Abstract
The genetic architecture of brain structure and function is largely unknown. To investigate this, we carried out genome-wide association studies of 3,144 functional and structural brain imaging phenotypes from UK Biobank (discovery dataset 8,428 subjects). Here we show that many of these phenotypes are heritable. We identify 148 clusters of associations between single nucleotide polymorphisms and imaging phenotypes that replicate at P < 0.05, when we would expect 21 to replicate by chance. Notable significant, interpretable associations include: iron transport and storage genes, related to magnetic susceptibility of subcortical brain tissue; extracellular matrix and epidermal growth factor genes, associated with white matter micro-structure and lesions; genes that regulate mid-line axon development, associated with organization of the pontine crossing tract; and overall 17 genes involved in development, pathway signalling and plasticity. Our results provide insights into the genetic architecture of the brain that are relevant to neurological and psychiatric disorders, brain development and ageing.
Highlights
The genetic architecture of brain structure and function is largely unknown
Brain connectivity can be divided into functional connectivity, where spontaneous temporal synchronizations between brain regions are measured using functional MRI (fMRI) with subjects scanned at rest, and structural connectivity, measured using diffusion magnetic resonance imaging (MRI), which images the physical connections between brain regions based on how water molecules diffuse within white matter tracts
One hundred and forty-eight of these clusters have a lead single-nucleotide polymorphisms (SNPs) that replicates at the 5% level in our replication set of 3,456 participants, and 91 below a 5% false discovery rate (FDR) threshold
Summary
Bringing together researchers with backgrounds in brain imaging and genetic association was key to this work. We uncovered enrichments of functional annotations for many of the structural and diffusion IDPs. A valuable aspect of this work has been to link the associated SNPs back to spatial properties of the voxel-level brain imaging data. P. et al Common genetic variants influence human subcortical brain structures. 9. Shen, L. et al Whole genome association study of brain-wide imaging phenotypes for identifying quantitative trait loci in MCI and AD: A study of the ADNI cohort. Den Braber, A. et al Heritability of subcortical brain measures: a perspective for future genome-wide association studies. E. et al Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence. International Consortium for Blood Pressure Genome-Wide Association Studies Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.
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