A genome-wide association study of bipolar disorder using a subphenotype: Sleeplessness symptom of bipolar mania

Objective: Dividing bipolar disorder (BD) into clinical subphenotypes is a possible approach to determine the genetic basis of BD. The goal of this study was to find genes associated with BD by performing a genome-wide association study (GWAS) based on the subphenotypes, i.e., sleeplessness symptom of bipolar mania (SBM) vs. non-sleeplessness symptom of bipolar mania (NSBM). Methods: A total of 2,191 cases, 1,434 controls, and 703,012 single nucleotide polymorphisms (SNPs) in the merged samples from the Translational Genomics Institute and the Genetic Association Information Network were investigated. In individuals with bipolar I disorder, a GWAS of SBM vs. NSBM was performed. Results: We identified 44 trait-associated SNPs with p<10^-4 in a case-only analysis. The most statistically significant peak p-value was observed for rs10492908 (odds ratio=0.1832; p=9.27×10^-7; Permuted p=1.00×10^-6), which is located within the region of the genome encoding WW domain-containing oxidoreductase (WWOX) on chromosome 16q23. A total of eight genomic regions of interest (ROIs) on chromosomes 3, 5, 8, 9, 12, and 17 were also identified, and ROR2 and ANKFN1 in two ROIs may be related with SBM. Conclusion: Our results suggest several candidate genes and pathways that are related to SBM. In particular, WWOX, ROR2, and ANKFN1 are candidate genes related to SBM. Additional replication studies are needed to confirm these results.