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

Malik, Rainer ; Traylor, Matthew ; Pulit, Sara L ; Bevan, Steve ; Hopewell, Jemma C ; Holliday, Elizabeth G ; Zhao, Wei ; Abrantes, Patricia ; Amouyel, Philippe and Attia, John R , et al. (2016) In Neurology 86(13). p.26-1217
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... (More)

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.

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organization
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type
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publication status
published
subject
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.
in
Neurology
volume
86
issue
13
pages
10 pages
publisher
Lippincott Williams & Wilkins
external identifiers
  • scopus:84962786535
  • wos:000372853000008
  • pmid:26935894
ISSN
1526-632X
DOI
10.1212/WNL.0000000000002528
language
English
LU publication?
yes
id
95b30b07-4ef0-412b-a3b1-535d16124e54
date added to LUP
2016-09-22 13:23:22
date last changed
2024-07-26 18:38:54
@article{95b30b07-4ef0-412b-a3b1-535d16124e54,
  abstract     = {{<p>OBJECTIVE: To investigate the influence of common and low-frequency genetic variants on the risk of ischemic stroke (all IS) and etiologic stroke subtypes.</p><p>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 &lt; 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.</p><p>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 &lt;5%) for both LVD and small vessel disease, and an enrichment of higher frequency variants (allele frequency 10% and 30%) for CE (all p &lt; 1E-5).</p><p>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.</p>}},
  author       = {{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}},
  issn         = {{1526-632X}},
  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.}},
  language     = {{eng}},
  month        = {{03}},
  number       = {{13}},
  pages        = {{26--1217}},
  publisher    = {{Lippincott Williams & Wilkins}},
  series       = {{Neurology}},
  title        = {{Low-frequency and common genetic variation in ischemic stroke : The METASTROKE collaboration}},
  url          = {{http://dx.doi.org/10.1212/WNL.0000000000002528}},
  doi          = {{10.1212/WNL.0000000000002528}},
  volume       = {{86}},
  year         = {{2016}},
}