Genetic architecture of the white matter connectome of the human brain

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.One sentence summaryVariability in white matter fiber tracts of the human brain is associated with hundreds of newly discovered genomic loci that especially implicate stem, neural and glial cells during prenatal development, and is also associated with polygenic dispositions to various brain disorders and behavioural traits.

Genetic architecture of the structural connectome

“…In parallel to ours, another study also examined the genetic architecture of white-matter structural connectivity in the UK Biobank 160 . Unlike our study, the authors used a multivariate GWAS technique, MOSTest 161 , to boost power by leveraging the fact that GWAS variants associated with structural connectivity tend to be associated with connectivity changes in multiple parts of the brain.…”

Specificity and overlap in the genetic architectures of functional and structural connectivity within cerebral resting-state networks

“…RSNs were traditionally discovered based on FC 2 and correlate with the structural connectivity (SC) architecture of white matter in the brain 14–16 to varying degrees across RSNs 17 . The genetic architecture of RSNs-SC has not been investigated to date, but the substantial heritability of multiple properties of major white matter tracts (mean 25.18% - 34.9%) 18–20 suggests the importance of genetic factors for the anatomical backbone of RSNs. Describing the genetic architecture of both RSN-FC and RSN-SC as well as annotation and interpretation of the genetic signal can give insight into a biological substrate relevant to a wide variety of neurological and psychiatric disorders 21 and additionally enables us to estimate to which degree RSN-SC relates to RSN-FC based on a shared genetic source.…”