The pleiotropic architecture of human impulsivity across biological scales

Abstract

AbstractImpulsivity is a complex psychological construct that represents a core feature of many psychiatric and neurological conditions. Here, we used multivariate methods to formally model the genetic architecture of impulsivity in humans, advancing genomic discovery and revealing pervasive pleiotropy that largely counters theories of impulsivity as a unitary construct. We identified 18 loci and 93 genes with diverse effects in GWAS and TWAS analyses, respectively, including a hotspot at 17q21.31 that harbors genes involved in neurodevelopmental and neurodegenerative disorders. Downstream analyses revealed that heterogeneous signals were localized to specific biological correlates, including expression in brain tissue during fetal development and cortical alterations in the inferior frontal gyrus. Polygenic score analyses suggested that liability for different forms of impulsivity may differentiate across development, operating via broad pathways early in life but affecting diverse outcomes by adulthood. Collectively, our study generates new insights into the pleiotropic architecture of impulsivity, which provides a more comprehensive understanding of its multi-faceted biology.