Abstract 9674: Stroke, Migraine, and Cervical Arterial Dissection: Shared Genetics Reveals Concordant and Opposing Risk Mechanisms

Abstract

Introduction: Migraine, stroke, and cervical artery dissection (CeAD) represent a triad of cerebrovascular disorders with pairwise comorbid relationships and vascular involvement. Systematic exploration of their shared genetics may inform shared and divergent etiology. Methods: The largest available GWASs for all three disorders were used, including for subtypes of stroke (ischemic stroke [IS], large artery stroke [LAS], small vessel stroke [SVS], cardioembolic stroke [CE]) and migraine (with aura [MA] and without aura [MO]). For each pair of disorders, genetic correlation was assessed both on a genome-wide basis and within candidate loci for each disorder. Cross-trait meta-analysis was used to identify shared novel candidate loci. Causality of migraine susceptibility on stroke and CeAD was evaluated by Mendelian randomization (MR). Results: Among all pairs of disorders, genome-wide genetic correlation was only observed for CeAD and migraine, particularly MO. Local genetic correlations were more extensive between migraine and CeAD than migraine and stroke or CeAD and stroke, identifying novel CeAD associations at rs6693567 ( ADAMTSL4/ECM1 ), rs11187838 ( PLCE1 ), and rs7940646 ( MRVI1 ), while strengthening prior subthreshold evidence at rs9486725 ( FHL5 ) and rs650724 ( LRP1 ). At known migraine loci, novel associations with stroke had concordant risk alleles for SVS at rs191602009 ( CARF ), and for CE at rs55884259 ( NKX2-5 ). However, at other migraine loci, there were novel associations with opposite risk alleles for all stroke, IS, and SVS at rs55928386 ( HTRA1 ), for LAS at rs11172113 ( LRP1 ), and for all stroke and IS, respectively, at rs1535791 and rs4942561 (both LRCH1 ). rs182923402 (near PTCH1 ) was a novel locus for both migraine and CE with concordant effects. MR supported causal influence of migraine on CeAD (OR [95%CI] per doubling migraine prevalence=1.69 [1.24-2.3], p=0.0009) with concordant risk, but with opposite risk on LAS (0.86 [0.76 - 0.96], p=0.0067). Conclusions: Genetic effects between migraine and CeAD had concordant effects on risk, highlighting vascular functions in migraine and novel CeAD loci. Most shared loci for migraine and stroke subtypes had opposite effects on risk. The LRP1 locus was common to all three disorders.