Tail-specific genetics: rare variants sculpt trait extremes under selection

A large study across 74 quantitative traits in UK Biobank and replication cohorts shows that while complex traits are broadly polygenic, the tails of their distributions are enriched for rare, large‑effect alleles. Using POPout and family‑based STANDout tests, researchers find widespread tail departures from common-variant expectations, replicated across ancestries and repeated measurements. Incorporating sequencing‑identified rare variants markedly reduces these tail deviations, indicating rare alleles drive trait extremes. Forward simulations support stabilizing selection as a mechanism, with lifetime reproductive success providing empirical support for selection. These results imply tail architecture is distinct from the population-wide polygenic pattern and have implications for rare-variant discovery and improving prediction of complex traits and diseases.