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

Normal 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 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 involve 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 support vector machines, 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. Significance statementThe coordinated patterns of changes in the human brain throughout life, driven by brain development, aging, and diseases, remain largely unexplored regarding their underlying genetic determinants. This study delineates 2003 multi-scale patterns of structural covariance (PSCs) and identifies 617 novel genomic loci, with the mapped genes enriched in biological pathways implicated in reelin signaling, apoptosis, neurogenesis, and appendage development. Overall, the 2003 PSCs provide new genetic insights into understanding human brain morphological changes and demonstrate great potential in predicting various neurologic conditions.