Common and rare genetic variants show network convergence for a majority of human traits

Abstract While both common and rare variants contribute to the genetic etiology of complex traits, whether their impacts manifest through the same effector genes and molecular mechanisms is not well understood. Here, we systematically analyze common and rare variants associated with each of 373 phenotypic traits within a large biological knowledge network of gene and protein interactions. While common and rare variants implicate few shared genes, they converge on shared molecular networks for more than 75% of traits. We demonstrate that the strength of this convergence is influenced by core factors such as trait heritability, gene selective constraint, and tissue specificity. Using neuropsychiatric traits as examples, we show that common and rare variants impact genes with shared functions across multiple levels of biological organization. These findings underscore the importance of integrating variants across the frequency spectrum and establish a foundation for network-based investigations of the genetics of diverse human diseases and phenotypes.