Low-frequency and common genetic variation in ischemic stroke: The METASTROKE collaboration

Research output: Contribution to journalArticle

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.

Details

Authors
  • Rainer Malik
  • Matthew Traylor
  • Sara L Pulit
  • Steve Bevan
  • Jemma C Hopewell
  • Elizabeth G Holliday
  • Wei Zhao
  • Patricia Abrantes
  • Philippe Amouyel
  • John R Attia
  • Thomas W K Battey
  • Klaus Berger
  • Giorgio B Boncoraglio
  • Ganesh Chauhan
  • Yu-Ching Cheng
  • Wei-Min Chen
  • Robert Clarke
  • Ioana Cotlarciuc
  • Stephanie Debette
  • Guido J Falcone
  • Jose M Ferro
  • Dale M Gamble
  • Andreea Ilinca
  • Steven J Kittner
  • Christina E Kourkoulis
  • Robin Lemmens
  • Christopher R Levi
  • Peter Lichtner
  • Arne Lindgren
  • Jingmin Liu
  • James F Meschia
  • Braxton D Mitchell
  • Sofia A Oliveira
  • Joana Pera
  • Alex P Reiner
  • Peter M Rothwell
  • Pankaj Sharma
  • Agnieszka Slowik
  • Cathie L M Sudlow
  • Turgut Tatlisumak
  • Vincent Thijs
  • Astrid M Vicente
  • Daniel Woo
  • Sudha Seshadri
  • Danish Saleheen
  • Jonathan Rosand
  • Hugh S Markus
  • Bradford B Worrall
  • Martin Dichgans
  • ISGC Analysis Group
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Neurology

Keywords

  • Brain Ischemia, Case-Control Studies, Cooperative Behavior, Genetic Variation, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Stroke, Journal Article, Meta-Analysis, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.
Original languageEnglish
Pages (from-to)1217-26
Number of pages10
JournalNeurology
Volume86
Issue number13
Publication statusPublished - 2016 Mar 29
Publication categoryResearch
Peer-reviewedYes