Integrative multi-omics QTL colocalization maps regulatory architecture in aging human brain

Multi-trait QTL (xQTL) colocalization has shown great promises in identifying causal variants with shared genetic etiology across multiple molecular modalities, contexts, and complex diseases. However, the lack of scalable and efficient methods to integrate large-scale multi-omics data limits deeper insights into xQTL regulation. Here, we proposeColocBoost, a multi-task learning colocalization method that can scale to hundreds of traits, while accounting for multiple causal variants within a genomic region of interest.ColocBoostemploys a specialized gradient boosting framework that can adaptively couple colocalized traits while performing causal variant selection, thereby enhancing the detection of weaker shared signals compared to existing pairwise and multi-trait colocalization methods. We appliedColocBoostgenome-wide to 17 gene-level single-nucleus and bulk xQTL data from the aging brain cortex of ROSMAP individuals (averageN= 595), encompassing 6 cell types, 3 brain regions and 3 molecular modalities (expression, splicing, and protein abundance). Across molecular xQTLs,ColocBoostidentified 16,503 distinct colocalization events, exhibiting 10.7(±0.74)-fold enrichment for heritability across 57 complex diseases/traits and showing strong concordance with element-gene pairs validated by CRISPR screening assays. When colocalized against Alzheimer’s disease (AD) GWAS,ColocBoostidentified up to 2.5-fold more distinct colocalized loci, explaining twice the AD disease heritability compared to fine-mapping without xQTL integration. This improvement is largely attributable toColocBoost’s enhanced sensitivity in detecting gene-distal colocalizations, as supported by strong concordance with known enhancer-gene links, highlighting its ability to identify biologically plausible AD susceptibility loci with underlying regulatory mechanisms. Notably, several genes includingBLNKandCTSHshowed sub-threshold associations in GWAS, but were identified through multi-omics colocalizations which provide new functional support for their involvement in AD pathogenesis.