Novel genomic loci and pathways influence patterns of structural covariance in the human brain

Abstract

AbstractNormal and pathologic neurobiological processes influence brain morphology in coordinated ways that give rise to patterns of structural covariance (PSC) across brain regions and individuals during brain aging and brain diseases. The genetic underpinnings of these patterns remain largely unknown. We apply a stochastic multivariate factorization method to a diverse population of 50,699 individuals (12 studies, 130 sites) and derive data-driven, multi-scale PSCs of regional brain size. PSCs were significantly correlated with 915 genomic loci in the discovery set, 617 of which are novel, and 72% were independently replicated. Key pathways influencing PSCs involved reelin signaling, apoptosis, neurogenesis, and appendage development, while pathways of breast cancer indicate potential interplays between brain metastasis and PSCs associated with neurodegeneration and dementia. Using machine learning, multi-scale PSCs effectively derive imaging signatures of several brain diseases. Our results elucidate new genetic and biological underpinnings that influence structural covariance patterns in the human brain.