Genome-wide association study of the human brain functional connectome reveals strong vascular component underlying global network efficiency.

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Bell, Steven 
Tozer, Daniel J 
Markus, Hugh S 

Complex brain networks play a central role in integrating activity across the human brain, and such networks can be identified in the absence of any external stimulus. We performed 10 genome-wide association studies of resting state network measures of intrinsic brain activity in up to 36,150 participants of European ancestry in the UK Biobank. We found that the heritability of global network efficiency was largely explained by blood oxygen level-dependent (BOLD) resting state fluctuation amplitudes (RSFA), which are thought to reflect the vascular component of the BOLD signal. RSFA itself had a significant genetic component and we identified 24 genomic loci associated with RSFA, 157 genes whose predicted expression correlated with it, and 3 proteins in the dorsolateral prefrontal cortex and 4 in plasma. We observed correlations with cardiovascular traits, and single-cell RNA specificity analyses revealed enrichment of vascular related cells. Our analyses also revealed a potential role of lipid transport, store-operated calcium channel activity, and inositol 1,4,5-trisphosphate binding in resting-state BOLD fluctuations. We conclude that that the heritability of global network efficiency is largely explained by the vascular component of the BOLD response as ascertained by RSFA, which itself has a significant genetic component.

Brain, Brain Mapping, Connectome, Genome-Wide Association Study, Humans, Magnetic Resonance Imaging, Rest
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Springer Science and Business Media LLC
British Heart Foundation (RG/16/4/32218)
National Institute for Health Research (IS-BRC-1215-20014)
This work was supported by a British Heart Foundation Programme Grant (RG/16/4/32218). H.S.M. is supported by a National Institute for Health Research (NIHR) Senior Investigator award. D.J.T is funded by the Medical Research Council under grant MR/No26896/1 for work unconnected to this study. This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. The funding organisations had no role in any of the following: design and conduct of the study; collection, management, analysis, and interpretation of the data; review, or approval of the manuscript.