Large-scale GWAS reveals genetic architecture of brain white matter microstructure and genetic overlap with cognitive and mental health traits (n=17,706)
Brain genetics is an active research area. The degree to which genetic variants impact variations in brain structure and function remains largely unknown. We examined the heritability of regional brain volumes (P ~ 100) captured by single-nucleotide polymorphisms (SNPs) in UK Biobank (n ~ 9000). We found that regional brain volumes are highly heritable in this study population and common genetic variants can explain up to 80% of their variabilities (median heritability 34.8%). We observed omnigenic impact across the genome and examined the enrichment of SNPs in active chromatin regions. Principal components derived from regional volume data are also highly heritable, but the amount of variance in brain volume explained by the component did not seem to be related to its heritability. Heritability estimates vary substantially across large-scale functional networks, exhibit a symmetric pattern across left and right hemispheres, and are consistent in females and males (correlation = 0.638). We repeated the main analysis in Alzheimer's Disease Neuroimaging Initiative (n ~ 1100), Philadelphia Neurodevelopmental Cohort (n ~ 600), and Pediatric Imaging, Neurocognition, and Genetics (n ~ 500) datasets, which demonstrated that more stable estimates can be obtained from the UK Biobank.
Microstructural changes of white matter (WM) tracts are known to be associated with various neuropsychiatric disorders/diseases. Heritability of structural changes of WM tracts has been examined using diffusion tensor imaging (DTI) in family-based studies for different age groups. The availability of genetic and DTI data from recent large population-based studies offers opportunity to further improve our understanding of genetic contributions. Here, we analyzed the genetic architecture of WM tracts using DTI and single-nucleotide polymorphism (SNP) data of unrelated individuals in the UK Biobank (n ∼ 8000). The DTI parameters were generated using the ENIGMA-DTI pipeline. We found that DTI parameters are substantially heritable on most WM tracts. We observed a highly polygenic or omnigenic architecture of genetic influence across the genome as well as the enrichment of SNPs in active chromatin regions. Our bivariate analyses showed strong genetic correlations for several pairs of WM tracts as well as pairs of DTI parameters. We performed voxel-based analysis to illustrate the pattern of genetic effects on selected parts of the tract-based spatial statistics skeleton. Comparing the estimates from the UK Biobank to those from small population-based studies, we illustrated that sufficiently large sample size is essential for genetic architecture discovery in imaging genetics. We confirmed this finding with a simulation study.
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