Genetic correlation, pleiotropic loci and shared risk genes between major depressive disorder and gastrointestinal...

Major depressive disorder (MDD) is associated with gastrointestinal tract (GIT) disorders, while genetic correlation, pleiotropic loci and shared risk genes remain to be explored.

Leveraging genome-wide association study statistics for MDD (n = 170,756), peptic ulcer disease (PUD; n = 16,666), gastroesophageal reflux disease (GORD; n = 54,854), PUD and/or GORD and/or medications (PGM; n = 90,175), irritable bowel syndrome (IBS; n = 28,518), and inflammatory bowel disease (IBD; n = 7045), we determined global and local genetic correlations, identified pleiotropic loci, performed gene-level evaluations, and inferred causal associations using bidirectional Mendelian randomization.

We found global correlation of MDD with PUD (r_g = 0.444, P = 3.135 × 10^-24), GORD (r_g = 0.459, P = 2.568 × 10^-65), PGM (r_g = 0.498, P = 6.094 × 10^-114), IBS (r_g = 0.621, P = 2.483 × 10^-63), and IBD (r_g = 0.171, P = 1.824 × 10^-5). We identified 12 locally correlated regions between MDD and GIT disorders except for IBD, and one shared region (chr11:111985737-113,103,996) for PGM, GORD, and IBS. We found one pleiotropic locus for PUD, 12 for GORD, 30 for PGM, eight for IBS, and seven for IBD, and five shared loci (rs138786869, rs2284189, rs3130063, rs35789010, rs7568369) for GORD and PGM. We respectively observed 14 and 20 overlapping genes for MDD-GORD and MDD-PGM. We showed genetic liabilities to GORD, PGM, and IBS causally increase MDD risk, while all reverse causalities are significant.

Our work identifies genetic architectures shared between MDD and GIT disorders, contributes genetic insights to understand depression in the context of gut-brain interactions, and provides potential targets to treat gastrointestinal symptoms in depressive patients.