Genome-wide association study of working memory brain activation

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 (h(2) > 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 x 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 x 10(-5). Two SNPs (rs7917410 and rs7672408) were associated at a significance level of p < 1 x 10(-7). Only one, most strongly affecting BOLD signal change in the left supramarginal gyrus (R-2 = 5.5%), had multiple SNPs associated at p < 1 x 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. (C) 2016 Elsevier B.V. All rights reserved.