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A Novel MMP12 Locus Is Associated with Large Artery Atherosclerotic Stroke Using a Genome-Wide Age-at-Onset Informed Approach
- Source :
- Traylor, M, Mäkelä, K-M, Kilarski, L L, Holliday, E G, Devan, W J, Nalls, M A, Wiggins, K L, 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, J M, Walters, M, Algra, A, Sharma, P, Attia, J R, Boncoraglio, G B, Rothwell, P M, de Bakker, P I W, Bis, J C, Saleheen, D, Kittner, S J, Mitchell, B D, Rosand, J, Meschia, J F, Levi, C, Dichgans, M, Lehtimäki, T & Lewis, C M & Markus, H S 2014, ' A Novel MMP12 Locus Is Associated with Large Artery Atherosclerotic Stroke Using a Genome-Wide Age-at-Onset Informed Approach ', PL o S Genetics, vol. 10, no. 7, e1004469, pp. 1-11 . https://doi.org/10.1371/journal.pgen.1004469, PLoS Genetics, PLoS Genetics; 10(7), no e1004469 (2014)
- Publication Year :
- 2014
-
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<br />Author Summary Ischaemic stroke places an enormous burden on global healthcare. However, the disease processes that lead to stroke are not fully understood. Genome-wide association studies have recently established that common genetic variants can increase risk of ischaemic stroke and its subtypes. In this study, we aimed to identify novel genetic associations with ischaemic stroke and its subtypes by addressing the fact that younger onset cases may have a stronger genetic component, and using this information in our analyses. We identify a novel genetic variant on chromosome 11 (rs660599), which is associated with increased risk of large artery stroke. We also show that mRNA expression of the nearest gene (MMP12) is higher in arteries with the disease process underlying large artery stroke (atherosclerosis). Finally, we evaluate our novel analysis approach, and show that our method is likely to identify further associations with ischaemic stroke.
- Subjects :
- Adult
Male
Cerebrovascular Diseases
Myocardial Infarction
Cardiology
Gene Expression
Coronary Artery Disease
Polymorphism, Single Nucleotide
Vascular Medicine
Matrix Metalloproteinase 12
Genome-Wide Association Studies
Genetics
Medicine and Health Sciences
Humans
Age of Onset
Aged
Glycosaminoglycans
Ischemic Stroke
Biology and Life Sciences
Computational Biology
Arteries
Middle Aged
Genome Analysis
Atherosclerosis
Stroke
Neurology
Female
Developmental Biology
Genome-Wide Association Study
Research Article
Subjects
Details
- Language :
- English
- ISSN :
- 15537390 and 15537404
- Database :
- OpenAIRE
- Journal :
- Traylor, M, Mäkelä, K-M, Kilarski, L L, Holliday, E G, Devan, W J, Nalls, M A, Wiggins, K L, 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, J M, Walters, M, Algra, A, Sharma, P, Attia, J R, Boncoraglio, G B, Rothwell, P M, de Bakker, P I W, Bis, J C, Saleheen, D, Kittner, S J, Mitchell, B D, Rosand, J, Meschia, J F, Levi, C, Dichgans, M, Lehtimäki, T & Lewis, C M & Markus, H S 2014, ' A Novel MMP12 Locus Is Associated with Large Artery Atherosclerotic Stroke Using a Genome-Wide Age-at-Onset Informed Approach ', PL o S Genetics, vol. 10, no. 7, e1004469, pp. 1-11 . https://doi.org/10.1371/journal.pgen.1004469, PLoS Genetics, PLoS Genetics; 10(7), no e1004469 (2014)
- Accession number :
- edsair.pmid.dedup....8107c8a60124459fadc922e9c4b4569a