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Genetic overlap between diagnostic subtypes of ischemic stroke #MMPMID25613305
Holliday EG; Traylor M; Malik R; Bevan S; Falcone G; Hopewell JC; Cheng YC; Cotlarciuc I; Bis JC; Boerwinkle E; Boncoraglio GB; Clarke R; Cole JW; Fornage M; Furie KL; Ikram MA; Jannes J; Kittner SJ; Lincz LF; Maguire JM; Meschia JF; Mosley TH; Nalls MA; Oldmeadow C; Parati EA; Psaty BM; Rothwell PM; Seshadri S; Scott RJ; Sharma P; Sudlow C; Wiggins KL; Worrall BB; Rosand J; Mitchell BD; Dichgans M; Markus HS; Levi C; Attia J; Wray NR
Stroke 2015[Mar]; 46 (3): 615-9 PMID25613305show ga
Background and Purpose: Despite moderate heritability, the phenotypic heterogeneity of ischemic stroke has hampered gene discovery, motivating analyses of diagnostic subtypes with reduced sample sizes. We assessed evidence for shared genetic etiology among the three major subtypes: large artery atherosclerosis (LAA), cardioembolism (CE) and small vessel disease (SVD), to inform potential cross-subtype analyses. Methods: Analyses used genome-wide summary data for 12,389 ischemic stroke cases (including 2,167 LAA, 2,405 CE and 1,854 SVD) and 62,004 controls from the Metastroke consortium. For 4,561 cases and 7,094 controls, individual-level genotype data were also available. Genetic correlations between subtypes were estimated using linear mixed models (LMM) and polygenic profile scores. Meta-analysis of a combined LAA-SVD phenotype (4,021 cases, 51,976 controls) was performed to identify shared risk alleles. Results: High genetic correlation was identified between LAA and SVD using LMM (rg=0.96, SE=0.47, P=9×10?4) and profile scores (rg=0.72; 95% CI: 0.52 ? 0.93). Between LAA and CE, and SVD and CE, correlation was moderate using LMM but not significantly different from zero for profile scoring. Joint meta-analysis of LAA and SVD identified strong association (P=1×10?7) for SNPs near the opioid receptor ?1 (OPRM1) gene. Conclusions: Our results suggest that LAA and SVD, which have been hitherto treated as genetically distinct, may share a substantial genetic component. Combined analyses of LAA and SVD may increase power to identify small-effect alleles influencing shared pathophysiological processes.
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Stroke 2015 ; 46 (3): 615-9
