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Exome array analysis of ischaemic stroke : results from a southern Swedish study

Söderholm, M LU ; Almgren, P LU ; Jood, K ; Stanne, T M ; Olsson, Mats ; Ilinca, A LU orcid ; Lorentzen, E ; Norrving, B LU ; Engström, G LU and Melander, O LU orcid , et al. (2016) In European Journal of Neurology 23(12). p.1722-1728
Abstract

BACKGROUND AND PURPOSE: Genome-wide association (GWA) studies have identified a few risk loci for ischaemic stroke, but these variants explain only a small part of the genetic contribution to the disease. Coding variants associated with amino acid substitutions or premature termination of protein synthesis could have a large effect on disease risk. We performed an exome array analysis for ischaemic stroke.

METHODS: Patients with ischaemic stroke (n = 2385) and control subjects (n = 6077) from three Swedish studies were genotyped with the Illumina HumanOmniExpressExome BeadChip. Single-variant association analysis and gene-based tests were performed of exome variants with minor allele frequency of < 5%. A separate GWA analysis... (More)

BACKGROUND AND PURPOSE: Genome-wide association (GWA) studies have identified a few risk loci for ischaemic stroke, but these variants explain only a small part of the genetic contribution to the disease. Coding variants associated with amino acid substitutions or premature termination of protein synthesis could have a large effect on disease risk. We performed an exome array analysis for ischaemic stroke.

METHODS: Patients with ischaemic stroke (n = 2385) and control subjects (n = 6077) from three Swedish studies were genotyped with the Illumina HumanOmniExpressExome BeadChip. Single-variant association analysis and gene-based tests were performed of exome variants with minor allele frequency of < 5%. A separate GWA analysis was also performed, based on 700 000 genotyped common markers and subsequent imputation.

RESULTS: No exome variant or gene was significantly associated with all ischaemic stroke after Bonferroni correction (all P > 1.8 × 10(-6) for single-variant and >4.15 × 10(-6) for gene-based analysis). The strongest association in single-variant analysis was found for a missense variant in the DNAH11 gene (rs143362381; P = 5.01 × 10(-6) ). In gene-based tests, the strongest association was for the ZBTB20 gene (P = 7.9 × 10(-5) ). The GWA analysis showed that the sample was homogenous (median genomic inflation factor = 1.006). No genome-wide significant association with overall ischaemic stroke risk was found. However, previously reported associations for the PITX2 and ZFHX3 gene loci with cardioembolic stroke subtype were replicated (P = 7 × 10(-15) and 6 × 10(-3) ).

CONCLUSIONS: This exome array analysis did not identify any single variants or genes reaching the pre-defined significance level for association with ischaemic stroke. Further studies on exome variants should be performed in even larger, well-defined and subtyped samples.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
stroke, exome array
in
European Journal of Neurology
volume
23
issue
12
pages
7 pages
publisher
Wiley-Blackwell
external identifiers
  • wos:000389135300009
  • scopus:84994410776
  • pmid:27469034
ISSN
1351-5101
DOI
10.1111/ene.13086
language
English
LU publication?
yes
id
54d70dc0-2154-4a66-a91a-d82193e6cbb2
alternative location
http://onlinelibrary.wiley.com/doi/10.1111/ene.13086/full
date added to LUP
2016-09-22 13:22:50
date last changed
2025-01-12 11:50:00
@article{54d70dc0-2154-4a66-a91a-d82193e6cbb2,
  abstract     = {{<p>BACKGROUND AND PURPOSE: Genome-wide association (GWA) studies have identified a few risk loci for ischaemic stroke, but these variants explain only a small part of the genetic contribution to the disease. Coding variants associated with amino acid substitutions or premature termination of protein synthesis could have a large effect on disease risk. We performed an exome array analysis for ischaemic stroke.</p><p>METHODS: Patients with ischaemic stroke (n = 2385) and control subjects (n = 6077) from three Swedish studies were genotyped with the Illumina HumanOmniExpressExome BeadChip. Single-variant association analysis and gene-based tests were performed of exome variants with minor allele frequency of &lt; 5%. A separate GWA analysis was also performed, based on 700 000 genotyped common markers and subsequent imputation.</p><p>RESULTS: No exome variant or gene was significantly associated with all ischaemic stroke after Bonferroni correction (all P &gt; 1.8 × 10(-6) for single-variant and &gt;4.15 × 10(-6) for gene-based analysis). The strongest association in single-variant analysis was found for a missense variant in the DNAH11 gene (rs143362381; P = 5.01 × 10(-6) ). In gene-based tests, the strongest association was for the ZBTB20 gene (P = 7.9 × 10(-5) ). The GWA analysis showed that the sample was homogenous (median genomic inflation factor = 1.006). No genome-wide significant association with overall ischaemic stroke risk was found. However, previously reported associations for the PITX2 and ZFHX3 gene loci with cardioembolic stroke subtype were replicated (P = 7 × 10(-15) and 6 × 10(-3) ).</p><p>CONCLUSIONS: This exome array analysis did not identify any single variants or genes reaching the pre-defined significance level for association with ischaemic stroke. Further studies on exome variants should be performed in even larger, well-defined and subtyped samples.</p>}},
  author       = {{Söderholm, M and Almgren, P and Jood, K and Stanne, T M and Olsson, Mats and Ilinca, A and Lorentzen, E and Norrving, B and Engström, G and Melander, O and Jern, C and Lindgren, Arne}},
  issn         = {{1351-5101}},
  keywords     = {{stroke; exome  array}},
  language     = {{eng}},
  month        = {{07}},
  number       = {{12}},
  pages        = {{1722--1728}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{European Journal of Neurology}},
  title        = {{Exome array analysis of ischaemic stroke : results from a southern Swedish study}},
  url          = {{http://dx.doi.org/10.1111/ene.13086}},
  doi          = {{10.1111/ene.13086}},
  volume       = {{23}},
  year         = {{2016}},
}