Abstract
Genome-wide association studies (GWAS) have not consistently detected replicable genetic risk factors for ischemic stroke, potentially due to etiological heterogeneity of this trait. We performed GWAS of ischemic stroke and a major ischemic stroke subtype (large artery atherosclerosis, LAA) using 1,162 ischemic stroke cases (including 421 LAA cases) and 1,244 population controls from Australia. Evidence for a genetic influence on ischemic stroke risk was detected, but this influence was higher and more significant for the LAA subtype. We identified a new LAA susceptibility locus on chromosome 6p21.1 (rs556621: odds ratio (OR) = 1.62, P = 3.9 × 10−8) and replicated this association in 1,715 LAA cases and 52,695 population controls from 10 independent population cohorts (meta-analysis replication OR = 1.15, P = 3.9 × 10−4; discovery and replication combined OR = 1.21, P = 4.7 × 10−8). This study identifies a genetic risk locus for LAA and shows how analyzing etiological subtypes may better identify genetic risk alleles for ischemic stroke.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
World Health Organization. Atlas of Heart Disease and Stroke. (World Health Organization, Geneva, 2004).
Feigin, V.L., Lawes, C.M., Bennett, D.A., Barker-Collo, S.L. & Parag, V. Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol. 8, 355–369 (2009).
Strong, K., Mathers, C. & Bonita, R. Preventing stroke: saving lives around the world. Lancet Neurol. 6, 182–187 (2007).
O'Donnell, M.J. et al. Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study. Lancet 376, 112–123 (2010).
Flossmann, E., Schulz, U.G. & Rothwell, P.M. Systematic review of methods and results of studies of the genetic epidemiology of ischemic stroke. Stroke 35, 212–227 (2004).
Jerrard-Dunne, P., Cloud, G., Hassan, A. & Markus, H.S. Evaluating the genetic component of ischemic stroke subtypes: a family history study. Stroke 34, 1364–1369 (2003).
Fox, C.S. et al. Genetic and environmental contributions to atherosclerosis phenotypes in men and women: heritability of carotid intima-media thickness in the Framingham Heart Study. Stroke 34, 397–401 (2003).
Moskau, S. et al. Heritability of carotid artery atherosclerotic lesions: an ultrasound study in 154 families. Stroke 36, 5–8 (2005).
Turner, S.T. et al. Heritability of leukoaraiosis in hypertensive sibships. Hypertension 43, 483–487 (2004).
Carmelli, D. et al. Evidence for genetic variance in white matter hyperintensity volume in normal elderly male twins. Stroke 29, 1177–1181 (1998).
Kääb, S. et al. Large scale replication and meta-analysis of variants on chromosome 4q25 associated with atrial fibrillation. Eur. Heart J. 30, 813–819 (2009).
Gretarsdottir, S. et al. Risk variants for atrial fibrillation on chromosome 4q25 associate with ischemic stroke. Ann. Neurol. 64, 402–409 (2008).
Palomaki, G.E., Melillo, S. & Bradley, L.A. Association between 9p21 genomic markers and heart disease: a meta-analysis. J. Am. Med. Assoc. 303, 648–656 (2010).
Smith, J.G. et al. Common genetic variants on chromosome 9p21 confers risk of ischemic stroke: a large-scale genetic association study. Circ. Cardiovasc. Genet. 2, 159–164 (2009).
Bellenguez, C. et al. Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke. Nat. Genet. 44, 328–333 (2012).
Adams, H.P. Jr. et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 24, 35–41 (1993).
Flossmann, E., Schulz, U.G. & Rothwell, P.M. Potential confounding by intermediate phenotypes in studies of the genetics of ischaemic stroke. Cerebrovasc. Dis. 19, 1–10 (2005).
Yang, J., Lee, S.H., Goddard, M.E. & Visscher, P.M. GCTA: a tool for genome-wide complex trait analysis. Am. J. Hum. Genet. 88, 76–82 (2011).
Heintzman, N.D. et al. Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature 459, 108–112 (2009).
Page, N.M., Butlin, D.J., Lomthaisong, K. & Lowry, P.J. The human apolipoprotein L gene cluster: identification, classification, and sites of distribution. Genomics 74, 71–78 (2001).
Duchateau, P.N. et al. Plasma apolipoprotein L concentrations correlate with plasma triglycerides and cholesterol levels in normolipidemic, hyperlipidemic, and diabetic subjects. J. Lipid Res. 41, 1231–1236 (2000).
Horrevoets, A.J. et al. Vascular endothelial genes that are responsive to tumor necrosis factor-α in vitro are expressed in atherosclerotic lesions, including inhibitor of apoptosis protein-1, stannin, and two novel genes. Blood 93, 3418–3431 (1999).
Monajemi, H., Fontijn, R.D., Pannekoek, H. & Horrevoets, A.J. The apolipoprotein L gene cluster has emerged recently in evolution and is expressed in human vascular tissue. Genomics 79, 539–546 (2002).
Sana, T.R., Janatpour, M.J., Sathe, M., McEvoy, L.M. & McClanahan, T.K. Microarray analysis of primary endothelial cells challenged with different inflammatory and immune cytokines. Cytokine 29, 256–269 (2005).
McEvoy, M. et al. Cohort profile: The Hunter Community Study. Int. J. Epidemiol. 39, 1452–1463 (2010).
Yang, J. et al. Common SNPs explain a large proportion of the heritability for human height. Nat. Genet. 42, 565–569 (2010).
Lee, S.H., Wray, N.R., Goddard, M.E. & Visscher, P.M. Estimating missing heritability for disease from genome-wide association studies. Am. J. Hum. Genet. 88, 294–305 (2011).
Painter, J.N. et al. Genome-wide association study identifies a locus at 7p15.2 associated with endometriosis. Nat. Genet. 43, 51–54 (2011).
de Bakker, P.I. et al. Practical aspects of imputation-driven meta-analysis of genome-wide association studies. Hum. Mol. Genet. 17, R122–R128 (2008).
Li, Y., Willer, C., Sanna, S. & Abecasis, G. Genotype imputation. Annu. Rev. Genomics Hum. Genet. 10, 387–406 (2009).
Li, Y., Willer, C.J., Ding, J., Scheet, P. & Abecasis, G.R. MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet. Epidemiol. 34, 816–834 (2010).
Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).
Dudbridge, F. Likelihood-based association analysis for nuclear families and unrelated subjects with missing genotype data. Hum. Hered. 66, 87–98 (2008).
Pruim, R.J. et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26, 2336–2337 (2010).
Zheng, S.L. et al. Cumulative association of five genetic variants with prostate cancer. N. Engl. J. Med. 358, 910–919 (2008).
StataCorp. Stata: Release 11. Statistical Software. (StataCorp LP, College Station, Texas, 2009).
Webster, J.A. et al. Genetic control of human brain transcript expression in Alzheimer disease. Am. J. Hum. Genet. 84, 445–458 (2009).
Acknowledgements
A complete list of funding acknowledgments is included in the Supplementary Note. We are grateful to the participants with ischemic stroke and also to their families for participating in this study. Australian population control data were derived from the Hunter Community Study. We also thank the University of Newcastle for funding and the men and women of the Hunter region who participated in this study. This research was funded by grants from the Australian National Health and Medical Research Council (NHMRC; project grant 569257), the Australian National Heart Foundation (NHF; project grant G 04S 1623), the University of Newcastle, the Gladys M Brawn Fellowship scheme and the Vincent Fairfax Family Foundation in Australia. E.G.H. is supported by the Australian NHMRC Fellowship scheme. J.G. is supported by a Practitioner Fellowship from the NHMRC and a Senior Clinical Research Fellowship from the Australian Office of Health and Medical Research. The principal funding for the Wellcome Trust Case Control Consortium 2 (WTCCC2) ischemic stroke study was provided by the Wellcome Trust, as part of the WTCCC2 project (085475/B/08/Z, 085475/Z/08/Z and WT084724MA). This work was also supported by the European Community's Sixth Framework Programme (LSHM-CT-2007-037273), the Wellcome Trust core award (090532/Z/09/Z) and AstraZeneca. M. Farrall is a member of the Oxford British Heart Foundation (BHF) Centre of Research Excellence. The Siblings with Ischemic Stroke Study (SWISS) and the Ischemic Stroke Genetics Study (ISGS) were funded by grants from the US National Institute of Neurological Disorders and Stroke. Additional funding was provided by the US National Institute of Neurological Disorders and Stroke (U01NS069208). The Rotterdam Study received principal funding for this report from the Netherlands Heart Foundation (grant 2009B102).
Author information
Authors and Affiliations
Consortia
Contributions
S.A.K., J.W.S., L.F.L., P.M., R.J.S., C.L. and J.A. designed the study. E.G.H. performed statistical analyses in the discovery cohort, meta-analyses of replication data and wrote the first draft of the manuscript. T.-J.E. and R.J.S. coordinated genotyping of the discovery cohort. J.M.M., J.G., J.J., G.J.H., R.B., M.W.P., J.W.S., L.F.L., C.L., M.M., R.P., W.S. and J.A. performed phenotype collection and data management in the Australian sample. E. Biros, M.D.L. and C.O. performed bioinformatic analyses. Replication data were provided by S. Barlera, S. Bevan, J.C.B., E. Boerwinkle, G.B.B., T.G.B., R.D.B., Y.-C.C., J.W.C., I.C., W.J.D., M. Fornage, K.L.F., S.G., A.G., M.A.I., W.T.L., R.M., J.F.M., B.D.M., T.H.M., M.A.N., E.A.P., B.M.P., P.S., K.S., G.T., M.T., U.T., B.F.J.V., K.L.W., B.B.W., C.S., P.M.R., M. Farrall, M.D., J.R. and H.S.M. All authors critically reviewed the manuscript and gave advice on the contents of the paper.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Additional information
A full list of members is provided in the Supplementary Note.
A full list of members is provided in the Supplementary Note.
A full list of members is provided in the Supplementary Note.
Supplementary information
Supplementary Text and Figures
Supplementary Tables 1–12, Supplementary Figures 1–7 and Supplementary Note (PDF 1137 kb)
Rights and permissions
About this article
Cite this article
Holliday, E., Maguire, J., Evans, TJ. et al. Common variants at 6p21.1 are associated with large artery atherosclerotic stroke. Nat Genet 44, 1147–1151 (2012). https://doi.org/10.1038/ng.2397
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng.2397
This article is cited by
-
Metabolomics study in severe extracranial carotid artery stenosis
BMC Neurology (2019)
-
Obesity-Related Genetic Determinants of Heart Failure Prognosis
Cardiovascular Drugs and Therapy (2019)
-
Monogenic, Polygenic, and MicroRNA Markers for Ischemic Stroke
Molecular Neurobiology (2019)
-
Involvement of polymorphisms of the nerve growth factor and its receptor encoding genes in the etiopathogenesis of ischemic stroke
BMC Medical Genetics (2018)
-
The polymorphism rs6918289 located in the downstream region of the TREM2 gene is associated with TNF-α levels and IMT-F
Scientific Reports (2018)