Abstract
White matter keeps human brain globally connected and shapes communication and connectivity patterns among brain regions. White matter microstructure influences brain structural integrity and may underpin brain functions and disorders. Although under strong genetic control, a large number of genetic variants of white matter remain undiscovered. Here we analyzed the genetic architecture of white matter using diffusion magnetic resonance image (dMRI) of 42,279 individuals (35,101 in the UK Biobank). The dMRIs were consistently processed to generate 215 neuroimaging traits, including 105 measures from tract-specific functional principal component analysis. Genome-wide association analysis identified hundreds of novel independent risk variants (P < 2.3 × 10−10) for white matter microstructural differences. We uncovered 760 pairs of significant genetic correlation between white matter tracts and 60 other complex traits (P < 2.3 × 10−3), including stroke, brain-related disorders (e.g., ADHD, bipolar disorder, major depressive disorder), cognition, neuroticism, chronotype, as well as non-brain traits, such as hypertension, type 2 diabetes, lung function, coronary artery disease, and bone mineral density. Hi-C coupled gene-based analysis identified a large number of pleiotropic genes associated with both white matter and the above complex traits. Gene-set analysis indicated pathways involved in brain disease pathogenesis, developments and abnormalities of neural cells, and repair of white matter damage (P < 1.5 × 10−8). In summary, this large-scale tract-specific study provides a big step forward in understanding the genetics of white matter and its genetic links to other complex traits.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
List of Pediatric Imaging, Neurocognition and Genetics (PING) authors provided in the supplemental materials.