Striking Departures from Polygenic Architecture in the Tails of Complex Traits.

ABSTRACT: Understanding the genetic architecture of human traits is of key biological, medical and evolutionary importance^[1]. Despite much progress, little is known about how genetic architecture varies across the trait continuum and, in particular, if it differs in the tails of complex traits, where disease often occurs. Here, applying a novel approach based on polygenic scores, we reveal striking departures from polygenic architecture across 148 quantitative trait tails, consistent with distinct concentrations of high-impact rare alleles in one or both tails of most of the traits. We demonstrate replication of these results across ancestries, cohorts, repeat measures, and using an orthogonal family-based approach^[2]. Furthermore, trait tails with inferred enrichment of rare

SUBMITTER: Souaiaia T 

PROVIDER: S-EPMC11601658 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature