Low-frequency and common genetic variation in ischemic stroke

Malik, Rainer and Traylor, Matthew and Pulit, Sara L. and Bevan, Steve and Hopewell, Jemma C. and Holliday, Elizabeth G. and Zhao, Wei and Abrantes, Patricia and Amouyel, Philippe and Attia, John R. and Battey, Thomas W.K. and Berger, Klaus and Boncoraglio, Giorgio B. and Chauhan, Ganesh and Cheng, Yu-Ching and Chen, Wei-Min and Clarke, Robert and Cotlarciuc, Ioana and Debette, Stephanie and Falcone, Guido J. and Ferro, Jose M. and Gamble, Dale M. and Ilinca, Andreea and Kittner, Steven J. and Kourkoulis, Christina E. and Lemmens, Robin and Levi, Christopher R. and Lichtner, Peter and Lindgren, Arne and Liu, Jingmin and Meschia, James F. and Mitchell, Braxton D. and Oliveira, Sofia A. and Pera, Joana and Reiner, Alex P. and Rothwell, Peter M. and Sharma, Pankaj and Slowik, Agnieszka and Sudlow, Cathie L.M. and Tatlisumak, Turgut and Thijs, Vincent and Vicente, Astrid M. and Woo, Daniel and Seshadri, Sudha and Saleheen, Danish and Rosand, Jonathan and Markus, Hugh S. and Worrall, Bradford B. and Dichgans, Martin (2016) Low-frequency and common genetic variation in ischemic stroke. Neurology, 86 (13). pp. 1217-1226. ISSN 0028-3878

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Item Type:Article
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Abstract

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.

Keywords:stroke, NotOAChecked
Subjects:C Biological Sciences > C400 Genetics
C Biological Sciences > C420 Human Genetics
C Biological Sciences > C440 Molecular Genetics
C Biological Sciences > C431 Medical Genetics
Divisions:College of Science > School of Life Sciences
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ID Code:27845
Deposited On:13 Jul 2017 13:02

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