Genetic association of cyclic AMP signaling genes with bipolar disorder

Abstract

The genetic basis for bipolar disorder (BPD) is complex with the involvement of multiple genes. As it is well established that cyclic adenosine monophosphate (cAMP) signaling regulates behavior, we tested variants in 29 genes that encode components of this signaling pathway for associations with BPD type I (BPD I) and BPD type II (BPD II). A total of 1172 individuals with BPD I, 516 individuals with BPD II and 1728 controls were analyzed. Single SNP (single-nucleotide polymorphism), haplotype and SNP × SNP interactions were examined for association with BPD. Several statistically significant single-SNP associations were observed between BPD I and variants in the PDE10A gene and between BPD II and variants in the DISC1 and GNAS genes. Haplotype analysis supported the conclusion that variation in these genes is associated with BPD. We followed-up PDE10A's association with BPD I by sequencing a 23-kb region in 30 subjects homozygous for seven minor allele risk SNPs and discovered eight additional rare variants (minor allele frequency < 1%). These single-nucleotide variants were genotyped in 999 BPD cases and 801 controls. We obtained a significant association for these variants in the combined sample using multiple methods for rare variant analysis. After using newly developed methods to account for potential bias from sequencing BPD cases only, the results remained significant. In addition, SNP × SNP interaction studies suggested that variants in several cAMP signaling pathway genes interact to increase the risk of BPD. This report is among the first to use multiple rare variant analysis methods following common tagSNPs associations with BPD.

Figure 1

PDE10A association with bipolar disorder I (BPD I). The points in panel (a) represent genotyped (black circles) and imputed (open triangles) single-nucleotide polymorphisms (SNPs) and their probability of association with BPD I. Panel (b) illustrates probability as a sequential sliding window with three SNPs per window for the genotyped SNPs (empirical haplotype) and all SNPs (haplotype). The results were adjusted for age and population substructure. Panel (c) shows the structure of the PDE10A gene aligned with panels A and B with exons represented by bars. The direction of transcription, 5′→3′ is from right to left in this figure.

Figure 2

PDE10A region 1 risk linkage disequilibrium (LD) plot. Shading and values in cells correspond to r² values between single-nucleotide polymorphism (SNP) pairs. The SNPs within region 1 and with odds ratio (OR) >1.0 were used to define the boundaries for subsequent sequencing.

Figure 3

DISC1 association with bipolar disorder II (BPD II). The points in panel (a) represent genotyped. (black circles) and imputed (open triangles) single-nucleotide polymorphisms (SNPs) and their probability of association with BPD II. Panel (b) illustrates probability as a sequential sliding window with three SNPs per window for the genotyped SNPs (empirical haplotype) and all SNPs (haplotype). The results were adjusted for age and population substructure. Panel (c) shows the structure of the DISC1 gene aligned with panels (a) and (b) with exons represented by bars. The direction of transcription, 5′→3′ is from left to right in this figure.

Figure 4

GNAS association with bipolar disorder II (BPD II). The points in panel (a) represent genotyped. (black circles) and imputed (open triangles) single-nucleotide polymorphisms (SNPs) and their probability of association with BPD II. Panel (b) illustrates probability as a sequential sliding window with three SNPs per window for the genotyped SNPs (empirical haplotype) and all SNPs (haplotype). Panel (c) shows the structure of the GNAS gene aligned with panels (a) and (b) with exons represented by bars. The direction of transcription, 5′→3′ is from right to left in this figure.