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PLoS Genet DOI:10.1371/journal.pgen.1004469

A novel MMP12 locus is associated with large artery atherosclerotic stroke using a genome-wide age-at-onset informed approach.

Publication TypeJournal Article
Year of Publication2014
AuthorsTraylor, M, Mäkelä, K-M, Kilarski, LL, Holliday, EG, Devan, WJ, Nalls, MA, Wiggins, KL, Zhao, W, Cheng, Y-C, Achterberg, S, Malik, R, Sudlow, C, Bevan, S, Raitoharju, E, Oksala, N, Thijs, V, Lemmens, R, Lindgren, A, Slowik, A, Maguire, JM, Walters, M, Algra, A, Sharma, P, Attia, JR, Boncoraglio, GB, Rothwell, PM, de Bakker, PIW, Bis, JC, Saleheen, D, Kittner, SJ, Mitchell, BD, Rosand, J, Meschia, JF, Levi, C, Dichgans, M, Lehtimäki, T, Lewis, CM, Markus, HS
Corporate AuthorsMETASTROKE, International Stroke Genetics Consortium, Wellcome Trust Case Consortium 2 (WTCCC2)
JournalPLoS Genet
Date Published2014 Jul
KeywordsAdult, Age of Onset, Aged, Arteries, Coronary Artery Disease, Female, Genome-Wide Association Study, Glycosaminoglycans, Humans, Male, Matrix Metalloproteinase 12, Middle Aged, Myocardial Infarction, Polymorphism, Single Nucleotide

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


Alternate JournalPLoS Genet.
PubMed ID25078452
PubMed Central IDPMC4117446
Grant ListU01 HG 004446 / HG / NHGRI NIH HHS / United States
R01 HL087676 / HL / NHLBI NIH HHS / United States
R01 NS45012 / NS / NINDS NIH HHS / United States
R01 HL073410 / HL / NHLBI NIH HHS / United States
U01 NS069208 / NS / NINDS NIH HHS / United States
095626 / / Wellcome Trust / United Kingdom
U54 RR020278 / RR / NCRR NIH HHS / United States
Z01 AG-000015-50 / AG / NIA NIH HHS / United States
R01 HL085251 / HL / NHLBI NIH HHS / United States
R01 NS-42733 / NS / NINDS NIH HHS / United States
/ / Intramural NIH HHS / United States
P30 DK072488 / DK / NIDDK NIH HHS / United States
WT084724MA / / Wellcome Trust / United Kingdom
Z01 AG-000954-06 / AG / NIA NIH HHS / United States
OSRP2/1006 / / The Dunhill Medical Trust / United Kingdom
U01 NS069208-01 / NS / NINDS NIH HHS / United States
HHSN268200782096C / / PHS HHS / United States
U01 HG004436 / HG / NHGRI NIH HHS / United States
085475/Z/08/Z / / Wellcome Trust / United Kingdom
R01 NS-39987 / NS / NINDS NIH HHS / United States
085475/B/08/Z and / / Wellcome Trust / United Kingdom