Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4

Abstract

We conducted a combined genome-wide association (GWAS) analysis of 7,481 individuals affected with bipolar disorder and 9,250 control individuals within the Psychiatric Genomewide Association Study Consortium Bipolar Disorder group (PGC-BD). We performed a replication study in which we tested 34 independent SNPs in 4,493 independent bipolar disorder cases and 42,542 independent controls and found strong evidence for replication. In the replication sample, 18 of 34 SNPs had P value < 0.05, and 31 of 34 SNPs had signals with the same direction of effect (P = 3.8 × 10−7). In the combined analysis of all 63,766 subjects (11,974 cases and 51,792 controls), genome-wide significant evidence for association was confirmed for CACNA1C and found for a novel gene ODZ4. In a combined analysis of non-overlapping schizophrenia and bipolar GWAS samples we observed strong evidence for association with SNPs in CACNA1C and in the region of NEK4/ITIH1,3,4. Pathway analysis identified a pathway comprised of subunits of calcium channels enriched in the bipolar disorder association intervals. The strength of the replication data implies that increasing samples sizes in bipolar disorder will confirm many additional loci.

Assessment of first and second degree relatives of individuals with bipolar disorder shows increased genetic risk scores in both affected relatives and young At‐Risk Individuals

“…The majority of SNPs (n = 26) imputed with <10% missing data, but some SNPs had higher failure rates (Supporting Information Table S1). The allele frequencies of each SNP in all European ancestry subjects were close to those previously reported [Sklar et al, 2011] for Europeans (±0.022–0.032), and were similar for both directly observed and imputed SNPs (±0.031 and ±0.025, respectively) (Supporting Information Table S1).…”

“…We chose for genotyping 38 SNPs that were robustly implicated in bipolar disorder risk, on the basis of prior evidence of genetic association ( P  < 5 × 10 −5 ) from the PGC [Sklar et al, 2011]; two (rs3968, rs8006348) failed sassay design.…”

“…The remaining 36 SNPs [Sklar et al, 2011] were genotyped at two sites, using iPLEX GOLD chemistry on the Sequenom MassArray (Supporting Information Table S1]. Tests for Hardy–Weinberg equilibrium, linkage disequilibrium, genotype missingness and allelic, and genotypic frequency comparisons were conducted using PLINK [Purcell et al, 2007].…”

“…In 2011, Sklar et al identified 38 variants (pared to 34 by assessment of independence with linkage disequilibrium) that contribute to disease risk ( P  < 5 × 10 −5 ) using a discovery sample of 7,481 individuals with BP and 9,250 controls. These SNPs were replicated in an independent cohort comprising 4,496 cases and 42,422 controls, with more SNPs than expected showing P  < 0.01, P  < 0.05, and the same direction of effect [Sklar et al, 2011]. Hence, a substantial number of these SNPs may be expected to represent true risk variants (or markers for such alleles) for bipolar disorder.…”

“…Large scale collaborative genome‐wide association studies (GWAS) have identified a number of risk loci significantly associated with bipolar disorder (BP), including ODZ4 [Sklar et al, 2011; Muhleisen et al, 2014], CACNA1C [Ferreira et al, 2008; Sklar et al, 2008], ANK3 [Ferreira et al, 2008; Schulze et al, 2009; Muhleisen et al, 2014], NCAN [Cichon et al, 2011], C15ORF53 [Ferreira et al, 2008], and DGKH [Baum et al, 2008a,2008b]. Individually, each of those genes/loci contributes only a small fraction toward overall disease risk, typically <1% of the phenotypic variance [Ferreira et al, 2008].…”