Genome-wide association study of working memory brain activation

Int J Psychophysiol. 2017 May;115:98-111. doi: 10.1016/j.ijpsycho.2016.09.010. Epub 2016 Sep 23.

Abstract

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.

Keywords: BOLD signal; Functional MRI; Genome-wide association study; Region-of-interest; Working memory; n-back.

Publication types

  • Twin Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Brain / diagnostic imaging
  • Brain / physiology*
  • Community Health Planning
  • Female
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Image Processing, Computer-Assisted
  • Magnetic Resonance Imaging
  • Male
  • Memory, Short-Term / physiology*
  • Models, Genetic
  • Neuropsychological Tests
  • Oxygen / blood
  • Phenotype
  • Polymorphism, Single Nucleotide / genetics*
  • Reproducibility of Results
  • Twins
  • Young Adult

Substances

  • Oxygen