Genome-Wide Association Analysis of Ischemic Stroke in Young Adults

Ischemic stroke (IS) is among the leading causes of death in Western countries. There is a significant genetic component to IS susceptibility, especially among young adults. To date, research to identify genetic loci predisposing to stroke has met only with limited success. We performed a genome-wide association (GWA) analysis of early-onset IS to identify potential stroke susceptibility loci. The GWA analysis was conducted by genotyping 1 million SNPs in a biracial population of 889 IS cases and 927 controls, ages 15–49 years. Genotypes were imputed using the HapMap3 reference panel to provide 1.4 million SNPs for analysis. Logistic regression models adjusting for age, recruitment stages, and population structure were used to determine the association of IS with individual SNPs. Although no single SNP reached genome-wide significance (P < 5 × 10−8), we identified two SNPs in chromosome 2q23.3, rs2304556 (in FMNL2; P = 1.2 × 10−7) and rs1986743 (in ARL6IP6; P = 2.7 × 10−7), strongly associated with early-onset stroke. These data suggest that a novel locus on human chromosome 2q23.3 may be associated with IS susceptibility among young adults.

[1]  P. Kelly,et al.  Stroke Subtype Classification to Mechanism-Specific and Undetermined Categories by TOAST, A-S-C-O, and Causative Classification System: Direct Comparison in the North Dublin Population Stroke Study , 2010, Stroke.

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

[3]  O. Pertz,et al.  Formin-like 2 drives amoeboid invasive cell motility downstream of RhoC , 2010, Oncogene.

[4]  Raimund Erbel,et al.  Two New Loci for Body-Weight Regulation Identified in a Joint Analysis of Genome-Wide Association Studies for Early-Onset Extreme Obesity in French and German Study Groups , 2010, PLoS genetics.

[5]  Tomi D. Berney,et al.  High-density SNP association study and copy number variation analysis of the AUTS1 and AUTS5 loci implicate the IMMP2L–DOCK4 gene region in autism susceptibility , 2009, Molecular Psychiatry.

[6]  M. Uhlén,et al.  Characterization of Diaphanous-related formin FMNL2 in human tissues , 2010, BMC Cell Biology.

[7]  Johan Van Limbergen,et al.  Common variants at five new loci associated with early-onset inflammatory bowel disease , 2009, Nature Genetics.

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

[9]  B. Browning,et al.  A unified approach to genotype imputation and haplotype-phase inference for large data sets of trios and unrelated individuals. , 2009, American journal of human genetics.

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

[11]  V. Steen,et al.  An 8.9 Mb 19p13 duplication associated with precocious puberty and a sporadic 3.9 Mb 2q23.3q24.1 deletion containing NR4A2 in mentally retarded members of a family with an intrachromosomal 19p-into-19q between-arm insertion , 2009, European Journal of Human Genetics.

[12]  Eric E Schadt,et al.  Accuracy of Genome-wide Imputation of Untyped Markers and Impacts on Statistical Power for Association Studies , 2009 .

[13]  Andrew D. Johnson,et al.  SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap , 2008, Bioinform..

[14]  K. Furie,et al.  Heart disease and stroke statistics--2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. , 2008, Circulation.

[15]  Harald Grallert,et al.  Genome Wide Association (GWA) Study for Early Onset Extreme Obesity Supports the Role of Fat Mass and Obesity Associated Gene (FTO) Variants , 2007, PloS one.

[16]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[17]  A. Dürr,et al.  Rare heterozygous parkin variants in French early-onset Parkinson disease patients and controls , 2007, Journal of Medical Genetics.

[18]  G. Abecasis,et al.  A Genome-Wide Association Study of Type 2 Diabetes in Finns Detects Multiple Susceptibility Variants , 2007, Science.

[19]  M. McCarthy,et al.  Replication of Genome-Wide Association Signals in UK Samples Reveals Risk Loci for Type 2 Diabetes , 2007, Science.

[20]  J. Gulcher,et al.  A variant in CDKAL1 influences insulin response and risk of type 2 diabetes , 2007, Nature Genetics.

[21]  S. Kittner,et al.  Familial aggregation of ischemic stroke in young women: the Stroke Prevention in Young Women Study , 2006, Genetic epidemiology.

[22]  T. Walsh,et al.  Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. , 2006, JAMA.

[23]  T. Walsh,et al.  Spectrum of Mutations in BRCA 1 , BRCA 2 , CHEK 2 , and TP 53 in Families at High Risk of Breast Cancer , 2006 .

[24]  P. Rothwell,et al.  Heritability of Ischemic Stroke in Relation to Age, Vascular Risk Factors, and Subtypes of Incident Stroke in Population-Based Studies , 2004, Stroke.

[25]  P. Rothwell,et al.  Systematic Review of Methods and Results of Studies of the Genetic Epidemiology of Ischemic Stroke , 2003, Stroke.

[26]  Stephen J. Guter,et al.  A genomewide screen for autism: strong evidence for linkage to chromosomes 2q, 7q, and 16p. , 2001, American journal of human genetics.

[27]  H. Markus,et al.  Genetics and ischaemic stroke. , 2000, Brain : a journal of neurology.

[28]  R. Macko,et al.  Cerebral infarction in young adults , 1998, Neurology.

[29]  S. Kittner,et al.  Interrater reliability of an etiologic classification of ischemic stroke. , 1995, Stroke.

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

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