{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Cellular Biology, SUNY Downstate Health Sciences University, Brooklyn, NY, USA. tade.souaiaia@gmail.com",
    "Department of Genetics and Genomic Sciences, Icahn School of Medicine, Mount Sinai, New York, NY, USA. heiman.wu@mssm.edu",
    "Department of Genetics and Genomic Sciences, Icahn School of Medicine, Mount Sinai, New York, NY, USA",
    "Department of Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Tade Souaiaia",
      "orcid": "0000-0003-3922-1372"
    },
    {
      "affs": [
        1
      ],
      "name": "Hei Man Wu",
      "orcid": "0000-0003-1559-7586"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "A.P.S. Ori"
    },
    {
      "affs": [
        2
      ],
      "name": "S.-K. Choi",
      "orcid": "0000-0003-2747-8277"
    },
    {
      "affs": [
        2
      ],
      "name": "C. J. Hoggart"
    },
    {
      "affs": [
        2
      ],
      "name": "P.F. O’Reilly",
      "orcid": "0000-0001-7515-0845"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/csqkyyq0n29w0.bib",
  "cited_by": 8,
  "doi": "10.1038/s41586-026-10516-5",
  "fulltext_url": null,
  "id": "csqkyyq0n29w0",
  "issns": [
    "0028-0836",
    "1476-4687"
  ],
  "landing_url": "https://doi.org/10.1038/s41586-026-10516-5",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1311|Genetic Associations and Epidemiology"
    ]
  ],
  "openalex": "W7162526370",
  "pdf_url": null,
  "pmcid": "PMC11601658",
  "pmid": "39605697",
  "published": "2026-05-27",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/csqkyyq0n29w0.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T13:21:07Z",
      "native_id": "W7162526370",
      "source": "openalex",
      "url": "https://doi.org/10.1038/s41586-026-10516-5"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:1311|Genetic Associations and Epidemiology",
      "subfield": "genetics-genomics"
    }
  ],
  "title": "Distinct genetic architecture in the tails of complex traits",
  "title_text": "Distinct genetic architecture in the tails of complex traits",
  "type": "peer-reviewed",
  "updated_at": "2026-11-04T13:21:07Z",
  "url": "https://research.draconitic.com/paper/csqkyyq0n29w0",
  "venue": "Nature",
  "versions": []
}