A0736
Title: Integrative multi-omics QTL colocalization maps regulatory architecture in aging human brain
Authors: Kushal Dey - Memorial Sloan Kettering Cancer Center (United States) [presenting]
Abstract: Multi-trait QTL (xQTL) colocalization has shown great promise in identifying causal variants with shared genetic etiology across multiple molecular modalities, contexts, and complex diseases. ColocBoost is proposed, a multi-task learning colocalization method that can scale to hundreds of traits while accounting for multiple causal variants. ColocBoost employs 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. ColocBoost is applied genome-wide to 17 gene-level single-nucleus and bulk xQTL data from the aging brain cortex of ROSMAP individuals (average N = 595), encompassing 6 cell types, 3 brain regions and 3 molecular modalities (expression, splicing, and protein abundance). Across molecular xQTLs, ColocBoost identified 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, ColocBoost identified up to 2.5-fold more distinct colocalized loci. Several genes, like BLNK and CTSH, showed sub-threshold associations in GWAS but were identified through multi-omics colocalizations showing functional involvement in AD pathogenesis.
