Abstract
Genome-wide association studies (GWAS) have implicated ANK3 as a susceptibility gene for bipolar disorder (BP). We examined whether epistasis with ANK3 may contribute to the “missing heritability” in BP. We first identified via the STRING database 14 genes encoding proteins with prior biological evidence that they interact molecularly with ANK3. We then tested for statistical evidence of interactions between SNPs in these genes in association with BP in a discovery GWAS dataset and two replication GWAS datasets. The most significant interaction in the discovery GWAS was between SNPs in ANK3 and KCNQ2 (p = 3.18 × 10−8). A total of 31 pair-wise interactions involving combinations between two SNPs from KCNQ2 and 16 different SNPs in ANK3 were significant after permutation. Of these, 28 pair-wise interactions were significant in the first replication GWAS. None were significant in the second replication GWAS, but the two SNPs from KCNQ2 were found to significantly interact with five other SNPs in ANK3, suggesting possible allelic heterogeneity. KCNQ2 forms homo- and hetero-meric complexes with KCNQ3 that constitute voltage-gated potassium channels in neurons. ANK3 is an adaptor protein that, through its interaction with KCNQ2 and KCNQ3, directs the localization of this channel in the axon initial segment (AIS). At the AIS, the KCNQ2/3 complex gives rise to the M-current, which stabilizes the neuronal resting potential and inhibits repetitive firing of action potentials. Thus, these channels act as “dampening” components and prevent neuronal hyperactivity. The interactions between ANK3 and KCNQ2 merit further investigation, and if confirmed, may motivate a new line of research into a novel therapeutic target for BP.
Highlights
Genome-wide association studies (GWAS) offer an unbiased, high-throughput approach for searching the entire genome to identify disease-causing variants
SAMPLES Discovery We tested for statistical evidence of interactions with ANK3 using a GWAS dataset that consisted of two samples collected by the NIMH Genetics Initiative Bipolar Disorder Consortium, the Genetic Association Information Network Bipolar Disorder (GAIN) sample, and the Translational Genomics Research Institute Bipolar Disorder (TGEN) sample
We analyzed the GAINTGEN dataset to assess the statistical evidence for interactions between ANK3 and genes encoding each of the 14 identified proteins in association with bipolar disorder (BP) (Table 2)
Summary
Genome-wide association studies (GWAS) offer an unbiased, high-throughput approach for searching the entire genome to identify disease-causing variants. This approach has generated much enthusiasm in the study of complex disorders such as bipolar disorder (BP) that have been more difficult than Mendelian diseases to genetically map with linkage and candidate gene association approaches. There was little agreement in the findings from the initial GWAS of BP (Craddock and Sklar, 2009) These initial studies were likely under-powered to identify susceptibility loci for BP. A subsequent community-wide effort to combine GWAS from existing studies of BP, referred to as the Psychiatric GWAS Consortium (PGC), identified several additional susceptibility loci and provided further evidence for the association with ANK3 (rs10994397, p = 7.1 × 10−9) (Psychiatric GWAS Consortium Bipolar Disorder Working Group, 2011). Much of the genetic architecture of this disorder remains to be elucidated
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