{
  "abstract": "While polygenic gene-by-environment (GxE) signals are increasingly detected in biobank data, it is often unclear whether they reflect the phenotypes measurement scale or one of two biologically distinct mechanisms: heterogeneous genetic effects across environmental strata (effect heterogeneity) or systematically larger but correlated effects in one stratum (amplification). We introduce REGENA (Robust Estimator of Gene-ENvironment Architectures), a variance-component method that disentangles these contributions at biobank scale by learning a phenotype transformation that minimizes scale-induced GxE, thereby assessing scale-dependence while jointly estimating the cross-environment genetic correlation and environment-specific genetic variances. In simulations, REGENA is well-calibrated and powerful while recovering the transformation underlying scale-dependent GxE. Applied to 43 quantitative traits and seven environmental exposures in 291,273 UK Biobank individuals, REGENA finds that roughly half of trait-environment pairs with significant GxE are scale-dependent. Among the remaining scale-independent trait-environment pairs, GxE heritability accounted for an average of 15% of additive heritability and was driven primarily by effect heterogeneity (accounting for 71% of GxE heritability on average) although there was substantial variation in its relative contribution across trait-environment pairs. Environment-specific effects tend to make a larger contribution at lower allele frequencies, accounting for 6% of genetic variance in low-frequency variants versus 3.9% at common variants (signed test p = 1.7 x 10-24). Modeling these distinctions improves environment-specific polygenic prediction (14% on average), with the largest gains for pairs whose genetic effects are least correlated across environments (p = 4.0 x 10-3; 3.8-fold for testosterone stratified by sex and 2.32-fold for waist-hip ratio stratified by alcohol consumption). Further, environment-stratified GWAS detects 174 loci missed by pooled GWAS with 67 having opposite-signed effects across strata.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "name": "Zhengtong Liu",
      "orcid": "0009-0008-2467-9376"
    },
    {
      "name": "Aakarsh Anand"
    },
    {
      "name": "Xinyue Qie"
    },
    {
      "name": "Manuela Costantino"
    },
    {
      "name": "Moonseong Jeong"
    },
    {
      "name": "Aditya Gorla"
    },
    {
      "name": "Noah Zaitlen"
    },
    {
      "name": "Andy Dahl"
    },
    {
      "name": "Sriram Sankararaman"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/7twh2nd4yk2zj.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.15.26365681",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.10.15.26365681v1.full",
  "id": "7twh2nd4yk2zj",
  "issns": [],
  "landing_url": "https://www.medrxiv.org/content/10.64898/2026.10.15.26365681v1",
  "language": "en",
  "licence": "CC-BY-NC",
  "licence_label": "CC BY-NC",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Article"
    ],
    [
      "medrxiv",
      "genetic and genomic medicine"
    ],
    [
      "openalex",
      "1311|Genetic Associations and Epidemiology"
    ]
  ],
  "openalex": "W7223042250",
  "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.10.15.26365681v1.full.pdf",
  "pmcid": "PMC13738851",
  "pmid": "42996209",
  "published": "2026-10-15",
  "publisher": "Cold Spring Harbor Laboratory Preprints",
  "ris": "https://research.draconitic.com/paper/7twh2nd4yk2zj.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:21:16Z",
      "native_id": "10.64898/2026.10.15.26365681",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.10.15.26365681v1"
    },
    {
      "first_seen": "2026-11-09T12:23:46Z",
      "native_id": "PMC13738851",
      "source": "pmc",
      "url": "https://doi.org/10.64898/2026.10.15.26365681"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "medrxiv:genetic and genomic medicine",
      "subfield": "human-genetics"
    }
  ],
  "title": "Disentangling phenotype scale, amplification, and effect heterogeneity underlying polygenic GxE architecture of complex traits",
  "title_text": "Disentangling phenotype scale, amplification, and effect heterogeneity underlying polygenic GxE architecture of complex traits",
  "type": "preprint",
  "updated_at": "2026-11-09T12:23:46Z",
  "url": "https://research.draconitic.com/paper/7twh2nd4yk2zj",
  "venue": "medRxiv",
  "versions": []
}