Low-frequency and common genetic variation in ischemic stroke

Malik, Rainer; Traylor, Matthew; Pulit, Sara L.; Bevan, Steve; Hopewell, Jemma C.; Holliday, Elizabeth G.; Zhao, Wei; Abrantes, Patrícia; Amouyel, Philippe; Attia, John; Battey, Thomas W.K.; Berger, Klaus; Boncoraglio, Giorgio B.; Chauhan, Ganesh; Cheng, Yu Ching; Chen, Wei Min; Clarke, Robert; Cotlarciuc, Ioana; Debette, Stéphanie; Falcone, Guido J; Ferro, José M.; Gamble, Dale M; Ilinca, Andreea; Kittner, Steven J.; Kourkoulis, Christina; Lemmens, Robin; Levi, Christopher; Lichtner, Peter; Lindgren, Arne; Liu, Jingmin; Meschia, James F.; Mitchell, Braxton D.; Oliveira, Sofia A.; Pera, Joanna; Reiner, Alex P.; Rothwell, Peter M.; Sharma, Pankaj; Słowik, Agnieszka; Sudlow, Cathie; Tatlısumak, Turgut; Thijs, Vincent; Vicente, Astrid M.; Woo, Daniel; Seshadri, Sudha; Saleheen, Danish; Rosand, Jonathan; Markus, Hugh S.; Worrall, Bradford B.; Dichgans, Martin

doi:10.1212/wnl.0000000000002528

Cited by 132 publications

(131 citation statements)

References 39 publications

Supporting

Mentioning

127

Contrasting

Unclassified

Order By: Relevance

“…Previous genome-wide association studies (GWAS) in predominantly European-ancestry groups have identified ten loci robustly associated with stroke 3–12 . In most instances, the associations with stroke were attributed to individual subtypes of ischemic stroke, such as LAS 5,8,9 , CES 3,4 , and SVS 10,12 , or of ICH 6 , although some loci were associated with two or more stroke subtypes 7,9,11,13 or with any stroke 10 . We hypothesized that combining a substantially larger sample size with a transancestral analytic approach would identify additional risk loci and improve fine mapping of causal variants.…”

mentioning

confidence: 98%

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

2018

Self Cite

View full text Add to dashboard Cite

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.

show abstract

mentioning

confidence: 98%

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

2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…This MR analysis was conducted with summary statistics from 2 large ischemic stroke genetics consortia: the METASTROKE Collaboration 3,8 and the National Institute of Neurologic Disorders and Stroke (NINDS)-Stroke Genetics Network (SiGN). 9 GWAS from these consortia contributed a total of 18,476 ischemic stroke cases and 37,296 controls of mainly European ancestry.…”

Section: Discussionmentioning

confidence: 99%

“…All cohorts underwent genotype imputation with the 1000 Genomes (1KG) phase I reference panel before metaanalysis. 8,11 Data from NINDS-SiGN were imputed to a merged reference panel that included the 1KG project phase I and Genome of the Netherlands. 12 Standard protocol approvals, registrations, and patient consents.…”

Section: Discussionmentioning

confidence: 99%

“…Summary statistics for the association of each SNP with the risk factors and ischemic stroke as a whole and the 3 main subtypes (large artery, small vessel, and cardioembolic strokes) were acquired from previously published GWAS of the risk factors [13][14][15][16][17][18] and 2 stroke consortia (METASTROKE and NINDS-SiGN) , respectively. 8,9 The SNP-risk factor and SNPstroke associations were used to compute estimates of each risk factor-stroke association using an inverse-variance weighted method 19 (hereafter referred to as conventional MR analysis). We conducted complementary analyses using the weighted median and MR-Egger regression methods.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Type 2 diabetes, glucose, insulin, BMI, and ischemic stroke subtypes

Larsson¹,

Scott²,

Traylor³

et al. 2017

Neurology

Self Cite

101

View full text Add to dashboard Cite

Objective: To implement a mendelian randomization (MR) approach to determine whether type 2 diabetes mellitus (T2D), fasting glucose, fasting insulin, and body mass index (BMI) are causally associated with specific ischemic stroke subtypes.Methods: MR estimates of the association between each possible risk factor and ischemic stroke subtypes were calculated with inverse-variance weighted (conventional) and weighted median approaches, and MR-Egger regression was used to explore pleiotropy. The number of single nucleotide polymorphisms (SNPs) used as instrumental variables was 49 for T2D, 36 for fasting glucose, 18 for fasting insulin, and 77 for BMI. Genome-wide association study data of SNPstroke associations were derived from METASTROKE and the Stroke Genetics Network (n 5 18,476 ischemic stroke cases and 37,296 controls).Results: Conventional MR analysis showed associations between genetically predicted T2D and large artery stroke (odds ratio [OR] 1.28, 95% confidence interval [CI] 1.16-1.40, p 5 3.3 3 10 27 ) and small vessel stroke (OR 1.21, 95% CI 1.10-1.33, p 5 8.9 3 10 25 ) but not cardioembolic stroke (OR 1.06, 95% CI 0.97-1.15, p 5 0.17). The association of T2D with large artery stroke but not small vessel stroke was consistent in a sensitivity analysis using the weighted median method, and there was no evidence of pleiotropy. Genetically predicted fasting glucose and fasting insulin levels and BMI were not statistically significantly associated with any ischemic stroke subtype. Conclusions:This study provides support that T2D may be causally associated with large artery stroke. Neurology ® 2017;89:454-460 GLOSSARY BMI 5 body mass index; CI 5 confidence interval; GWAS 5 genome-wide association studies; MR 5 mendelian randomization; NINDS 5 National Institute of Neurologic Disorders and Stroke; 1KG 5 1000 Genomes; OR 5 odds ratio; SiGN 5 Stroke Genetics Network; SNP 5 single nucleotide polymorphism; TOAST 5 Trial of Org 10172 in Acute Stroke Treatment; T2D 5 type 2 diabetes mellitus.Stroke is one of the leading causes of disability and death worldwide.1 The burden of stroke is projected to increase considerably in the next decades. Hence, there is a need to develop effective prevention strategies for stroke, which necessitates a better understanding of the underlying risk factors. About 80% of all strokes are ischemic, 1 but this term describes a syndrome caused by a number of different pathologies, which may have different treatments.2 The major etiologies of ischemic stroke are large artery atherosclerosis (large artery stroke), small vessel atherosclerosis (small vessel stroke), and cardioembolism (cardioembolic stroke). Recent data from genomewide association studies (GWAS) have shown that these subtypes have distinctive risk factor profiles and, by implication, diverse pathophysiologic bases. Type 2 diabetes mellitus (T2D) is associated with an increased risk of ischemic stroke, 4 but its relative contribution to different ischemic stroke subtypes is unknown. Moreover, several risk factors t...

show abstract

“…Genome-wide meta-analyses of IS involving >10 000 IS cases have, to date, only identified a few susceptibility loci. 6,7 Furthermore, most genetic associations with IS are subtype specific for which power is more limited. Genetic risk factors for hemorrhagic stroke are summarized elsewhere.…”

Section: Genetic Architecture Of Stroke and Its Risk Factorsmentioning

confidence: 99%