Genome‐wide meta‐analysis identifies 3 novel loci associated with stroke

Abstract

We conducted a European‐only and transancestral genome‐wide association meta‐analysis in 72,147 stroke patients and 823,869 controls using data from UK Biobank (UKB) and the MEGASTROKE consortium. We identified an exonic polymorphism in NOS3 (rs1799983, p.Glu298Asp; p = 2.2E‐8, odds ratio [OR] = 1.05, 95% confidence interval [CI] = 1.04–1.07) and variants in an intron of COL4A1 (rs9521634; p = 3.8E‐8, OR = 1.04, 95% CI = 1.03–1.06) and near DYRK1A (rs720470; p = 6.1E‐9, OR = 1.05, 95% CI = 1.03–1.07) at genome‐wide significance for stroke. Effect sizes of known stroke loci were highly correlated between UKB and MEGASTROKE. Using Mendelian randomization, we further show that genetic variation in the nitric oxide synthase–nitric oxide pathway in part affects stroke risk via variation in blood pressure. Ann Neurol 2018;84:934–939

Interleukin-6 signaling effects on ischemic stroke and other cardiovascular outcomes: a Mendelian Randomization study

“…29,30 Hence, MR has become a powerful strategy to prioritize interventions for exploration in clinical trials. 28 Here, leveraging data from large genome-wide association studies (GWASs) [31][32][33] and applying MR analyses, we aimed to: (i) identify genetic proxies for downregulated IL-6 signaling on the basis of their effects on CRP levels, a well-established IL-6 signaling downstream effector, 13,20,34 (ii) validate their utility by comparing the consistency of their effects on upstream regulators and downstream effectors of the IL-6 signaling pathway with the effects of pharmacological IL-6R inhibition, as derived from clinical trials, (iii) explore associations of genetic predisposition to downregulated IL-6 signaling with the risk of ischemic stroke and coronary artery disease, (iv) examine associations with major etiological subtypes of ischemic stroke (large artery, cardioembolic, and small vessel stroke), and (v) examine associations with a broad range of other cardiovascular phenotypes. To derive clinically meaningful effect sizes that would be comparable to those derived from potential future clinical trials, we weighted our instruments based on the CRP-decreasing effects of tocilizumab, a monoclonal antibody targeting IL-6R.…”

Genomic risk score offers predictive performance comparable to clinical risk factors for ischaemic stroke

“…The risk of ischaemic stroke is determined by a complex interplay of genetic and environmental factors partly acting through modifiable risk factors such as hypertension and diabetes. Roughly thirty-five genomic loci have been robustly associated with stroke [4][5][6][7] , and many more genetic associations have been reported for stroke-related risk factors [8][9][10][11][12][13][14] , e.g., over 1,000 loci have been associated with blood pressure (BP) 11,[15][16][17][18][19] and >100 with atrial fibrillation (AF) 10,20 . These data are now beginning to be harnessed to aid risk prediction.…”

Alternate approach to stroke phenotyping identifies a genetic risk locus for small vessel stroke

“…We checked for SNPs that are not in a locus that had already been reported as an associated locus in MEGASTROKE, resulting in a list of 5 new SNPs (2 for SVS and 3 for CES), which we looked up for replication. To this end, we ran the MEGASTROKE GWAS again (European and trans-ancestry analysis per subtype using TOAST [31]) without the SiGN cohort, to ensure summary statistics independent from the discovery GWAS. We set Bonferroni p-value thresholds to adjust for the number of SNPs looked-up for the phenotype in question, and for the number of GWAS it was looked up in (2, for the European and trans-ancestry analyses).…”