Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder

Abstract

To identify susceptibility loci for bipolar disorder, we tested 1.8 million variants in 4,387 cases and 6,209 controls and identified a region of strong association (rs10994336, P = 9.1 x 10(-9)) in ANK3 (ankyrin G). We also found further support for the previously reported CACNA1C (alpha 1C subunit of the L-type voltage-gated calcium channel; combined P = 7.0 x 10(-8), rs1006737). Our results suggest that ion channelopathies may be involved in the pathogenesis of bipolar disorder.

Figure 1

Association results for the combined analysis of the WTCCC, STEP-UCL and ED-DUB-STEP2 studies. (a) Genome-wide results (-log₁₀P) are shown in chromosomal order for directly genotyped (N = 325,690) and imputed (N = 1,444,258) SNPs that were tested for association in the overall sample of 4,387 bipolar cases and 6,209 controls. Horizontal lines indicate a P value of 5 × 10^-8 (dashed) and 1 × 10^-6 (dotted). (b) Plots for the three regions of strongest association. Results (-log₁₀P) are shown for directly genotyped (diamonds) and imputed (circles) SNPs. The most associated SNP for each region is shown in blue, and the color of the remaining markers reflects the linkage disequilibrium (r²) with the top SNP in each panel (increasing red hue associated with increasing r²). The recombination rate (second y axis) is plotted in light blue and is based on the CEU HapMap population. The dashed horizontal line indicates a P = 5 × 10^-8. Exons for each gene are represented by vertical bars, based on all isoforms available from the Mar 2006 UCSC genome browser assembly.