Genomic Risk Profiling of Ischemic Stroke: Results of an International Genome-Wide Association Meta-Analysis

被引：13

作者：

Meschia, James F. ^{[1
]}

Singleton, Andrew ^{[4
]}

Nalls, Michael A. ^{[4
]}

Rich, Stephen S. ^{[5
,6
]}

Sharma, Pankaj ^{[7
,8
]}

Ferrucci, Luigi ^{[4
]}

Matarin, Mar ^{[9
]}

Hernandez, Dena G. ^{[4
]}

Pearce, Kerra ^{[10
,11
]}

Brott, Thomas G.

Brown, Robert D., Jr. ^{[2
]}

Hardy, John ^{[3
]}

Worrall, Bradford B. ^{[5
,12
]}

机构：

[1] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA

[2] Mayo Clin, Dept Neurol, Rochester, MN USA

[3] UCL, Inst Neurol, Dept Mol Neurosci, London, England

[4] NIA, Bethesda, MD 20892 USA

[5] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA

[6] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA

[7] Univ London Imperial Coll Sci Technol & Med, ICCRU, London, England

[8] Hammersmith Hosp, London, England

[9] UCL, Inst Neurol, Dept Clin & Expt Epilepsy, London, England

[10] Univ Coll London Genom, London, England

[11] Inst Child Hlth, London, England

[12] Univ Virginia, Dept Neurol, Charlottesville, VA USA

来源：

PLOS ONE | 2011年 / 6卷 / 09期

基金：

美国国家卫生研究院;

关键词：

ATRIAL-FIBRILLATION; POPULATION; CLASSIFICATION; VARIANTS; SEQUENCE; SUBTYPES;

D O I：

10.1371/journal.pone.0023161

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Introduction: Familial aggregation of ischemic stroke derives from shared genetic and environmental factors. We present a meta-analysis of genome-wide association scans (GWAS) from 3 cohorts to identify the contribution of common variants to ischemic stroke risk. Methods: This study involved 1464 ischemic stroke cases and 1932 controls. Cases were genotyped using the Illumina 610 or 660 genotyping arrays; controls, with Illumina HumanHap 550Kv1 or 550Kv3 genotyping arrays. Imputation was performed with the 1000 Genomes European ancestry haplotypes (August 2010 release) as a reference. A total of 5,156,597 single-nucleotide polymorphisms (SNPs) were incorporated into the fixed effects meta-analysis. All SNPs associated with ischemic stroke (P < 1 x 10(-5)) were incorporated into a multivariate risk profile model. Results: No SNP reached genome-wide significance for ischemic stroke (P < 5 x 10(-8)). Secondary analysis identified a significant cumulative effect for age at onset of stroke (first versus fifth quintile of cumulative profiles based on SNPs associated with late onset, beta = 14.77 [10.85, 18.68], P = 5.5 x 10(-12)), as well as a strong effect showing increased risk across samples with a high propensity for stroke among samples with enriched counts of suggestive risk alleles (P < 5 x 10(-6)). Risk profile scores based only on genomic information offered little incremental prediction. Discussion: There is little evidence of a common genetic variant contributing to moderate risk of ischemic stroke. Quintiles based on genetic loading of alleles associated with a younger age at onset of ischemic stroke revealed a significant difference in age at onset between those in the upper and lower quintiles. Using common variants from GWAS and imputation, genomic profiling remains inferior to family history of stroke for defining risk. Inclusion of genomic (rare variant) information may be required to improve clinical risk profiling.

引用

页数：7

共 26 条

[1] CLASSIFICATION OF SUBTYPE OF ACUTE ISCHEMIC STROKE - DEFINITIONS FOR USE IN A MULTICENTER CLINICAL-TRIAL [J].

ADAMS, HP ;

BENDIXEN, BH ;

KAPPELLE, LJ ;

BILLER, J ;

LOVE, BB ;

GORDON, DL ;

MARSH, EE ;

KASE, CS ;

WOLF, PA ;

BABIKIAN, VL ;

LICATAGEHR, EE ;

ALLEN, N ;

BRASS, LM ;

FAYAD, PB ;

PAVALKIS, FJ ;

WEINBERGER, JM ;

TUHRIM, S ;

RUDOLPH, SH ;

HOROWITZ, DR ;

BITTON, A ;

MOHR, JP ;

SACCO, RL ;

CLAVIJO, M ;

ROSENBAUM, DM ;

SPARR, SA ;

KATZ, P ;

KLONOWSKI, E ;

CULEBRAS, A ;

CAREY, G ;

MARTIR, NI ;

FICARRA, C ;

HOGAN, EL ;

CARTER, T ;

GURECKI, P ;

MUNTZ, BK ;

RAMIREZLASSEPAS, M ;

TULLOCH, JW ;

QUINONES, MR ;

MENDEZ, M ;

ZHANG, SM ;

ALA, T ;

JOHNSTON, KC ;

ANDERSON, DC ;

TARREL, RM ;

NANCE, MA ;

BUDLIE, SR ;

DIERICH, M ;

HELGASON, CM ;

HIER, DB ;

SHAPIRO, RA .

STROKE, 1993, 24 (01) :35-41

[2] A map of human genome variation from population-scale sequencing [J].

Altshuler, David ;

Durbin, Richard M. ;

Abecasis, Goncalo R. ;

Bentley, David R. ;

Chakravarti, Aravinda ;

Clark, Andrew G. ;

Collins, Francis S. ;

De la Vega, Francisco M. ;

Donnelly, Peter ;

Egholm, Michael ;

Flicek, Paul ;

Gabriel, Stacey B. ;

Gibbs, Richard A. ;

Knoppers, Bartha M. ;

Lander, Eric S. ;

Lehrach, Hans ;

Mardis, Elaine R. ;

McVean, Gil A. ;

Nickerson, DebbieA. ;

Peltonen, Leena ;

Schafer, Alan J. ;

Sherry, Stephen T. ;

Wang, Jun ;

Wilson, Richard K. ;

Gibbs, Richard A. ;

Deiros, David ;

Metzker, Mike ;

Muzny, Donna ;

Reid, Jeff ;

Wheeler, David ;

Wang, Jun ;

Li, Jingxiang ;

Jian, Min ;

Li, Guoqing ;

Li, Ruiqiang ;

Liang, Huiqing ;

Tian, Geng ;

Wang, Bo ;

Wang, Jian ;

Wang, Wei ;

Yang, Huanming ;

Zhang, Xiuqing ;

Zheng, Huisong ;

Lander, Eric S. ;

Altshuler, David L. ;

Ambrogio, Lauren ;

Bloom, Toby ;

Cibulskis, Kristian ;

Fennell, Tim J. ;

Gabriel, Stacey B. .

NATURE, 2010, 467 (7319) :1061-1073

[3] Chromosome 9p21 in Ischemic Stroke Population Structure and Meta-Analysis [J].

Anderson, Christopher D. ;

Biffi, Alessandro ;

Rost, Natalia S. ;

Cortellini, Lynelle ;

Furie, Karen L. ;

Rosand, Jonathan .

STROKE, 2010, 41 (06) :1123-1131

[4] CLASSIFICATION AND NATURAL-HISTORY OF CLINICALLY IDENTIFIABLE SUBTYPES OF CEREBRAL INFARCTION [J].

BAMFORD, J ;

SANDERCOCK, P ;

DENNIS, M ;

BURN, J ;

WARLOW, C .

LANCET, 1991, 337 (8756) :1521-1526

[5] A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke [J].

Gudbjartsson, Daniel F. ;

Holm, Hilma ;

Gretarsdottir, Solveig ;

Thorleifsson, Gudmar ;

Walters, G. Bragi ;

Thorgeirsson, Gudmundur ;

Gulcher, Jeffrey ;

Mathiesen, Ellisiv B. ;

Njolstad, Inger ;

Nyrnes, Audhild ;

Wilsgaard, Tom ;

Hald, Erin M. ;

Hveem, Kristian ;

Stoltenberg, Camilla ;

Kucera, Gayle ;

Stubblefield, Tanya ;

Carter, Shannon ;

Roden, Dan ;

Ng, Maggie C. Y. ;

Baum, Larry ;

So, Wing Yee ;

Wong, Ka Sing ;

Chan, Juliana C. N. ;

Gieger, Christian ;

Wichmann, H-Erich ;

Gschwendtner, Andreas ;

Dichgans, Martin ;

Kuhlenbaeumer, Gregor ;

Berger, Klaus ;

Ringelstein, E. Bernd ;

Bevan, Steve ;

Markus, Hugh S. ;

Kostulas, Konstantinos ;

Hillert, Jan ;

Sveinbjornsdottir, Sigurlaug ;

Valdimarsson, Einar M. ;

Lochen, Maja-Lisa ;

Ma, Ronald C. W. ;

Darbar, Dawood ;

Kong, Augustine ;

Arnar, David O. ;

Thorsteinsdottir, Unnur ;

Stefansson, Kari .

NATURE GENETICS, 2009, 41 (08) :876-878

[6] Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease [J].

Harold, Denise ;

Abraham, Richard ;

Hollingworth, Paul ;

Sims, Rebecca ;

Gerrish, Amy ;

Hamshere, Marian L. ;

Pahwa, Jaspreet Singh ;

Moskvina, Valentina ;

Dowzell, Kimberley ;

Williams, Amy ;

Jones, Nicola ;

Thomas, Charlene ;

Stretton, Alexandra ;

Morgan, Angharad R. ;

Lovestone, Simon ;

Powell, John ;

Proitsi, Petroula ;

Lupton, Michelle K. ;

Brayne, Carol ;

Rubinsztein, David C. ;

Gill, Michael ;

Lawlor, Brian ;

Lynch, Aoibhinn ;

Morgan, Kevin ;

Brown, Kristelle S. ;

Passmore, Peter A. ;

Craig, David ;

McGuinness, Bernadette ;

Todd, Stephen ;

Holmes, Clive ;

Mann, David ;

Smith, A. David ;

Love, Seth ;

Kehoe, Patrick G. ;

Hardy, John ;

Mead, Simon ;

Fox, Nick ;

Rossor, Martin ;

Collinge, John ;

Maier, Wolfgang ;

Jessen, Frank ;

Schuermann, Britta ;

van den Bussche, Hendrik ;

Heuser, Isabella ;

Kornhuber, Johannes ;

Wiltfang, Jens ;

Dichgans, Martin ;

Froelich, Lutz ;

Hampel, Harald ;

Huell, Michael .

NATURE GENETICS, 2009, 41 (10) :1088-U61

[7] High prevalence of stroke symptoms among persons without a diagnosis of stroke or transient ischemic attack in a general population - The REasons for geographic and racial differences in stroke (REGARDS) study [J].

Howard, Virginia J. ;

McClure, Leslie A. ;

Meschia, James F. ;

Pulley, LeaVonne ;

Orr, Sean C. ;

Friday, Gary H. .

ARCHIVES OF INTERNAL MEDICINE, 2006, 166 (18) :1952-1958

[8] Genomewide Association Studies of Stroke [J].

Ikram, M. Arfan ;

Seshadri, Sudha ;

Bis, Joshua C. ;

Fornage, Myriam ;

DeStefano, Anita L. ;

Aulchenko, Yurii S. ;

Debette, Stephanie ;

Lumley, Thomas ;

Folsom, Aaron R. ;

van den Herik, Evita G. ;

Bos, Michiel J. ;

Beiser, Alexa ;

Cushman, Mary ;

Launer, Lenore J. ;

Shahar, Eyal ;

Struchalin, Maksim ;

Du, Yangchun ;

Glazer, Nicole L. ;

Rosamond, Wayne D. ;

Rivadeneira, Fernando ;

Kelly-Hayes, Margaret ;

Lopez, Oscar L. ;

Coresh, Josef ;

Hofman, Albert ;

DeCarli, Charles ;

Heckbert, Susan R. ;

Koudstaal, Peter J. ;

Yang, Qiong ;

Smith, Nicholas L. ;

Kase, Carlos S. ;

Rice, Kenneth ;

Haritunians, Talin ;

Roks, Gerwin ;

de Kort, Paul L. M. ;

Taylor, Kent D. ;

de Lau, Lonneke M. ;

Oostra, Ben A. ;

Uitterlinden, Andre G. ;

Rotter, Jerome I. ;

Boerwinkle, Eric ;

Psaty, Bruce M. ;

Mosley, Thomas H. ;

van Duijn, Cornelia M. ;

Breteler, Monique M. B. ;

Longstreth, W. T., Jr. ;

Wolf, Philip A. .

NEW ENGLAND JOURNAL OF MEDICINE, 2009, 360 (17) :1718-1728

[9] INTERRATER RELIABILITY OF AN ETIOLOGIC CLASSIFICATION OF ISCHEMIC STROKE [J].

JOHNSON, CJ ;

KITTNER, SJ ;

MCCARTER, RJ ;

SLOAN, MA ;

STERN, BJ ;

BUCHHOLZ, D ;

PRICE, TR .

STROKE, 1995, 26 (01) :46-51

[10] The Association of the 4q25 Susceptibility Variant for Atrial Fibrillation With Stroke Is Limited to Stroke of Cardioembolic Etiology [J].

Lemmens, Robin ;

Buysschaert, Ian ;

Geelen, Veerle ;

Fernandez-Cadenas, Israel ;

Montaner, Joan ;

Schmidt, Helena ;

Schmidt, Reinhold ;

Attia, John ;

Maguire, Jane ;

Levi, Christopher ;

Jood, Katarina ;

Blomstrand, Christian ;

Jern, Christina ;

Wnuk, Marcin ;

Slowik, Agniezska ;

Lambrechts, Diether ;

Thijs, Vincent .

STROKE, 2010, 41 (09) :1850-1857

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