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Genome-wide association study of working memory brain activation.

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.

SUBMITTER: Blokland GAM

PROVIDER: S-EPMC5364069 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Genome-wide association study of working memory brain activation.

Blokland Gabriëlla A M GAM Wallace Angus K AK Hansell Narelle K NK Thompson Paul M PM Hickie Ian B IB Montgomery Grant W GW Martin Nicholas G NG McMahon Katie L KL de Zubicaray Greig I GI Wright Margaret J MJ

International journal of psychophysiology : official journal of the International Organization of Psychophysiology 20160923

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 ...[more]

PMID: 27671502

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Project description:Recent neuroimaging studies have reported an age-related reduction in brain activations in response to working memory load in task-sensitive brain regions. The current fMRI study investigated the age-related differences in brain activations of the updating mechanism in working memory, which was not investigated in previous studies. With a hybrid block/event-related design, this study was able to examine changes in BOLD signals (i.e., neuromodulation) to increase in updating, a type of cognitive control that is understudied. Older adults were separated into young-old and old-old cohorts to examine whether, within healthy aging, the neuromodulation to cognitive control decreases with age. Our results show that younger adults activate left precentral gyrus and right cerebellum more during trials that require updating than trials that do not require updating. Although older adults showed reduced neuromodulation in these two regions, the old-old cohort failed to show any significant neuromodulation in response to updating. Moreover, older adults not only showed reduced suppressions of the default mode network (DMN) regions during the task, they also overactivated some of the DMN regions, esp. the old-old, when compared to the younger adults. Older adults also showed overactivations in a region (right precentral gyrus) that is contralateral to a task-sensitive region that was activated in the younger adults during updating. Brain-behavior correlations suggest that age-related overactivations of these DMN regions and the right precentral gyrus are maladaptive to their performance. Our results suggest that not only the neuromodulation in response to updating demands is diminished in healthy aging, older adults also show maladaptive increases in activations of task-irrelevant regions and reduced hemispheric specificity during updating. These effects are most pronounced in old-old cohort, compared to young-old, suggesting that age-related declines in neuromodulation during cognitive control is more pronounced in older cohorts within healthy aging.

Dataset Information

Genome-wide association study of working memory brain activation.

Publications

Genome-wide association study of working memory brain activation.

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