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Sökning: WFRF:(Lindgren Arne G.) > (2010-2014) > A Novel MMP12 Locus...

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FältnamnIndikatorerMetadata
00005080naa a2200781 4500
001oai:lup.lub.lu.se:f1c94f96-f94f-452d-9a4f-565689a974c1
003SwePub
008160401s2014 | |||||||||||000 ||eng|
0247 a https://lup.lub.lu.se/record/46159472 URI
0247 a https://doi.org/10.1371/journal.pgen.10044692 DOI
040 a (SwePub)lu
041 a engb eng
042 9 SwePub
072 7a art2 swepub-publicationtype
072 7a ref2 swepub-contenttype
1001 a Traylor, Matthew4 aut
2451 0a A Novel MMP12 Locus Is Associated with Large Artery Atherosclerotic Stroke Using a Genome-Wide Age-at-Onset Informed Approach.
264 c 2014-07-31
264 1b Public Library of Science (PLoS),c 2014
338 a electronic2 rdacarrier
520 a 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.
650 7a MEDICIN OCH HÄLSOVETENSKAPx Klinisk medicinx Neurologi0 (SwePub)302072 hsv//swe
650 7a MEDICAL AND HEALTH SCIENCESx Clinical Medicinex Neurology0 (SwePub)302072 hsv//eng
7001 a Mäkelä, Kari-Matti4 aut
7001 a Kilarski, Laura L4 aut
7001 a Holliday, Elizabeth G4 aut
7001 a Devan, William J4 aut
7001 a Nalls, Mike A4 aut
7001 a Wiggins, Kerri L4 aut
7001 a Zhao, Wei4 aut
7001 a Cheng, Yu-Ching4 aut
7001 a Achterberg, Sefanja4 aut
7001 a Malik, Rainer4 aut
7001 a Sudlow, Cathie4 aut
7001 a Bevan, Steve4 aut
7001 a Raitoharju, Emma4 aut
7001 a Oksala, Niku4 aut
7001 a Thijs, Vincent4 aut
7001 a Lemmens, Robin4 aut
7001 a Lindgren, Arneu Lund University,Lunds universitet,Neurologi, Lund,Sektion IV,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Neurology, Lund,Section IV,Department of Clinical Sciences, Lund,Faculty of Medicine4 aut0 (Swepub:lu)neur-ali
7001 a Slowik, Agnieszka4 aut
7001 a Maguire, Jane M4 aut
7001 a Walters, Matthew4 aut
7001 a Algra, Ale4 aut
7001 a Sharma, Pankaj4 aut
7001 a Attia, John R4 aut
7001 a Boncoraglio, Giorgio B4 aut
7001 a Rothwell, Peter M4 aut
7001 a de Bakker, Paul I W4 aut
7001 a Bis, Joshua C4 aut
7001 a Saleheen, Danish4 aut
7001 a Kittner, Steven J4 aut
7001 a Mitchell, Braxton D4 aut
7001 a Rosand, Jonathan4 aut
7001 a Meschia, James F4 aut
7001 a Levi, Christopher4 aut
7001 a Dichgans, Martin4 aut
7001 a Lehtimäki, Terho4 aut
7001 a Lewis, Cathryn M4 aut
7001 a Markus, Hugh S4 aut
7102 a Neurologi, Lundb Sektion IV4 org
7730 t PLoS Geneticsd : Public Library of Science (PLoS)g 10:7q 10:7x 1553-7404
8564 u https://portal.research.lu.se/files/2449499/8146603.pdfx primaryx freey FULLTEXT
8564 u http://www.ncbi.nlm.nih.gov/pubmed/25078452?dopt=Abstractx freey FULLTEXT
8564 u http://dx.doi.org/10.1371/journal.pgen.1004469x freey FULLTEXT
8564 u https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1004469&type=printable
8564 8u https://lup.lub.lu.se/record/4615947
8564 8u https://doi.org/10.1371/journal.pgen.1004469

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