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

Matthew Traylor, Kari Matti Mäkelä, Laura L. Kilarski, Elizabeth G. Holliday, William J. Devan, Mike A. Nalls, Kerri L. Wiggins, Wei Zhao, Yu Ching Cheng, Sefanja Achterberg, Rainer Malik, Cathie Sudlow, Steve Bevan, Emma Raitoharju, Niku Oksala, Vincent Thijs, Robin Lemmens, Arne Lindgren, Agnieszka Slowik, Jane M. MaguireMatthew Walters, Ale Algra, Pankaj Sharma, John R. Attia, Giorgio B. Boncoraglio, Peter M. Rothwell, Paul I W de Bakker, Joshua C. Bis, Danish Saleheen, Steven J. Kittner, Braxton D. Mitchell, Jonathan Rosand, James F Meschia, Christopher Levi, Martin Dichgans, Terho Lehtimäki, Cathryn M. Lewis, Hugh S. Markus

Research output: Contribution to journalArticle

46 Citations (Scopus)

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<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.

Original languageEnglish (US)
Article numbere1004469
JournalPLoS Genetics
Volume10
Issue number7
DOIs
StatePublished - 2014

Fingerprint

stroke
Age of Onset
arteries
genome
Arteries
Stroke
Genome
atherosclerosis
loci
Atherosclerosis
Genome-Wide Association Study
ancestry
gene
carotid arteries
Carotid Stenosis
meta-analysis
Genetic Predisposition to Disease
liability
conditioning
Genes

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Traylor, M., Mäkelä, K. M., Kilarski, L. L., Holliday, E. G., Devan, W. J., Nalls, M. A., ... Markus, H. S. (2014). A Novel MMP12 Locus Is Associated with Large Artery Atherosclerotic Stroke Using a Genome-Wide Age-at-Onset Informed Approach. PLoS Genetics, 10(7), [e1004469]. https://doi.org/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. / 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; Achterberg, Sefanja; Malik, Rainer; Sudlow, Cathie; Bevan, Steve; Raitoharju, Emma; Oksala, Niku; Thijs, Vincent; Lemmens, Robin; Lindgren, Arne; Slowik, Agnieszka; Maguire, Jane M.; Walters, Matthew; Algra, Ale; Sharma, Pankaj; Attia, John R.; Boncoraglio, Giorgio B.; Rothwell, Peter M.; de Bakker, Paul I W; Bis, Joshua C.; Saleheen, Danish; Kittner, Steven J.; Mitchell, Braxton D.; Rosand, Jonathan; Meschia, James F; Levi, Christopher; Dichgans, Martin; Lehtimäki, Terho; Lewis, Cathryn M.; Markus, Hugh S.

In: PLoS Genetics, Vol. 10, No. 7, e1004469, 2014.

Research output: Contribution to journalArticle

Traylor, M, Mäkelä, KM, Kilarski, LL, Holliday, EG, Devan, WJ, Nalls, MA, Wiggins, KL, Zhao, W, Cheng, YC, 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 2014, 'A Novel MMP12 Locus Is Associated with Large Artery Atherosclerotic Stroke Using a Genome-Wide Age-at-Onset Informed Approach', PLoS Genetics, vol. 10, no. 7, e1004469. https://doi.org/10.1371/journal.pgen.1004469
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 ; Achterberg, Sefanja ; Malik, Rainer ; Sudlow, Cathie ; Bevan, Steve ; Raitoharju, Emma ; Oksala, Niku ; Thijs, Vincent ; Lemmens, Robin ; Lindgren, Arne ; Slowik, Agnieszka ; Maguire, Jane M. ; Walters, Matthew ; Algra, Ale ; Sharma, Pankaj ; Attia, John R. ; Boncoraglio, Giorgio B. ; Rothwell, Peter M. ; de Bakker, Paul I W ; Bis, Joshua C. ; Saleheen, Danish ; Kittner, Steven J. ; Mitchell, Braxton D. ; Rosand, Jonathan ; Meschia, James F ; Levi, Christopher ; Dichgans, Martin ; Lehtimäki, Terho ; Lewis, Cathryn M. ; Markus, Hugh S. / A Novel MMP12 Locus Is Associated with Large Artery Atherosclerotic Stroke Using a Genome-Wide Age-at-Onset Informed Approach. In: PLoS Genetics. 2014 ; Vol. 10, No. 7.
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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<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.",
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AU - Traylor, Matthew

AU - Mäkelä, Kari Matti

AU - Kilarski, Laura L.

AU - Holliday, Elizabeth G.

AU - Devan, William J.

AU - Nalls, Mike A.

AU - Wiggins, Kerri L.

AU - Zhao, Wei

AU - Cheng, Yu Ching

AU - Achterberg, Sefanja

AU - Malik, Rainer

AU - Sudlow, Cathie

AU - Bevan, Steve

AU - Raitoharju, Emma

AU - Oksala, Niku

AU - Thijs, Vincent

AU - Lemmens, Robin

AU - Lindgren, Arne

AU - Slowik, Agnieszka

AU - Maguire, Jane M.

AU - Walters, Matthew

AU - Algra, Ale

AU - Sharma, Pankaj

AU - Attia, John R.

AU - Boncoraglio, Giorgio B.

AU - Rothwell, Peter M.

AU - de Bakker, Paul I W

AU - Bis, Joshua C.

AU - Saleheen, Danish

AU - Kittner, Steven J.

AU - Mitchell, Braxton D.

AU - Rosand, Jonathan

AU - Meschia, James F

AU - Levi, Christopher

AU - Dichgans, Martin

AU - Lehtimäki, Terho

AU - Lewis, Cathryn M.

AU - Markus, Hugh S.

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