{
  "abstract": "Mapping genetic effects on distal genes and regulatory programs is essential for understanding how genetic variation influences complex diseases; yet trans-QTL discovery remains limited by weak effect sizes, extensive multiple testing and poor reproducibility. Here, we introduce TransMap, a generalizable computational framework that combines multi-scale trans-QTL mapping with multi-phenotype genetic colocalization to improve the discovery and interpretation of distal regulatory variants. Beyond individual trans-eGenes, TransMap constructs local co-regulatory program phenotypes that account for background expression variation to improve the detection of weak, coordinated distal genetic effects. Across a broad range of simulation settings, TransMap achieved 9.2-36.7% higher trans-QTL discovery power than existing methods while maintaining well-controlled type I error rates. We applied TransMap to bulk and single-nucleus transcriptomic profiles from the aging human brain in the ADSP Functional Genomics Consortium (FunGen-AD), further integrating proteomic, glycoproteomic and metabolomic biomarker measurements (average N=476 donors). Genome-wide fine-mapping of TransMap single-gene and program-level QTL yielded variant annotations with 2.75-2.88x heritability enrichment across 57 complex diseases and traits (average N=307K), with complementary heritability information captured across regulatory scales. Multi-phenotype colocalization identified 49,532 trans-regulatory events supported by shared genetic signals with cis-eQTL or biomarker-QTL, including 1,825 candidate cis-trans-biomarker regulatory configurations. TransMap further revealed an asymmetric cross-cell-type regulatory architecture in which neuronal cis-regulatory signals preferentially associate with coordinated glial trans-regulatory responses, supported by co-culture experiments and spatial transcriptomics. Alzheimer's disease (AD) GWAS-prioritized colocalization identified trans-regulatory associations in 115 AD-associated loci, including a KNOP1 cis-eQTL associated in trans with a microglial regulatory program containing MS4A4E, with additional support from statistical mediation analysis. TransMap provides a multi-scale, cell-type-resolved atlas of trans-regulatory variation and a generalizable framework for elucidating the regulatory architecture of complex diseases.",
  "abstract_shown": true,
  "affiliations": [
    "Memorial Sloan Kettering Cancer Center"
  ],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 20,
  "authors": [
    {
      "name": "X. Cao"
    },
    {
      "name": "Y. Wang"
    },
    {
      "name": "H. Sun"
    },
    {
      "name": "R. Feng"
    },
    {
      "name": "H. Zhang"
    },
    {
      "name": "Y. Li"
    },
    {
      "name": "H. Lee"
    },
    {
      "name": "B. Karaahmet"
    },
    {
      "name": "B. Li"
    },
    {
      "name": "C. Gersbach"
    },
    {
      "name": "G. E. Crawford"
    },
    {
      "name": "M. Taga"
    },
    {
      "name": "M. S. Beeri"
    },
    {
      "name": "A. S. Buchman"
    },
    {
      "name": "H.-U. Klein"
    },
    {
      "name": "P. De Jager"
    },
    {
      "name": "D. A. Bennett"
    },
    {
      "name": "The Alzheimer's Disease Functional Genomics Consortium"
    },
    {
      "name": "G. Wang"
    },
    {
      "affs": [
        0
      ],
      "name": "K. K. Dey"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/6mnp9gh9ps94b.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.11.05.26367384",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.11.05.26367384v1.full",
  "id": "6mnp9gh9ps94b",
  "issns": [],
  "landing_url": "https://www.medrxiv.org/content/10.64898/2026.11.05.26367384v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "medrxiv",
      "neurology"
    ]
  ],
  "openalex": null,
  "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.11.05.26367384v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-05",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/6mnp9gh9ps94b.ris",
  "sources": [
    {
      "first_seen": "2026-11-09T00:20:54Z",
      "native_id": "10.64898/2026.11.05.26367384",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.11.05.26367384v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "medrxiv:neurology",
      "subfield": "neurology"
    }
  ],
  "title": "A multi-scale cell-type resolved map of trans-regulatory architecture in the aging human brain",
  "title_text": "A multi-scale cell-type resolved map of trans-regulatory architecture in the aging human brain",
  "type": "preprint",
  "updated_at": "2026-11-10T00:21:44Z",
  "url": "https://research.draconitic.com/paper/6mnp9gh9ps94b",
  "venue": "medRxiv",
  "versions": []
}