A multi-scale cell-type resolved map of trans-regulatory architecture in the aging human brain
- 1Memorial Sloan Kettering Cancer Center
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.
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BibTeX
@misc{cao2026multiscale,
title = {{A multi-scale cell-type resolved map of trans-regulatory architecture in the aging human brain}},
author = {X. Cao and Y. Wang and H. Sun and R. Feng and H. Zhang and Y. Li and H. Lee and B. Karaahmet and B. Li and C. Gersbach and G. E. Crawford and M. Taga and M. S. Beeri and A. S. Buchman and H.-U. Klein and P. De Jager and D. A. Bennett and The Alzheimer's Disease Functional Genomics Consortium and G. Wang and K. K. Dey},
howpublished = {medRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.05.26367384},
url = {https://www.medrxiv.org/content/10.64898/2026.11.05.26367384v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - A multi-scale cell-type resolved map of trans-regulatory architecture in the aging human brain
AU - X. Cao
AU - Y. Wang
AU - H. Sun
AU - R. Feng
AU - H. Zhang
AU - Y. Li
AU - H. Lee
AU - B. Karaahmet
AU - B. Li
AU - C. Gersbach
AU - G. E. Crawford
AU - M. Taga
AU - M. S. Beeri
AU - A. S. Buchman
AU - H.-U. Klein
AU - P. De Jager
AU - D. A. Bennett
AU - The Alzheimer's Disease Functional Genomics Consortium
AU - G. Wang
AU - K. K. Dey
PY - 2026
DA - 2026/11/05
PB - medRxiv
DO - 10.64898/2026.11.05.26367384
UR - https://www.medrxiv.org/content/10.64898/2026.11.05.26367384v1
AB - 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.
ER -