Using linkage information to weight a genome-wide association of bipolar disorder

Issues of multiple-testing and statistical significance in genomewide association studies (GWAS) have prompted statistical methods utilizing prior data to increase the power of association results. Using prior findings from genome-wide linkage studies on bipolar disorder (BPD), we employed a weighted false discovery approach (wFDR; [Roeder et al. 2006. Am J Hum Genet 78(2): 243–252]) to previously reported GWAS data drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Using this method, association signals are up or down-weighted given the linkage score in that genomic region. Although no SNPs in our sample reached genome-wide significance through the wFDR approach, the strongest single SNP result from the original GWAS results (rs4939921 in myosin VB) is strongly up-weighted as it occurs on a linkage peak of chromosome 18. We also identify regions on chromosome 9, 17, and 18 where modestly associated SNP clusters coincide with strong linkage scores, implicating them as possible candidate regions for further analysis. Moving forward, we believe the application of prior linkage information will be increasingly useful to future GWAS studies that incorporate rarer variants into their analysis.