Chromatin interactions and expression quantitative trait loci reveal genetic drivers of multimorbidities

Clinical studies of non-communicable diseases identify multimorbidities that suggest a common set of predisposing factors. Despite the fact that humans have ~24,000 genes, we do not understand the genetic pathways that contribute to the development of multimorbid non-communicable disease. Here we create a multimorbidity atlas of traits based on pleiotropy of spatially regulated genes. Using chromatin interaction and expression Quantitative Trait Loci (eQTL) data, we analyse 20,782 variants (p < 5 × 10^-6) associated with 1351 phenotypes to identify 16,248 putative spatial eQTL-eGene pairs that are involved in 76,013 short- and long-range regulatory interactions (FDR < 0.05) in different human tissues. Convex biclustering of spatial eGenes that are shared among phenotypes identifies complex interrelationships between nominally different phenotype-associated SNPs. Our approach enables the simultaneous elucidation of variant interactions with target genes that are drivers of multimorbidity, and those that contribute to unique phenotype associated characteristics.