Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

Abstract

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

Mendelian Randomization Study of Obesity and Cerebrovascular Disease

“…ICH was subclassified into lobar and nonlobar ICH, given the different pathophysiology by location . Genetic data for ischemic stroke (including the etiological subtypes) and for ICH were derived from the MEGASTROKE consortium and the International Stroke Genetics Consortium GWAS for ICH, respectively. In brief we utilized the results obtained from inverse‐variance meta‐analysis restricted to subjects of European ancestry after adjusting for age, sex, and principal components reflecting ancestry (40,585 cases; 406,111 controls).…”

“…Genotyping and bioinformatic genetic analysis of each of these GWAS followed standardized procedures that are harmonized and comparable across the studies. Detailed genotype and phenotype assessment procedures have been previously published . Additional demographic and phenotypic information on the included studies is available in the Table.…”

“…Ischemic stroke was analyzed in toto (all-cause ischemic strokes) and further as subclassified into large-artery atherosclerotic stroke (LAS), cardioembolic stroke (CES), and small vessel stroke (SVS). 9 ICH was subclassified into lobar and nonlobar ICH, given the different pathophysiology by location. 10 Genetic data for ischemic stroke (including the etiological subtypes) and for ICH were derived from the MEGASTROKE consortium 9 and the International Stroke Genetics Consortium GWAS for ICH, 11 respectively.…”

“…Detailed genotype and phenotype assessment procedures have been previously published. 8,9,11,[19][20][21] Additional demographic and phenotypic information on the included studies is available in the Table.…”

A flexible and nearly optimal sequential testing approach to randomized testing: QUICK‐STOP

“…Rare genetic variants, imbalanced case control ratios, phenotypic outliers (Stranger et al, ), or non‐normally distributed phenotypes can lead to scenarios in which standard asymptotic theory does not provide reliable results. For some test statistics of interest, for example in gene‐based/region‐based analysis (Chen, Hsu, Gamazon, Cox, & Nicolae, ; Lee, Abecasis, Boehnke, & Lin, ; Liu et al, ; Mishra & Macgregor, ), the asymptotic distribution of the test statistic is even not tractable and permutation/simulation procedures have to be applied, which can be computationally challenging (Malik et al, ; Sugasawa, Noma, Otani, Nishino, & Matsui, ).…”