the Ashkenazim provides suggestive evidence for chromosome 12p and the GRIN2B gene

PurposeWe had previously performed a genome-wide linkage scan for bipolar affective disorder in an Ashkenazi Jewish sample, a population likely to have reduced genetic heterogeneity. This study is a second stage follow-up focusing on regions that showed positive linkage scores in our previous scan but were not fine-mapped at that time. MethodsWe genotyped an additional 145 highly polymorphic microsatellites and conducted linkage analyses using standard laboratory and analytical methods. ResultsWe saw an improvement of the evidence for linkage in most regions, with the most notable change on chromosome 12p13.1-p12.3, where the evidence of linkage is now suggestive. This region harbors the gene encoding the ionotropic glutamate receptor subunit 2B (GRIN2B), a gene that previously yielded evidence for association in a candidate gene study on 323 Ashkenazi Jewish bipolar case-parent trios. We find that the evidence for linkage is significantly correlated with the presence of the putative high-risk allele identified in our candidate gene study. ConclusionsFollowing up weaker signals can significantly improve linkage signals even after relatively small increases in information content. Our results on chromosome 12p support GRIN2B as a candidate gene for bipolar disorder that needs further investigation.

Increase in GSK3β gene copy number variation in bipolar disorder

The analysis of submicroscopic copy number variations (CNVs), also known as copy number polymorphisms (CNPs), is emerging as a new tool for understanding the genetic basis of cancer, developmental disorders, and complex traits. One area where this may be particularly useful is in the identification of genetic variants underlying schizophrenia (SZ) and bipolar disorder (BD). Linkage analysis and pharmacological studies carried out over the past decade have implicated a number of positional and physiological candidate genes. Yet, despite extensive analysis, the underlying allelic variants responsible for disease susceptibility have remained, largely, elusive. Although the borders of most CNV have not been precisely mapped, it appears that a considerable number of SZ and BD candidate genes have their coding elements disrupted by polymorphic CNVs, suggesting that these would be good variants to consider for underlying disease susceptibility. One such gene is GSK3beta, which codes for glycogen synthase kinase, a key component of the Wnt signaling pathway and a target of lithium salts. A CNV in the GSK3beta locus at chromosome 3q13.3 appears to disrupt the gene's 3'-coding elements. The CNV also affects two other annotated genes. We now report that patients with BD have an increased frequency of this CNV-primarily the duplication variant-compared with controls (P = 0.002). The finding suggests that GSK3beta may be involved in BD susceptibility in some individuals and that CNVs in this and other candidate genes for psychiatric disorders should be analyzed as causative functional genetic variants.

Lack of association of an insertion/deletion polymorphism in the G protein-coupled receptor 50 with bipolar disorder in a Northern Swedish population

GPR50 is a G protein-coupled receptor, located on Xq28 and related to the melatonin receptor family. It is suggested as a functional and positional candidate gene for bipolar disorder (BP). Recently an insertion/deletion polymorphism in GPR50, Delta502-505, was found to be associated with BP in a Scottish association sample (P=0.007). When the analysis was restricted to female subjects, the association increased in significance (P=0.00023). We attempted to replicate this finding in a Northern Swedish association sample, but no significant association was detected (P=0.7, women only: P=0.65).

Lack of association between variations in the melanocortin 5 receptor gene and bipolar disorder

The melanocortin 5 receptor gene maps to the bipolar susceptibility locus on chromosome 18p11.2. Given the biological role of melanocortins and their influence on the hypothalamic-pituitary-adrenal axis, the melanocortin 5 receptor gene is a plausible candidate gene for bipolar disorder. We tested the hypothesis that the potential functional variation Phe209Leu confers susceptibility to bipolar disorder in a case-control study. Genotypes for two variations in the coding region and one variation approximately 7 kb upstream from the coding region were obtained from 345 unrelated bipolar I patients and 275 control samples. Genotypes and allele frequencies were compared between groups using chi(2) contingency analysis. Allele frequencies of the Phe209Leu polymorphism did not differ significantly between bipolar patients and controls (P=0.679). Allele frequencies of the C744T and the intergenic A/G polymorphism did not differ significantly between bipolar patients and controls. All variations were in strong linkage disequilibrium. Variations in the melanocortin 5 receptor gene are unlikely to confer susceptibility to bipolar disorder in this sample. Further studies are required to elucidate the susceptibility locus for bipolar disorder on chromosome 18p11.