Schizophrenia (SCZ) and bipolar disorder (BD) are highly heritable disorders that share a significant proportion of common risk variation. Understanding the genetic factors underlying the specific symptoms of these disorders will be crucial for improving diagnosis, intervention and treatment. In case-control data consisting of 53,555 cases (20,129 BD, 33,426 SCZ) and 54,065 controls, we identified 114 genome-wide significant loci (GWS) when comparing all cases to controls, of which 41 represented novel findings. Two genome-wide significant loci were identified when comparing SCZ to BD and a third was found when directly incorporating functional information. Regional joint association identified a genomic region of overlapping association in BD and SCZ with disease-independent causal variants indicating a fourth region contributing to differences between these disorders. Regional SNP-heritability analyses demonstrated that the estimated heritability of BD based on the SCZ GWS regions was significantly higher than that based on the average genomic region (91 regions, p = 1.2×10−6) while the inverse was not significant (19 regions, p=0.89). Using our BD and SCZ GWAS we calculated polygenic risk scores and identified several significant correlations with: 1) SCZ subphenotypes: negative symptoms (SCZ, p=3.6×10−6) and manic symptoms (BD, p=2×10−5), 2) BD subphenotypes: psychotic features (SCZ p=1.2×10−10, BD p=5.3×10−5) and age of onset (SCZ p=7.9×10−4). Finally, we show that psychotic features in BD has significant SNP-heritability (h2 snp=0.15, SE=0.06), and a significant genetic correlation with SCZ (rg=0.34) in addition there is a significant sign test result between SCZ GWAS and a GWAS of BD cases contrasting those with and without psychotic features (p=0.0038, one-side binomial test). For the first time, we have identified specific loci pointing to a potential role of 4 genes ( DARS2 , ARFGEF2 , DCAKD and GATAD2A ) that distinguish between BD and SCZ, providing an opportunity to understand the biology contributing to clinical differences of these disorders. Our results provide the best evidence so far of genomic components distinguishing between BD and SCZ that contribute directly to specific symptom dimensions.

Background Schizophrenia is a highly heritable, neuropsychiatric disorder characterized by episodic psychosis and altered cognitive function. Despite success in identifying genetic variants associated with schizophrenia, there remains uncertainty about the causal genes involved in disease pathogenesis and how their function is regulated. Results We performed a multi-stage epigenome-wide association study, quantifying genome-wide patterns of DNA methylation in a total of 1714 individuals from three independent sample cohorts. We have identified multiple differentially methylated positions and regions consistently associated with schizophrenia across the three cohorts; these effects are independent of important confounders such as smoking. We also show that epigenetic variation at multiple loci across the genome contributes to the polygenic nature of schizophrenia. Finally, we show how DNA methylation quantitative trait loci in combination with Bayesian co-localization analyses can be used to annotate extended genomic regions nominated by studies of schizophrenia, and to identify potential regulatory variation causally involved in disease. Conclusions This study represents the first systematic integrated analysis of genetic and epigenetic variation in schizophrenia, introducing a methodological approach that can be used to inform epigenome-wide association study analyses of other complex traits and diseases. We demonstrate the utility of using a polygenic risk score to identify molecular variation associated with etiological variation, and of using DNA methylation quantitative trait loci to refine the functional and regulatory variation associated with schizophrenia risk variants. Finally, we present strong evidence for the co-localization of genetic associations for schizophrenia and differential DNA methylation.

Genomic copy number variants (CNVs) have been strongly implicated in the etiology of schizophrenia (SCZ). However, apart from a small number of risk variants, elucidation of the CNV contribution to risk has been difficult due to the rarity of risk alleles, all occurring in less than 1% of cases. We sought to address this obstacle through a collaborative effort in which we applied a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. We observed a global enrichment of CNV burden in cases (OR=1.11, P=5.7e−15), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7e−6). CNV burden is also enriched for genes associated with synaptic function (OR = 1.68, P = 2.8e−11) and neurobehavioral phenotypes in mouse (OR = 1.18, P=7.3e−5). We identified genome-wide significant support for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. We find support at a suggestive level for nine additional candidate susceptibility and protective loci, which consist predominantly of CNVs mediated by non-allelic homologous recombination (NAHR).

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 × 10-15), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10-6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10-11) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 10-5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.

OBJECTIVES:Genetic markers in the genes encoding ankyrin 3 (ANK3) and the α-calcium channel subunit (CACNA1C) are associated with bipolar disorder (BP). The associated variants in the CACNA1C gene are mainly within intron 3 of the gene. ANK3 BP-associated variants are in two distinct clusters at the ends of the gene, indicating disease allele heterogeneity.METHODS:In order to screen both coding and non-coding regions to identify potential aetiological variants, we used whole-genome sequencing in 99 BP cases. Variants with markedly different allele frequencies in the BP samples and the 1,000 genomes project European data were genotyped in 1,510 BP cases and 1,095 controls.RESULTS:We found that the CACNA1C intron 3 variant, rs79398153, potentially affecting an ENCyclopedia of DNA Elements (ENCODE)-defined region, showed an association with BP (p = 0.015). We also found the ANK3 BP-associated variant rs139972937, responsible for an asparagine to serine change (p = 0.042). However, a previous study had not found support for an association between rs139972937 and BP. The variants at ANK3 and CACNA1C previously known to be associated with BP were not in linkage disequilibrium with either of the two variants that we identified and these are therefore independent of the previous haplotypes implicated by genome-wide association.CONCLUSIONS:Sequencing in additional BP samples is needed to find the molecular pathology that explains the previous association findings. If changes similar to those we have found can be shown to have an effect on the expression and function of ANK3 and CACNA1C, they might help to explain the so-called 'missing heritability' of BP.

Genetic markers at the GRM7 gene have shown allelic association with bipolar disorder (BP) in several case–control samples including our own sample. In this report, we present results of resequencing the GRM7 gene in 32 bipolar samples and 32 random controls selected from 553 bipolar cases and 547 control samples (UCL1). Novel and potential etiological base pair changes discovered by resequencing were genotyped in the entire UCL case–control sample. We also report on the association between GRM7 and BP in a second sample of 593 patients and 642 controls (UCL2). The three most significantly associated SNPs in the original UCL1 BP GWAS sample were genotyped in the UCL2 sample, of which none were associated. After combining the genotype data for the two samples only two (rs1508724 and rs6769814) of the original three SNP markers remained significantly associated with BP. DNA sequencing revealed mutations in three cases which were absent in control subjects. A 3′‐UTR SNP rs56173829 was found to be significantly associated with BP in the whole UCL sample ( P = 0.035; OR = 0.482), the rare allele being less common in cases compared to controls. Bioinformatic analyses predicted a change in the centroid secondary structure of RNA and alterations in the miRNA binding sites for the mutated base of rs56173829. We also validated two deletions and a duplication within GRM7 using quantitative‐PCR which provides further support for the pre‐existing evidence that copy number variants at GRM7 may have a role in the etiology of BP. © 2014 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Published by Wiley Periodicals, Inc.

OBJECTIVES: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.METHODS: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.RESULTS: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.CONCLUSIONS:Prior linkage evidence and our findings suggest NPTX1 as a novel candidate gene for BD.

Certain single nucleotide polymorphisms (SNPs) in genes encoding alcohol dehydrogenase (ADH) enzymes confer a significant protective effect against alcohol dependence syndrome (ADS) in East Asian populations. Recently, attention has focused on the role of these SNPs in determining ADS risk in European populations. To further elucidate these associations, SNPs of interest in ADH1B, ADH1C and the ADH1B/1C intergenic region were genotyped in a British and Irish population (ADS cases n = 1076: controls n = 1027) to assess their relative contribution to ADS risk. A highly significant, protective association was observed between the minor allele of rs1229984 in ADH1B and ADS risk [allelic P = 8.4 × 10(-6) , odds ratio (OR) = 0.26, 95 percent confidence interval, 0.14, 0.49]. Significant associations were also observed between ADS risk and the ADH1B/1C intergenic variant, rs1789891 [allelic P = 7.2 × 10(-5) , OR = 1.4 (1.2, 1.6)] and three non-synonymous SNPs rs698, rs1693482 and rs283413 in ADH1C. However, these associations were not completely independent; thus, while the ADH1B rs1229984 minor allele association was independent of those of the intergenic variant rs1789891 and the three ADH1C variants, the three ADH1C variants were not individually independent. In conclusion, the rare ADH1B rs1229984 mutation provides significant protection against ADS in this British and Irish population; other variants in the ADH gene cluster also alter ADS risk, although the strong linkage disequilibrium between SNPs at this location precluded clear identification of the variant(s) driving the associations.

Single nucleotide polymorphisms (SNPs) in the tachykinin receptor 1 gene ( TACR1 ) are nominally associated with bipolar affective disorder (BPAD) in a genome‐wide association study and in several case‐control samples of BPAD, alcohol dependence syndrome (ADS) and attention‐deficit hyperactivity disorder (ADHD). Eighteen TACR1 SNPs were associated with BPAD in a sample (506 subjects) from University College London (UCL1), the most significant being rs3771829, previously associated with ADHD. To further elucidate the role of TACR1 in affective disorders, rs3771829 was genotyped in a second BPAD sample of 593 subjects (UCL2), in 997 subjects with ADS, and a subsample of 143 individuals diagnosed with BPAD and comorbid alcohol dependence (BPALC). rs3771829 was associated with BPAD (UCL1 and UCL2 combined: P = 2.0 × 10 −3 ), ADS ( P = 2.0 × 10 −3 ) and BPALC ( P = 6.0 × 10 −4 ) compared with controls screened for the absence of mental illness and alcohol dependence. DNA sequencing in selected cases of BPAD and ADHD who had inherited TACR1 ‐susceptibility haplotypes identified 19 SNPs in the promoter region, 5′ UTR, exons, intron/exon junctions and 3′ UTR of TACR1 that could increase vulnerability to BPAD, ADS, ADHD, and BPALC. Alternative splicing of TACR1 excludes intron 4 and exon 5, giving rise to two variants of the neurokinin 1 receptor (NK1R) that differ in binding affinity of substance P by 10‐fold. A mutation in intron four, rs1106854, was associated with BPAD, although a regulatory role for rs1106854 is unclear. The association with TACR1 and BPAD, ADS, and ADHD suggests a shared molecular pathophysiology between these affective disorders. © 2014 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals.

The risk for developing the alcohol dependence syndrome (ADS) has a substantial genetic component. The human thiamine transporter protein 2 (hTHTR2) is encoded by the SLC19A3 gene, which is on chromosome 2q37. hTHTR2 is responsible for the cellular uptake of thiamine (B1), a water-soluble essential vitamin that plays a fundamental and ubiquitous role in carbohydrate metabolism. This gene was also found to be associated with biotin-responsive basal ganglia disease, an autosomal recessive metabolic disorder characterized by encephalopathy and ophthalmoplegia (Ozand et al., 1998; Zeng et al., 2005). Homozygous or compound heterozygous mutations in SLC19A3 cause two distinct clinical phenotypes: biotin-responsive basal ganglia disease and Wernicke’s-like encephalopathy. Biotin and/or thiamine are effective therapies for both diseases (Yamada et al., 2010). A missense mutation in exon 5 of the SLC19A3 was found in 18 cases of biotin/thiamine-responsive basal ganglion disease presenting with subacute encephalopathy and extrapyramidal signs (Alfadhel et al., 2013). Kono et al. (2009) described two Japanese brothers, who were both compound heterozygotes for the K44E and E320Q mutations in SLC19A3, who developed a syndrome of thiamine-responsive diplopia, ophthalmoplegia and ataxia, similar to Wernicke’s encephalopathy, despite normal serum thiamine levels (Kono et al., 2009). Yamada et al. (2010) reported a pathogenic homozygous mutation (c.958G>C, [p.E320Q]) in SLC19A3 in four patients from a single family. They report a wide variety of neurological signs in SLC19A3 mutation carriers. Our previous unpublished research found that four markers in the SLC19A3 gene showed significant allelic association with Wernicke–Korsakoff syndrome (WKS) in a sample of 120 cases when compared with normal controls. In the present study, the entire SLC19A3 gene was screened for DNA variation in a WKS subset (n=120) of a UK ADS case–control sample comprised of 1032 alcohol-dependent cases and 1022 controls. High resolution melting curve analysis, which is based on the melting characteristic of double-stranded DNA, was carried out using a LightCycler 480 Real-Time PCR System (Roche, Burgess Hill, UK). Genetic variation was validated with Sanger DNA sequencing. Thirteen single nucleotide variants were identified through high resolution melting analysis. Two exon 3 variants that were predicted to cause amino acid substitutions, 2:228563818T/C and rs148144444, were selected for genotyping in the entire ADS case–control sample using an allele-specific fluorescent PCR method (KasPar; LGC Genomics, Hoddesdon, UK). Statistical analysis was carried out on the previously unreported 2:228563818T/C change of a T to C substitution at position 228 563 818 on chromosome 2. This variant causes an R250G amino acid substitution in the largest cytoplasmic domain of the protein and it is, therefore, likely to affect post-translational function. rs148144444 causes the amino acid change G141S which is likely to exert an effect on protein phosphorylation and conformation because of the introduction of the aliphatic chain of serine. Neither the cases nor the controls in the present study had the SLC19A3 disease susceptibility variants that have been reported previously (Zeng et al., 2005; Kono et al., 2009). The minor allele of 2:228563818T/C was detected in five ADS cases, but was absent in the control samples (P=0.033). The minor allele of rs148144444 was detected in five ADS cases and in four controls and was not associated with ADS. Neither of these variants was present in the 120 WKS cases in our ADS sample. Our data suggest that genetic variation in the SLC19A3 thiamine transporter at 2:228563818T/C may make a modest contribution towards the genetic susceptibility to ADS. Acknowledgements This work was funded by the Brain Damage Research Trust. We would like to thank the NIHR (National Institute for Health Research) funded Mental Health Research Network for their help with ADS and healthy control sample ascertainment and collection. Conflicts of interest There are no conflicts of interest.

Schizophrenia (SZ) genome-wide association studies (GWASs) have identified common risk variants in >100 susceptibility loci; however, the contribution of rare variants at these loci remains largely unexplored. One of the strongly associated loci spans MIR137 (miR137) and MIR2682 (miR2682), two microRNA genes important for neuronal function. We sequenced ∼6.9 kb MIR137/MIR2682 and upstream regulatory sequences in 2,610 SZ cases and 2,611 controls of European ancestry. We identified 133 rare variants with minor allele frequency (MAF) <0.5%. The rare variant burden in promoters and enhancers, but not insulators, was associated with SZ (p = 0.021 for MAF < 0.5%, p = 0.003 for MAF < 0.1%). A rare enhancer SNP, 1:g.98515539A>T, presented exclusively in 11 SZ cases (nominal p = 4.8 × 10(-4)). We further identified its risk allele T in 2 of 2,434 additional SZ cases, 11 of 4,339 bipolar (BP) cases, and 3 of 3,572 SZ/BP study controls and 1,688 population controls; yielding combined p values of 0.0007, 0.0013, and 0.0001 for SZ, BP, and SZ/BP, respectively. The risk allele T of 1:g.98515539A>T reduced enhancer activity of its flanking sequence by >50% in human neuroblastoma cells, predicting lower expression of MIR137/MIR2682. Both empirical and computational analyses showed weaker transcription factor (YY1) binding by the risk allele. Chromatin conformation capture (3C) assay further indicated that 1:g.98515539A>T influenced MIR137/MIR2682, but not the nearby DPYD or LOC729987. Our results suggest that rare noncoding risk variants are associated with SZ and BP at MIR137/MIR2682 locus, with risk alleles decreasing MIR137/MIR2682 expression.

BACKGROUND:Recently, genome-wide association studies (GWAS) for cases versus controls using single nucleotide polymorphism microarray data have shown promising findings for complex neuropsychiatric disorders, including bipolar disorder (BD).METHODS:Here we describe a comprehensive genome-wide study of bipolar disorder (BD), cross-referencing analysis from a family-based study of 229 small families with association analysis from over 950 cases and 950 ethnicity-matched controls from the UK and Canada. Further, loci identified in these analyses were supported by pathways identified through pathway analysis on the samples.RESULTS:Although no genome-wide significant markers were identified, the combined GWAS findings have pointed to several genes of interest that support GWAS findings for BD from other groups or consortia, such as at SYNE1 on 6q25, PPP2R2C on 4p16.1, ZNF659 on 3p24.3, CNTNAP5 (2q14.3), and CDH13 (16q23.3). This apparent corroboration across multiple sites gives much confidence to the likelihood of genetic involvement in BD at these loci. In particular, our two-stage strategy found association in both our combined case/control analysis and the family-based analysis on 1q21.2 (closest gene: sphingosine-1-phosphate receptor 1 gene, S1PR1) and on 1q24.1 near the gene TMCO1, and at CSMD1 on 8p23.2, supporting several previous GWAS reports for BD and for schizophrenia. Pathway analysis suggests association of pathways involved in calcium signalling, neuropathic pain signalling, CREB signalling in neurons, glutamate receptor signalling and axonal guidance signalling.CONCLUSIONS:The findings presented here show support for a number of genes previously implicated genes in the etiology of BD, including CSMD1 and SYNE1, as well as evidence for previously unreported genes such as the brain-expressed genes ADCY2, NCALD, WDR60, SCN7A and SPAG16.

IMPORTANCE:Schizophrenia (SCZ) is a devastating psychiatric condition. Identifying the specific genetic variants and pathways that increase susceptibility to SCZ is critical to improve disease understanding and address the urgent need for new drug targets. OBJECTIVE:To identify SCZ susceptibility genes. DESIGN:We integrated results from a meta-analysis of 18 genome-wide association studies (GWAS) involving 1,085,772 single-nucleotide polymorphisms (SNPs) and 6 databases that showed significant informativeness for SCZ. The 9380 most promising SNPs were then specifically genotyped in an independent family-based replication study that, after quality control, consisted of 8107 SNPs. SETTING:Linkage meta-analysis, brain transcriptome meta-analysis, candidate gene database, OMIM, relevant mouse studies, and expression quantitative trait locus databases. PATIENTS:We included 11,185 cases and 10,768 control subjects from 6 databases and, after quality control 6298 individuals (including 3286 cases) from 1811 nuclear families. MAIN OUTCOMES AND MEASURES:Case-control status for SCZ. RESULTS:Replication results showed a highly significant enrichment of SNPs with small P values. Of the SNPs with replication values of P.01, the proportion of SNPs that had the same direction of effects as in the GWAS meta-analysis was 89% in the combined ancestry group (sign test, P < 2.20 x 10(-16) and 93% in subjects of European ancestry only (P < 2.20 < 10(-16)). Our results supported the major histocompatibility complex region showing a3.7-fold overall enrichment of replication values of P < .01 in subjects from European ancestry. We replicated SNPs in TCF4 (P = 2.53 x 10(-10)) and NOTCH4 (P = 3.16 x 10(-7)) that are among the most robust SCZ findings. More novel findings included POM121L2 (P = 3.51 x 10(-7)), AS3MT (P = 9.01 x 10(-7)), CNNM2 (P = 6.07 = 10(-7)), and NT5C2(P = 4.09 x 10(-7)). To explore the many small effects, we performed pathway analyses. The most significant pathways involved neuronal function (axonal guidance, neuronal systems, and L1 cell adhesion molecule interaction)and the immune system (antigen processing, cell adhesion molecules relevant to T cells, and translocation to immunological synapse). CONCLUSIONS AND RELEVANCE:We replicated novel SCZ disease genes and pathogenic pathways. Better understanding the molecular and biological mechanisms involved with schizophrenia may improve disease management and may identify new drug targets.

Recent reports suggest that somatic structural changes occur in the human genome, but how these genomic alterations might contribute to disease is unknown. Using samples collected as part of the International Schizophrenia Consortium (schizophrenia, n = 3518; control, n = 4238) recruited across multiple university research centers, we assessed single-nucleotide polymorphism genotyping arrays for evidence of chromosomal anomalies. Data from genotyping arrays on each individual were processed using Birdsuite and analyzed with PLINK. We validated potential chromosomal anomalies using custom nanostring probes and quantitative PCR. We estimate chromosomal alterations in the schizophrenia population to be 0.42%, which is not significantly different from controls (0.26%). We identified and validated a set of four extremely large (>10 Mb) chromosomal anomalies in subjects with schizophrenia, including a chromosome 8 trisomy and deletion of the q arm of chromosome 7. These data demonstrate that chromosomal anomalies are present at low frequency in blood cells of both control and schizophrenia subjects.

Alcohol dependence is a common, complex and debilitating disorder with genetic and environmental influences. Here we show that alcohol consumption increases following mutations to the γ-aminobutyric acid A receptor (GABA A R) β1 subunit gene ( Gabrb1 ). Using N -ethyl- N -nitrosourea mutagenesis on an alcohol-averse background (F1 BALB/cAnN x C3H/HeH), we develop a mouse model exhibiting strong heritable preference for ethanol resulting from a dominant mutation (L285R) in Gabrb1 . The mutation causes spontaneous GABA ion channel opening and increases GABA sensitivity of recombinant GABA A Rs, coupled to increased tonic currents in the nucleus accumbens, a region long-associated with alcohol reward. Mutant mice work harder to obtain ethanol, and are more sensitive to alcohol intoxication. Another spontaneous mutation (P228H) in Gabrb1 also causes high ethanol consumption accompanied by spontaneous GABA ion channel opening and increased accumbal tonic current. Our results provide a new and important link between GABA A R function and increased alcohol consumption that could underlie some forms of alcohol abuse.

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.