Genetic association of cyclic AMP signaling genes with bipolar disorder

M-L Mcdonald,R L Davis,S M Leal,C Macmullen,D J Liu

doi:10.1038/tp.2012.92

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.

Highlights

Bipolar disorder (BPD) affects B2.5% of the United States population aged 18 and older based on data from the population-based National Comorbidity Survey Replication.[1]
PDE4D tagSNP rs4699931 and ADCY8 tagSNP rs928136 interaction was associated with an increased ORinteraction of 3.65 for bipolar disorder I (BPD I) (P 1⁄4 1.06 Â 10 À 5), while PDE4B tagSNP rs12404118 and disrupted in schizophrenia 1 (DISC1) tagSNP rs823162 interaction was associated with an increased ORinteraction of 3.53 for BPD bipolar disorder II (II) (P 1⁄4 5.47 Â 10 À 5)
Our results indicate that some of the analyzed Single-nucleotide polymorphism (SNP) in several genes of the pathway are in linkage disequilibrium (LD) with causal variants for BPD I and bipolar disorder II (BPD II)

Summary

Introduction

Bipolar disorder (BPD) affects B2.5% of the United States population aged 18 and older based on data from the population-based National Comorbidity Survey Replication.[1]. Because of the well-established roles of cAMP in regulating behavioral processes, we hypothesize that genetic variation in the cAMP pathway genes is associated BPD etiology To test this hypothesis, and to identify the specific mutations within the signaling system that confer susceptibility to BPD, we focused our association study on the collection of genes comprising the cAMP signaling system, as opposed to testing a variety of genes representing many different signaling systems with unrelated functions in the central nervous system. To identify the specific mutations within the signaling system that confer susceptibility to BPD, we focused our association study on the collection of genes comprising the cAMP signaling system, as opposed to testing a variety of genes representing many different signaling systems with unrelated functions in the central nervous system These analyses detected associations of PDE10A with BPD I and of DISC1 and GNAS with BPD II. Significant associations were observed for interaction of variants in DISC1 and PDE4 for both BPD I and BPD II

Materials and methods

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Results

Discussion