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A Novel MMP12 Locus Is Associated with Large Artery Atherosclerotic Stroke Using a Genome-Wide Age-at-Onset Informed Approach.

Traylor, Matthew ; Mäkelä, Kari-Matti ; Kilarski, Laura L ; Holliday, Elizabeth G ; Devan, William J ; Nalls, Mike A ; Wiggins, Kerri L ; Zhao, Wei ; Cheng, Yu-Ching and Achterberg, Sefanja , et al. (2014) In PLoS Genetics 10(7).
Abstract
Genome-wide association studies (GWAS) have begun to identify the common genetic component to ischaemic stroke (IS). However, IS has considerable phenotypic heterogeneity. Where clinical covariates explain a large fraction of disease risk, covariate informed designs can increase power to detect associations. As prevalence rates in IS are markedly affected by age, and younger onset cases may have higher genetic predisposition, we investigated whether an age-at-onset informed approach could detect novel associations with IS and its subtypes; cardioembolic (CE), large artery atherosclerosis (LAA) and small vessel disease (SVD) in 6,778 cases of European ancestry and 12,095 ancestry-matched controls. Regression analysis to identify SNP... (More)
Genome-wide association studies (GWAS) have begun to identify the common genetic component to ischaemic stroke (IS). However, IS has considerable phenotypic heterogeneity. Where clinical covariates explain a large fraction of disease risk, covariate informed designs can increase power to detect associations. As prevalence rates in IS are markedly affected by age, and younger onset cases may have higher genetic predisposition, we investigated whether an age-at-onset informed approach could detect novel associations with IS and its subtypes; cardioembolic (CE), large artery atherosclerosis (LAA) and small vessel disease (SVD) in 6,778 cases of European ancestry and 12,095 ancestry-matched controls. Regression analysis to identify SNP associations was performed on posterior liabilities after conditioning on age-at-onset and affection status. We sought further evidence of an association with LAA in 1,881 cases and 50,817 controls, and examined mRNA expression levels of the nearby genes in atherosclerotic carotid artery plaques. Secondly, we performed permutation analyses to evaluate the extent to which age-at-onset informed analysis improves significance for novel loci. We identified a novel association with an MMP12 locus in LAA (rs660599; p = 2.5×10-7), with independent replication in a second population (p = 0.0048, OR(95% CI) = 1.18(1.05-1.32); meta-analysis p = 2.6×10-8). The nearby gene, MMP12, was significantly overexpressed in carotid plaques compared to atherosclerosis-free control arteries (p = 1.2×10-15; fold change = 335.6). Permutation analyses demonstrated improved significance for associations when accounting for age-at-onset in all four stroke phenotypes (p<0.001). Our results show that a covariate-informed design, by adjusting for age-at-onset of stroke, can detect variants not identified by conventional GWAS. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
PLoS Genetics
volume
10
issue
7
article number
e1004469
publisher
Public Library of Science (PLoS)
external identifiers
  • pmid:25078452
  • wos:000339902600025
  • scopus:84905454842
  • pmid:25078452
ISSN
1553-7404
DOI
10.1371/journal.pgen.1004469
language
English
LU publication?
yes
id
f1c94f96-f94f-452d-9a4f-565689a974c1 (old id 4615947)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/25078452?dopt=Abstract
date added to LUP
2016-04-01 11:10:58
date last changed
2021-09-15 03:33:42
@article{f1c94f96-f94f-452d-9a4f-565689a974c1,
  abstract     = {Genome-wide association studies (GWAS) have begun to identify the common genetic component to ischaemic stroke (IS). However, IS has considerable phenotypic heterogeneity. Where clinical covariates explain a large fraction of disease risk, covariate informed designs can increase power to detect associations. As prevalence rates in IS are markedly affected by age, and younger onset cases may have higher genetic predisposition, we investigated whether an age-at-onset informed approach could detect novel associations with IS and its subtypes; cardioembolic (CE), large artery atherosclerosis (LAA) and small vessel disease (SVD) in 6,778 cases of European ancestry and 12,095 ancestry-matched controls. Regression analysis to identify SNP associations was performed on posterior liabilities after conditioning on age-at-onset and affection status. We sought further evidence of an association with LAA in 1,881 cases and 50,817 controls, and examined mRNA expression levels of the nearby genes in atherosclerotic carotid artery plaques. Secondly, we performed permutation analyses to evaluate the extent to which age-at-onset informed analysis improves significance for novel loci. We identified a novel association with an MMP12 locus in LAA (rs660599; p = 2.5×10-7), with independent replication in a second population (p = 0.0048, OR(95% CI) = 1.18(1.05-1.32); meta-analysis p = 2.6×10-8). The nearby gene, MMP12, was significantly overexpressed in carotid plaques compared to atherosclerosis-free control arteries (p = 1.2×10-15; fold change = 335.6). Permutation analyses demonstrated improved significance for associations when accounting for age-at-onset in all four stroke phenotypes (p&lt;0.001). Our results show that a covariate-informed design, by adjusting for age-at-onset of stroke, can detect variants not identified by conventional GWAS.},
  author       = {Traylor, Matthew and Mäkelä, Kari-Matti and Kilarski, Laura L and Holliday, Elizabeth G and Devan, William J and Nalls, Mike A and Wiggins, Kerri L and Zhao, Wei and Cheng, Yu-Ching and Achterberg, Sefanja and Malik, Rainer and Sudlow, Cathie and Bevan, Steve and Raitoharju, Emma and Oksala, Niku and Thijs, Vincent and Lemmens, Robin and Lindgren, Arne and Slowik, Agnieszka and Maguire, Jane M and Walters, Matthew and Algra, Ale and Sharma, Pankaj and Attia, John R and Boncoraglio, Giorgio B and Rothwell, Peter M and de Bakker, Paul I W and Bis, Joshua C and Saleheen, Danish and Kittner, Steven J and Mitchell, Braxton D and Rosand, Jonathan and Meschia, James F and Levi, Christopher and Dichgans, Martin and Lehtimäki, Terho and Lewis, Cathryn M and Markus, Hugh S},
  issn         = {1553-7404},
  language     = {eng},
  number       = {7},
  publisher    = {Public Library of Science (PLoS)},
  series       = {PLoS Genetics},
  title        = {A Novel MMP12 Locus Is Associated with Large Artery Atherosclerotic Stroke Using a Genome-Wide Age-at-Onset Informed Approach.},
  url          = {https://lup.lub.lu.se/search/files/2449499/8146603.pdf},
  doi          = {10.1371/journal.pgen.1004469},
  volume       = {10},
  year         = {2014},
}