A multi-scale cell-type resolved map of trans-regulatory architecture in the aging human brain

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.