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Abstract:
White matter tracts form the structural basis of large-scale functional networks in the human brain. We applied
brain-wide tractography to diffusion images from 30,810 adult participants (UK Biobank), and found significant
heritability for 90 regional connectivity measures and 851 tract-wise connectivity measures. Multivariate genome-
wide association analyses identified 355 independently associated lead SNPs across the genome, of which 77%
had not been previously associated with human brain metrics. Enrichment analyses implicated
neurodevelopmental processes including neurogenesis, neural differentiation, neural migration, neural projection
guidance, and axon development, as well as prenatal brain expression especially in stem cells, astrocytes,
microglia and neurons. We used the multivariate association profiles of lead SNPs to identify 26 genomic loci
implicated in structural connectivity between core regions of the left-hemisphere language network, and also
identified 6 loci associated with hemispheric left-right asymmetry of structural connectivity. Polygenic scores for
schizophrenia, bipolar disorder, autism spectrum disorder, attention-deficit hyperactivity disorder, left-handedness,
Alzheimer’s disease, amyotrophic lateral sclerosis, and epilepsy showed significant multivariate associations with
structural connectivity, each implicating distinct sets of brain regions with trait-relevant functional profiles. This
large-scale mapping study revealed common genetic contributions to the structural connectome of the human
brain in the general adult population, highlighting links with polygenic disposition to brain disorders and behavioural traits.
