Risk variants for atrial fibrillation on chromosome 4q25 associate with ischemic stroke

• Published in: Annals of neurology Vol. 64; no. 4; pp. 402 - 409
• Main Authors: Gretarsdottir, Solveig, Thorleifsson, Gudmar, Manolescu, Andrei, Styrkarsdottir, Unnur, Helgadottir, Anna, Gschwendtner, Andreas, Kostulas, Konstantinos, Kuhlenbäumer, Gregor, Bevan, Steve, Jonsdottir, Thorbjorg, Bjarnason, Hjordis, Saemundsdottir, Jona, Palsson, Stefan, Arnar, David O., Holm, Hilma, Thorgeirsson, Gudmundur, Valdimarsson, Einar Mar, Sveinbjörnsdottir, Sigurlaug, Gieger, Christian, Berger, Klaus, Wichmann, H-Erich, Hillert, Jan, Markus, Hugh, Gulcher, Jeffrey Robert, Ringelstein, E. Bernd, Kong, Augustine, Dichgans, Martin, Gudbjartsson, Daniel Fannar, Thorsteinsdottir, Unnur, Stefansson, Kari
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.10.2008; Willey-Liss
• Subjects: Atrial Fibrillation - complications; Atrial Fibrillation - genetics; Biological and medical sciences; Chromosomes, Human, Pair 4; Confidence Intervals; European Continental Ancestry Group - genetics; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Male; Medical sciences; Medicin och hälsovetenskap; Neurology; Odds Ratio; Phenotype; Polymorphism, Single Nucleotide - genetics; Risk Factors; Stroke - etiology; Stroke - genetics; Vascular diseases and vascular malformations of the nervous system; Cerebral infarction; Stroke; Nervous system diseases; Arrhythmia; Atrial fibrillation; Cardiovascular disease; Chromosome; Excitability disorder; Cerebral disorder; Vascular disease; Heart disease; Central nervous system disease; Risk factor; Brain ischemia; Cerebrovascular disease
• ISSN: 0364-5134; 1531-8249; 1531-8249
• DOI: 10.1002/ana.21480

Objective To find sequence variants that associate with the risk for ischemic stroke (IS), we performed a genome‐wide association study. Methods We genotyped 1,661 Icelandic IS patients and 10,815 control subjects using the Infinium HumanHap300 chip (Illumina, San Diego, CA). A total of 310,881 single nucleotide polymorphisms (SNPs) were tested for association with IS, and the most significant signals were replicated in two large European IS sample sets (2,224 cases/2,583 control subjects). Two SNPs, rs2200733 and rs10033464, were tested further in additional European IS samples (2,327 patients and 16,760 control subjects). Results In the Icelandic samples and the two replication sets combined, rs2200733 associated significantly with cardioembolic stroke (CES) (odds ratio [OR], 1.54; p = 8.05 × 10−9). No other variants associated with IS or any of its subtypes. rs2200733 associated significantly with IS in all sample sets combined (OR, 1.26; p = 2.18 × 10−10), and both rs2200733 and its neighbour, rs10033464 associated strongly with CES (rs2200733: OR, 1.52; p = 5.8 × 10−12; rs10033464: OR, 1.27; p = 6.1 × 10−4). Interestingly, rs2200733 also showed significant association to IS not classified as CES. Interpretation We discovered that variants previously shown to associate with atrial fibrillation (AF), rs2200733 and rs10033464, significantly associated with IS, with the strongest risk for CES. The association with noncardiogenic stroke is intriguing and suggests that atrial fibrillation may be underdiagnosed in patients presenting with stroke. This discovery may have implications for workup and treatment of IS. Ann Neurol 2008;64:402–409