Genome-wide association study of working memory brain activation

•We used voxel-level BOLD heritability to define region-of-interest phenotypes.•We performed genome-wide association on 20 n-back functional MRI BOLD phenotypes.•A BANK1 SNP explained 5.5% of variance in supramarginal gyrus n-back BOLD signal.•31 independent SNPs were associated with BOLD signal change at p < 1 × 10−5.

In a population-based genome-wide association (GWA) study of n-back working memory task-related brain activation, we extracted the average percent BOLD signal change (2-back minus 0-back) from 46 regions-of-interest (ROIs) in functional MRI scans from 863 healthy twins and siblings. ROIs were obtained by creating spheres around group random effects analysis local maxima, and by thresholding a voxel-based heritability map of working memory brain activation at 50%. Quality control for test-retest reliability and heritability of ROI measures yielded 20 reliable (r > 0.7) and heritable (h2 > 20%) ROIs. For GWA analysis, the cohort was divided into a discovery (n = 679) and replication (n = 97) sample. No variants survived the stringent multiple-testing-corrected genome-wide significance threshold (p < 4.5 × 10−9), or were replicated (p < 0.0016), but several genes were identified that are worthy of further investigation. A search of 529,379 genomic markers resulted in discovery of 31 independent single nucleotide polymorphisms (SNPs) associated with BOLD signal change at a discovery level of p < 1 × 10−5. Two SNPs (rs7917410 and rs7672408) were associated at a significance level of p < 1 × 10−7. Only one, most strongly affecting BOLD signal change in the left supramarginal gyrus (R2 = 5.5%), had multiple SNPs associated at p < 1 × 10−5 in linkage disequilibrium with it, all located in and around the BANK1 gene. BANK1 encodes a B-cell-specific scaffold protein and has been shown to negatively regulate CD40-mediated AKT activation. AKT is part of the dopamine-signaling pathway, suggesting a mechanism for the involvement of BANK1 in the BOLD response to working memory. Variants identified here may be relevant to (the susceptibility to) common disorders affecting brain function.