To investigate potential genetic relationships and therefore biology that may underlie comorbidity of migraine and several gastrointestinal (GI) disorders.

Individuals who experience migraine have elevated risk of irritable bowel syndrome (IBS), gastroesophageal reflux disease (GERD), and peptic ulcer (PUD), but not autoimmune GI disorders.  Moreover, migraine treatments targeting CGRP and serotonin pathways are also effective for IBS.  The extent to which genetics informs and extends these risk and treatment relationships is unknown.

Analysis compared summary statistics from large-scale genome-wide association studies for migraine to those for IBS, PUD, GERD, diverticular disease (DD), and autoimmune GI disorders (inflammatory bowel disease, Crohn’s disease, and ulcerative colitis).  Shared genetics was investigated by evaluating pairwise global and local genetic correlations, identifying potential shared candidate loci, inferring tissues relevant to genetic overlaps, and assessing potential causal relationships with genetic instrumental analysis.

Genome-wide genetic correlation was strong for migraine with IBS (r_g=0.37), GERD (r_g=0.34), and PUD (r_g=0.29) (all p<5x10^-9), attenuated with DD (r_g=0.18, p=7x10^-7), and null with autoimmune GI disorders.  The overlaps implicated shared functions of cardiovascular tissues for IBS and of the central nervous system for PUD and GERD.  Locally, there were 10 novel loci among those shared with migraine: three loci for IBS; four different loci for GERD or PUD; and seven different loci for DD that partially overlapped nine loci for inflammatory disorders.  However, at loci encoding targets of migraine therapeutics, correlation was only nominally significant (CALCA) or null (HTR1F).  The local genetic signals of migraine with IBS, GERD, and PUD implicated functions of cerebellar, pituitary, and thyroid tissues.  Genetic causal inference supported GERD, PUD, and DD as potential causes of migraine but not vice versa.

Migraine shares genetics with IBS, GERD, PUD, and DD, although in distinct ways, thereby identifying novel loci, causal pathways, and potentially, tissues with shared biological functions.