RT Journal Article
SR Electronic
T1 Low-frequency and common genetic variation in ischemic stroke
JF Neurology
JO Neurology
FD Lippincott Williams & Wilkins
SP 1217
OP 1226
DO 10.1212/WNL.0000000000002528
VO 86
IS 13
A1 Malik, Rainer
A1 Traylor, Matthew
A1 Pulit, Sara L.
A1 Bevan, Steve
A1 Hopewell, Jemma C.
A1 Holliday, Elizabeth G.
A1 Zhao, Wei
A1 Abrantes, Patricia
A1 Amouyel, Philippe
A1 Attia, John R.
A1 Battey, Thomas W.K.
A1 Berger, Klaus
A1 Boncoraglio, Giorgio B.
A1 Chauhan, Ganesh
A1 Cheng, Yu-Ching
A1 Chen, Wei-Min
A1 Clarke, Robert
A1 Cotlarciuc, Ioana
A1 Debette, Stephanie
A1 Falcone, Guido J.
A1 Ferro, Jose M.
A1 Gamble, Dale M.
A1 Ilinca, Andreea
A1 Kittner, Steven J.
A1 Kourkoulis, Christina E.
A1 Lemmens, Robin
A1 Levi, Christopher R.
A1 Lichtner, Peter
A1 Lindgren, Arne
A1 Liu, Jingmin
A1 Meschia, James F.
A1 Mitchell, Braxton D.
A1 Oliveira, Sofia A.
A1 Pera, Joana
A1 Reiner, Alex P.
A1 Rothwell, Peter M.
A1 Sharma, Pankaj
A1 Slowik, Agnieszka
A1 Sudlow, Cathie L.M.
A1 Tatlisumak, Turgut
A1 Thijs, Vincent
A1 Vicente, Astrid M.
A1 Woo, Daniel
A1 Seshadri, Sudha
A1 Saleheen, Danish
A1 Rosand, Jonathan
A1 Markus, Hugh S.
A1 Worrall, Bradford B.
A1 Dichgans, Martin
A1 ,
A1 ,
A1 ,
A1 ,
YR 2016
UL http://n.neurology.org/content/86/13/1217.abstract
AB Objective: To investigate the influence of common and low-frequency genetic variants on the risk of ischemic stroke (all IS) and etiologic stroke subtypes.Methods: We meta-analyzed 12 individual genome-wide association studies comprising 10,307 cases and 19,326 controls imputed to the 1000 Genomes (1 KG) phase I reference panel. We selected variants showing the highest degree of association (p < 1E-5) in the discovery phase for replication in Caucasian (13,435 cases and 29,269 controls) and South Asian (2,385 cases and 5,193 controls) samples followed by a transethnic meta-analysis. We further investigated the p value distribution for different bins of allele frequencies for all IS and stroke subtypes.Results: We showed genome-wide significance for 4 loci: ABO for all IS, HDAC9 for large vessel disease (LVD), and both PITX2 and ZFHX3 for cardioembolic stroke (CE). We further refined the association peaks for ABO and PITX2. Analyzing different allele frequency bins, we showed significant enrichment in low-frequency variants (allele frequency <5%) for both LVD and small vessel disease, and an enrichment of higher frequency variants (allele frequency 10% and 30%) for CE (all p < 1E-5).Conclusions: Our findings suggest that the missing heritability in IS subtypes can in part be attributed to low-frequency and rare variants. Larger sample sizes are needed to identify the variants associated with all IS and stroke subtypes.AF=atrial fibrillation; CADISP=Cervical Artery Dissection and Ischemic Stroke Patients; CE=cardioembolic stroke; FDR=false discovery rate; GWAS=genome-wide association studies; IS=ischemic stroke; LD=linkage disequilibrium; LVD=large vessel disease; MAF=minor allele frequency; MAGENTA=Meta-Analysis Gene-set Enrichment of Variant Associations; NINDS-SiGN=National Institute of Neurological Disorders and Stroke–Stroke Genetics Network; NK=natural killer; NO=nitric oxide; RACE=Risk Assessment of Cardiovascular Events; SNP=single nucleotide polymorphism; SVD=small vessel disease; TOAST=Trial of Org 10172 in Acute Stroke Treatment