Genome-wide association study of bipolar disorder in European American and African American individuals

Abstract

To identify bipolar disorder (BD) genetic susceptibility factors, we conducted two genome-wide association (GWA) studies: one involving a sample of individuals of European ancestry (EA; n=1001 cases; n=1033 controls), and one involving a sample of individuals of African ancestry (AA; n=345 cases; n=670 controls). For the EA sample, single-nucleotide polymorphisms (SNPs) with the strongest statistical evidence for association included rs5907577 in an intergenic region at Xq27.1 (P=1.6 x 10(-6)) and rs10193871 in NAP5 at 2q21.2 (P=9.8 x 10(-6)). For the AA sample, SNPs with the strongest statistical evidence for association included rs2111504 in DPY19L3 at 19q13.11 (P=1.5 x 10(-6)) and rs2769605 in NTRK2 at 9q21.33 (P=4.5 x 10(-5)). We also investigated whether we could provide support for three regions previously associated with BD, and we showed that the ANK3 region replicates in our sample, along with some support for C15Orf53; other evidence implicates BD candidate genes such as SLITRK2. We also tested the hypothesis that BD susceptibility variants exhibit genetic background-dependent effects. SNPs with the strongest statistical evidence for genetic background effects included rs11208285 in ROR1 at 1p31.3 (P=1.4 x 10(-6)), rs4657247 in RGS5 at 1q23.3 (P=4.1 x 10(-6)), and rs7078071 in BTBD16 at 10q26.13 (P=4.5 x 10(-6)). This study is the first to conduct GWA of BD in individuals of AA and suggests that genetic variations that contribute to BD may vary as a function of ancestry.

Figure 1. Top genetic background-dependent SNPs

The region around the top background-dependent SNP. The primary SNP is colored in black. Other SNPs are colored according to linkage disequilibrium levels with the primary SNP (r2) calculated from Phase 3 HapMap data using the CEU ] population. Recombination rate (HapMap) is shown on the second y-axis in blue. RefSeq genes are shown with all possible exons; arrows indicate transcript direction. In the upper left hand corner of each graph, the genotype intensity plots are shown, with each color indicating the final genotype call (blue and red for homozygotes and purple for the heterozygote). B. Odds ratios for the top three background-dependent SNPs within groups showing different degrees of admixture. Low and High admixture groups are all of African Ancestry, but are split into two groups by the approximate median percent CEU. Lines indicate 95% confidence intervals.

Figure 2. Muliti-haplotype association in the ANK3 region suggests allelic heterogeneity

Each point summarizes the proportion of haplotypes within a given 10 SNP window. The proportion of the haplotypes that show a p < 0.05 for a given window is plotted on the y-axis. The x-axis is the physical position of the midpoint of the haplotype. The points are colored according to the number of haplotypes that show p < 0.05. The proportion was median smoothed over 101 windows (blue line). The red dotted line indicates the genome-wide mean proportion of haplotypes with a p < 0.05. RefSeq genes are shown below the x-axis.