Genetic Heritability of Ischemic Stroke and the Contribution of Previously Reported Candidate Gene and Genomewide Associations

Background and Purpose— The contribution of genetics to stroke risk, and whether this differs for different stroke subtypes, remains uncertain. Genomewide complex trait analysis allows heritability to be assessed from genomewide association study (GWAS) data. Previous candidate gene studies have identified many associations with stoke but whether these are important requires replication in large independent data sets. GWAS data sets provide a powerful resource to perform replication studies. Methods— We applied genomewide complex trait analysis to a GWAS data set of 3752 ischemic strokes and 5972 controls and determined heritability for all ischemic stroke and the most common subtypes: large-vessel disease, small-vessel disease, and cardioembolic stroke. By systematic review we identified previous candidate gene and GWAS associations with stroke and previous GWAS associations with related cardiovascular phenotypes (myocardial infarction, atrial fibrillation, and carotid intima-media thickness). Fifty associations were identified. Results— For all ischemic stroke, heritability was 37.9%. Heritability varied markedly by stroke subtype being 40.3% for large-vessel disease and 32.6% for cardioembolic but lower for small-vessel disease (16.1%). No previously reported candidate gene was significant after rigorous correction for multiple testing. In contrast, 3 loci from related cardiovascular GWAS studies were significant: PHACTR1 in large-vessel disease (P=2.63e−6), PITX2 in cardioembolic stroke (P=4.78e−8), and ZFHX3 in cardioembolic stroke (P=5.50e−7). Conclusions— There is substantial heritability for ischemic stroke, but this varies for different stroke subtypes. Previous candidate gene associations contribute little to this heritability, but GWAS studies in related cardiovascular phenotypes are identifying robust associations. The heritability data, and data from GWAS, suggest detecting additional associations will depend on careful stroke subtyping.

[1]  R. Hui,et al.  Association of Common Variants of CYP 4 A 11 and CYP 4 F 2 with Stroke in the Han Chinese Population , 2014 .

[2]  Shashaank Vattikuti,et al.  Heritability and Genetic Correlations Explained by Common SNPs for Metabolic Syndrome Traits , 2012, PLoS genetics.

[3]  M. Pirinen,et al.  Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke , 2012, Nature Genetics.

[4]  A. Munshi,et al.  Association of tumor necrosis factor‐α and matrix metalloproteinase‐3 gene variants with stroke , 2011, European journal of neurology.

[5]  O. Melander,et al.  Genetic variants in serum and glucocortocoid regulated kinase 1, a regulator of the epithelial sodium channel, are associated with ischaemic stroke , 2011, Journal of hypertension.

[6]  Daowen Wang,et al.  Genetic polymorphism of CYP11B2 gene and stroke intheHan Chinese population and a meta-analysis , 2011, Pharmacogenetics and genomics.

[7]  Y. Fujiwara,et al.  Association of a polymorphism of BTN2A1 with myocardial infarction in East Asian populations. , 2011, Atherosclerosis.

[8]  P. Visscher,et al.  GCTA: a tool for genome-wide complex trait analysis. , 2011, American journal of human genetics.

[9]  C. Gieger,et al.  Genome-wide association study identifies a new locus for coronary artery disease on chromosome 10p11.23. , 2011, European heart journal.

[10]  Yusuke Nakamura,et al.  SNPs on chromosome 5p15.3 associated with myocardial infarction in Japanese population , 2011, Journal of Human Genetics.

[11]  T. Trikalinos,et al.  Paraoxonase 1 polymorphisms and ischemic stroke risk: A systematic review and meta-analysis , 2010, Genetics in Medicine.

[12]  A. Munshi,et al.  Association of the −344C/T aldosterone synthase (CYP11B2) gene variant with hypertension and stroke , 2010, Journal of the Neurological Sciences.

[13]  O. Bang,et al.  Age and sex dependent genetic effects of neuropeptide Y promoter polymorphism on susceptibility to ischemic stroke in Koreans. , 2010, Clinica chimica acta; international journal of clinical chemistry.

[14]  Jinquan Cheng,et al.  The role of functional polymorphisms of the TNF-alpha gene promoter in the risk of ischemic stroke in Chinese Han and Uyghur populations: Two case-control studies. , 2010, Clinica chimica acta; international journal of clinical chemistry.

[15]  Yusuke Nakamura,et al.  Association study of the polymorphisms on chromosome 12p13 with atherothrombotic stroke in the Japanese population , 2010, Journal of Human Genetics.

[16]  R. Hui,et al.  A functional variant in the 3'-UTR of angiopoietin-1 might reduce stroke risk by interfering with the binding efficiency of microRNA 211. , 2010, Human molecular genetics.

[17]  I. Deary,et al.  Failure to validate association between 12p13 variants and ischemic stroke , 2010 .

[18]  R. Hui,et al.  A Novel Loss-of-Function DDAH1 Promoter Polymorphism Is Associated With Increased Susceptibility to Thrombosis Stroke and Coronary Heart Disease , 2010, Circulation research.

[19]  J. Ferro,et al.  Association of a Genetic Variant in the ALOX5AP with Higher Risk of Ischemic Stroke: A Case-Control, Meta-Analysis and Functional Study , 2010, Cerebrovascular Diseases.

[20]  R. Hui,et al.  Association of common variants of CYP4A11 and CYP4F2 with stroke in the Han Chinese population , 2010, Pharmacogenetics and genomics.

[21]  H. Markus.  Unravelling the Genetics of Ischaemic Stroke , 2010, PLoS medicine.

[22]  Thomas Meitinger,et al.  Common Variants in KCNN3 are Associated with Lone Atrial Fibrillation , 2010, Nature Genetics.

[23]  J. Polak,et al.  A genome-wide association study of carotid atherosclerosis in HIV-infected men , 2010, AIDS.

[24]  L. Smeeth,et al.  Causal Relationship of Susceptibility Genes to Ischemic Stroke: Comparison to Ischemic Heart Disease and Biochemical Determinants , 2010, PloS one.

[25]  A. Corvin.  Failure to validate association between 12p13 variants and ischaemic stroke , 2010 .

[26]  Jinquan Cheng,et al.  The association of functional polymorphisms of IL-6 gene promoter with ischemic stroke: analysis in two Chinese populations. , 2010, Biochemical and biophysical research communications.

[27]  C. Gieger,et al.  Genome-wide association study identifies a new locus for coronary artery disease on chromosome 10 p 11 . 23 , 2010 .

[28]  B. Melegh,et al.  Functional Variants of Glucokinase Regulatory Protein and Apolipoprotein A5 Genes in Ischemic Stroke , 2010, Journal of Molecular Neuroscience.

[29]  R. Hui,et al.  Angiopoietin-2 promoter haplotypes confer an increased risk of stroke in a Chinese Han population. , 2009, Clinical science.

[30]  O. Bang,et al.  Association of the C-399T promoter polymorphism of neuropeptide Y with susceptibility to ischemic stroke. , 2009, Clinical biochemistry.

[31]  Lin He,et al.  Association between the PDE4D gene and ischaemic stroke in the Chinese Han population. , 2009, Clinical science.

[32]  K. Lindpaintner,et al.  The 1425G/A SNP in PRKCH Is Associated With Ischemic Stroke and Cerebral Hemorrhage in a Chinese Population , 2009, Stroke.

[33]  C. Gieger,et al.  A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke , 2009, Nature Genetics.

[34]  Hong-miao Tao,et al.  Endothelial NO synthase gene polymorphisms and risk of ischemic stroke: A meta-analysis , 2009, Neuroscience Research.

[35]  Ricardo J Komotar,et al.  Genomewide Association Studies of Stroke. , 2009, Neurosurgery.

[36]  K. Furie,et al.  Sequence variants on chromosome 9p21.3 confer risk for atherosclerotic stroke , 2009, Annals of neurology.

[37]  Benjamin J. Wright,et al.  Genome-wide haplotype association study identifies the SLC22A3-LPAL2-LPA gene cluster as a risk locus for coronary artery disease , 2009, Nature Genetics.

[38]  Daniel F. Schwarz,et al.  New susceptibility locus for coronary artery disease on chromosome 3q22.3 , 2009, Nature Genetics.

[39]  Qi Wang,et al.  C-reactive protein polymorphisms and genetic susceptibility to ischemic stroke and hemorrhagic stroke in the Chinese Han population , 2009, Acta Pharmacologica Sinica.

[40]  Alberto Piazza,et al.  Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants , 2009, Nature Genetics.

[41]  Camilla,et al.  A sequence variant in ZFHX 3 on 16 q 22 associates with atrial fibrillation and ischemic stroke , 2009 .

[42]  Yongyong Shi,et al.  Association between the PDE 4 D gene and ischaemic stroke in the Chinese Han population , 2009 .

[43]  C. Gieger,et al.  Risk variants for atrial fibrillation on chromosome 4q25 associate with ischemic stroke , 2008, Annals of neurology.

[44]  B. Melegh,et al.  Apolipoprotein A5 gene IVS3+G476A allelic variant confers susceptibility for development of ischemic stroke. , 2008, Circulation journal : official journal of the Japanese Circulation Society.

[45]  Bruce M Psaty,et al.  Biomarkers of Inflammation and MRI-Defined Small Vessel Disease of the Brain: The Cardiovascular Health Study , 2008, Stroke.

[46]  J. Attia,et al.  Polymorphisms in Platelet Glycoprotein 1bα and Factor VII and Risk of Ischemic Stroke: A Meta-Analysis , 2008, Stroke.

[47]  M. McCarthy,et al.  Genome-wide association studies for complex traits: consensus, uncertainty and challenges , 2008, Nature Reviews Genetics.

[48]  T. Meitinger,et al.  Genetic Variation in Members of the Leukotriene Biosynthesis Pathway Confer an Increased Risk of Ischemic Stroke: A Replication Study in Two Independent Populations , 2008, Stroke.

[49]  F. Schmidt.  Meta-Analysis , 2008 .

[50]  Wei-Qing Chen,et al.  A meta-analysis of beta-fibrinogen gene-455G/A polymorphism and plasma fibrinogen level in Chinese cerebral infarction patients. , 2007, Biomedical and environmental sciences : BES.

[51]  Kari Stefansson,et al.  A common variant on chromosome 9p21 affects the risk of myocardial infarction. , 2007, Science.

[52]  Yibo Wang,et al.  Interaction of Genetic Risk Factors Confers Higher Risk for Thrombotic Stroke in Male Chinese: A Multicenter Case‐Control Study , 2007, Annals of human genetics.

[53]  C. Gieger,et al.  Genomewide association analysis of coronary artery disease. , 2007, The New England journal of medicine.

[54]  Eric E. Smith,et al.  Variants conferring risk of atrial fibrillation on chromosome 4q25 , 2007, Nature.

[55]  R. Scott,et al.  The PAI-1 4G/5G gene polymorphism and ischemic stroke: an association study and meta-analysis. , 2007, Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association.

[56]  A. Gylfason,et al.  A Common Variant on Chromosome 9p21 Affects the Risk of Myocardial Infarction , 2007, Science.

[57]  Yusuke Nakamura,et al.  A nonsynonymous SNP in PRKCH (protein kinase C η) increases the risk of cerebral infarction , 2007, Nature Genetics.

[58]  C. Carlson,et al.  Association of polymorphisms in the CRP gene with circulating C-reactive protein levels and cardiovascular events. , 2006, JAMA.

[59]  M. Khoury,et al.  Tracking the epidemiology of human genes in the literature: the HuGE Published Literature database. , 2006, American journal of epidemiology.

[60]  Yibo Wang,et al.  VKORC1 Haplotypes Are Associated With Arterial Vascular Diseases (Stroke, Coronary Heart Disease, and Aortic Dissection) , 2006, Circulation.

[61]  C. Sudlow,et al.  Does apolipoprotein E genotype influence the risk of ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage? Systematic review and meta-analyses of 31 studies among 5961 cases and 17,965 controls. , 2006, Stroke.

[62]  J. Li,et al.  Adjusting multiple testing in multilocus analyses using the eigenvalues of a correlation matrix , 2005, Heredity.

[63]  M. Dichgans,et al.  Genetic Association Studies in Stroke: Methodological Issues and Proposed Standard Criteria , 2005, Stroke.

[64]  A. Hingorani,et al.  Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18,000 cases and 58,000 controls. , 2004, Archives of neurology.

[65]  D. Nyholt.  A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. , 2004, American journal of human genetics.

[66]  Mark Gurney,et al.  The gene encoding phosphodiesterase 4D confers risk of ischemic stroke , 2003, Nature Genetics.

[67]  Geoffrey Cloud,et al.  Evaluating the Genetic Component of Ischemic Stroke Subtypes: A Family History Study , 2003, Stroke.

[68]  K. Christensen,et al.  Genetic Liability in Stroke: A Long-Term Follow-Up Study of Danish Twins , 2002, Stroke.

[69]  J. Hirschhorn,et al.  A comprehensive review of genetic association studies , 2002, Genetics in Medicine.

[70]  J. Ioannidis,et al.  Replication validity of genetic association studies , 2001, Nature Genetics.

[71]  David Lee Gordon,et al.  Classification of Subtype of Acute Ischemic Stroke: Definitions for Use in a Multicenter Clinical Trial , 1993, Stroke.

[72]  K. Merikangas,et al.  A Study of Twins and Stroke , 1992, Stroke.

[73]  C McRae,et al.  Myocardial infarction. , 2019, Australian family physician.

[74]  Barnett,et al.  Supplementary References , 2022 .