Shared Genetics of Migraine and Gastrointestinal Disorders Implicates Underlying Neurologic Mechanisms Yet Heterogeneous Etiologies.

Abstract

Background and objectives: Migraine is strongly comorbid with irritable bowel syndrome (IBS), one of several gastrointestinal (GI) conditions that are distinguished by symptomatic profiles that are partly overlapping. Potential shared mechanisms of migraine and the GI conditions were investigated by assessing shared genetics on a genome-wide basis.

Methods: Analyses leveraged genome-wide summary statistics from large-scale genetic studies for migraine, including by aura status, IBS, peptic ulcer disease (PUD), gastrointestinal reflux (GERD), functional dyspepsia (FD), diverticular disease (DD), and the immune-related inflammatory bowel disease (IBD) or its constituents, ulcerative colitis (UC) and Crohn disease (CD). Genetic correlation was evaluated on a genome-wide basis and at independent local regions, including those related to therapeutic targeting of serotonin and the calcitonin gene-related peptide. Genetic correlation was assessed for enrichment at genes according to tissue specificity of gene expression. Potential causality between migraine and the GI conditions was assessed by Mendelian randomization.

Results: Genetic correlation with migraine was strongly significant among the nonimmune GI disorders, maximally for IBS (rg [SE] = 0.37[0.04], p = 10^-21) and minimally for DD (0.18 (0.04), 7.5 × 10^-7), but null for IBD. There were distinct patterns of local genetic sharing with migraine across the GI conditions at 22 significant segments of the genome, 7 of which were novel for either migraine or GI or both. Enrichment analysis suggested involvement of the CNS in genetic overlap of GERD, IBS, and PUD with migraine. There was local genetic sharing with migraine at CALCA/CALCB (encoding calcitonin gene-related peptide [CGRP]) in an inverse sense for GERD and PUD, but with concordance and greater significance for DD, IBD, and UC. Mendelian randomization supported causal effects of PUD, GERD and particularly DD (OR[SE] = 1.90 (1.35-2.68, p = 2.2 × 10^-4) on migraine, but not of migraine on any GI condition.

Discussion: Genetic sharing of migraine and non-immune-related GI disorders was extensive yet distinct across GI disorders that have overlapping symptoms, with enrichment signals that imply neurologic mechanisms. Causal effects of some GI conditions on migraine were supported. A concordant local correlation at CALCA/CALCB of migraine with both DD and the immune-related disorders suggests potential benefit to these conditions from repurposed migraine therapeutics targeting CGRP.