Distinct genetic architecture in the tails of complex traits
4 affiliations
- 1Department of Cellular Biology, SUNY Downstate Health Sciences University, Brooklyn, NY, USA. [email protected]
- 2Department of Genetics and Genomic Sciences, Icahn School of Medicine, Mount Sinai, New York, NY, USA. [email protected]
- 3Department of Genetics and Genomic Sciences, Icahn School of Medicine, Mount Sinai, New York, NY, USA
- 4Department of Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
Abstract
Complex traits are highly polygenic, with heritability explained by many hundreds of common variants of small effect together with rare variants of large effect 1 . Yet how this genetic architecture varies along the trait continuum has been underexplored, as has the role of natural selection in shaping this variation. Here we developed an approach based on polygenic risk scores that reveals widespread departures from common-variant architecture in one or both of the tails of 74 quantitative traits. These observations were replicated across ancestries, cohorts and repeated measures and using an alternative family-based approach 2 . Incorporating rare variants identified from sequence data resulted in marked reductions in these deviations, suggesting that rare alleles of large effect are key drivers of trait-tail architecture. Forward simulations showed that stabilizing selection could generate the observed patterns, whereas modelling reproductive success provided empirical support for the role of selection. These findings show that although complex traits are polygenic in the population at large, they have a distinct and less polygenic architecture in their tails due to selection. This has implications for rare-variant discovery and complex trait and disease prediction.
Related
- Dynamic genetic architecture and integrative association analysis of milk nitrogen traits in primiparous and multiparous Holstein cows
- Intersectional genetic targeting of molecularly distinct melanin-concentrating hormone neuron subpopulations reveals distinct and overlapping subcircuit architecture
- Genome-wide cross-trait analysis to compare genetic architecture between Parkinson's disease and kidney-related traits.
- Factors underlying creativity show distinct genetic architecture and genetic correlations with psychiatric disorders
- Cross-trait analysis reveals shared genetic architecture between mental health and cardiovascular traits.
BibTeX
@article{souaiaia2026distinct,
title = {{Distinct genetic architecture in the tails of complex traits}},
author = {Tade Souaiaia and Hei Man Wu and A.P.S. Ori and S.-K. Choi and C. J. Hoggart and P.F. O’Reilly},
journal = {Nature},
year = {2026},
month = may,
doi = {10.1038/s41586-026-10516-5},
url = {https://doi.org/10.1038/s41586-026-10516-5},
note = {CC BY},
}
RIS
TY - JOUR
TI - Distinct genetic architecture in the tails of complex traits
AU - Tade Souaiaia
AU - Hei Man Wu
AU - A.P.S. Ori
AU - S.-K. Choi
AU - C. J. Hoggart
AU - P.F. O’Reilly
PY - 2026
DA - 2026/05/27
JO - Nature
DO - 10.1038/s41586-026-10516-5
UR - https://doi.org/10.1038/s41586-026-10516-5
AB - Complex traits are highly polygenic, with heritability explained by many hundreds of common variants of small effect together with rare variants of large effect 1 . Yet how this genetic architecture varies along the trait continuum has been underexplored, as has the role of natural selection in shaping this variation. Here we developed an approach based on polygenic risk scores that reveals widespread departures from common-variant architecture in one or both of the tails of 74 quantitative traits. These observations were replicated across ancestries, cohorts and repeated measures and using an alternative family-based approach 2 . Incorporating rare variants identified from sequence data resulted in marked reductions in these deviations, suggesting that rare alleles of large effect are key drivers of trait-tail architecture. Forward simulations showed that stabilizing selection could generate the observed patterns, whereas modelling reproductive success provided empirical support for the role of selection. These findings show that although complex traits are polygenic in the population at large, they have a distinct and less polygenic architecture in their tails due to selection. This has implications for rare-variant discovery and complex trait and disease prediction.
SN - 0028-0836
SN - 1476-4687
ER -