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

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 the opportunity to identify novel genetic variants of WM tracts and explore the genetic overlap with other brain-related complex traits. 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. We found that 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