Pleiotropic genes underlying genetic correlations across human diseases

Genetic correlation is a key characteristic of the global genetic similarity of human traits. Its primary underlying mechanism is pleiotropy, which operates at various biological levels. Gene-level pleiotropy is of particular interest, as genes are the fundamental functional units of the genome. Using publicly available results from genome-wide association studies for 324 diseases, we selected a set of 45 diseases in which every pair exhibited a significant genetic correlation. These diseases belonged to 10 nosological categories. The search for genes with pleiotropic effects was carried out using three approaches: (1) gene-based association analysis, (2) selection of single nucleotide polymorphisms (SNP) within gene coding regions significantly associated with at least two diseases, and (3) a cross-trait meta-analysis of SNP association signals followed by the identification of independent loci and gene prioritization within those loci. A comprehensive bioinformatic analysis was performed on all genes identified through these methods. We identified 167 pleiotropic genes implicated in 39 diseases. The most pleiotropic genes in our study were LPA, TCF7L2, SLC22A3, FES, CDKN2B, and APOE, which were associated with 7 to 9 diseases each. Bioinformatic analysis revealed that the pleiotropic genes identified for these 39 diseases are also involved in the genetic architecture of 501 other diseases and traits. This indicates a high degree of pleiotropy, facilitated by the involvement of these genes in diverse biological processes - including homeostasis, cell-cell signaling, regulation of cell proliferation, transport, and catalytic activity - and various molecular functions, such as signaling receptor binding. Thus, we demonstrated that 87% of diseases within a fully connected correlation network share associated genes with at least one other disease. This finding strongly suggests that genetic correlations between human diseases are largely driven by the pleiotropic effects of shared genes.