TY - JOUR
T1 - Genome-wide association study of working memory brain activation
AU - Blokland, Gabriëlla A.M.
AU - Wallace, Angus K.
AU - Hansell, Narelle K.
AU - Thompson, Paul M.
AU - Hickie, Ian B.
AU - Montgomery, Grant W.
AU - Martin, Nicholas G.
AU - McMahon, Katie L.
AU - de Zubicaray, Greig I.
AU - Wright, Margaret J.
PY - 2017/5
Y1 - 2017/5
N2 - 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.
AB - 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.
KW - BOLD signal
KW - Functional MRI
KW - Genome-wide association study
KW - n-back
KW - Region-of-interest
KW - Working memory
UR - http://www.scopus.com/inward/record.url?scp=84992188053&partnerID=8YFLogxK
U2 - 10.1016/j.ijpsycho.2016.09.010
DO - 10.1016/j.ijpsycho.2016.09.010
M3 - Article
C2 - 27671502
AN - SCOPUS:84992188053
SN - 0167-8760
VL - 115
SP - 98
EP - 111
JO - International Journal of Psychophysiology
JF - International Journal of Psychophysiology
ER -