Large-scale GWAS reveals genetic architecture of brain white matter microstructure and genetic overlap with cognitive and mental health traits (n=17,706)

Abstract Background Individual variations of white matter (WM) tracts are known to be associated with various cognitive and neuropsychiatric traits. Diffusion tensor imaging (DTI) and genome-wide single-nucleotide polymorphism (SNP) data from 17,706 UK Biobank participants offer opportunity to identify novel genetic variants of WM tracts and explore the genetic overlap with other brain-related complex traits. Method We analyzed the genetic architecture of 110 tract-based DTI parameters, carried out genome-wide association studies (GWAS) and performed post-GWAS analyses, including association lookups, gene-based association analysis, functional gene mapping, and genetic correlation estimation. Results DTI parameters are substantially heritable for all WM tracts (mean heritability 48.7%). We observed a highly polygenic architecture of genetic influence across the genome (p-value=1.67*10−05) as well as the enrichment of genetic effects for active SNPs annotated by central nervous system cells (p-value=8.95*10−12). GWAS identified 213 independent significant SNPs associated with 90 DTI parameters (696 SNP-level and 205 locus-level associations; p-value Conclusions The present study identifies many new genetic variants at SNP, locus and gene levels for integrity of brain WM tracts and provides the overview of pleiotropy with cognitive and mental health traits.