Shared genetics of migraine with irritable bowel syndrome, peptic ulcer, gastric reflux, diverticular disease, and autoimmune GI disorders (S19.005)

Abstract

<h3>Objective:</h3> To investigate potential genetic relationships and therefore biology that may underlie comorbidity of migraine and several gastrointestinal (GI) disorders. <h3>Background:</h3> 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. <h3>Design/Methods:</h3> 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. <h3>Results:</h3> 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&lt;5×10⁻⁹), attenuated with DD (r_g=0.18, p=7×10⁻⁷), 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 (<i>CALCA</i>) or null (<i>HTR1F</i>). 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. <h3>Conclusions:</h3> 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. <b>Disclosure:</b> Daniel Chasman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Takeda. Daniel Chasman has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Amgen. Daniel Chasman has received research support from Pfizer. Daniel Chasman has received intellectual property interests from a discovery or technology relating to health care. Prof. Guo has nothing to disclose. Dr. Chan has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bayer Pharma AG. Dr. Chan has received personal compensation in the range of $50,000-$99,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pfizer Inc. Dr. Chan has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Gastroenterology. Dr. Chan has received personal compensation in the range of $100,000-$499,999 for serving as an Expert Witness for Boehringer Ingelheim. The institution of Dr. Chan has received research support from Zoe Ltd. The institution of Dr. Chan has received research support from Pfizer Inc. Dr. Staller has received personal compensation in the range of $500-$4,999 for serving as a Consultant for GI Supply. Dr. Staller has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. Dr. Staller has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Anji. The institution of Dr. Staller has received research support from Urovant. The institution of Dr. Staller has received research support from Ironwood. Dr. Rist has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for American Heart Association. The institution of Dr. Rist has received research support from National Institutes of Health. The institution of Dr. Rist has received research support from Biogen, Inc. The institution of Dr. Rist has received research support from Brigham and Women’s Hospital.