title: Exome array analysis of ischaemic stroke: results from a southern Swedish study.
abstract: Genome-wide association (GWA) studies have identified a few risk loci for ischaemic stroke, but these variants explain only a small part of the genetic contribution to the disease. Coding variants associated with amino acid substitutions or premature termination of protein synthesis could have a large effect on disease risk. We performed an exome array analysis for ischaemic stroke.
  
  
  
  Patients with ischaemic stroke (n = 2385) and control subjects (n = 6077) from three Swedish studies were genotyped with the Illumina HumanOmniExpressExome BeadChip. Single-variant association analysis and gene-based tests were performed of exome variants with minor allele frequency of < 5%. A separate GWA analysis was also performed, based on 700 000 genotyped common markers and subsequent imputation.
  
  
  
  No exome variant or gene was significantly associated with all ischaemic stroke after Bonferroni correction (all P > 1.8 × 10-6for single-variant and >4.15 × 10-6for gene-based analysis). The strongest association in single-variant analysis was found for a missense variant in the DNAH11 gene (rs143362381; P = 5.01 × 10-6). In gene-based tests, the strongest association was for the ZBTB20 gene (P = 7.9 × 10-5). The GWA analysis showed that the sample was homogenous (median genomic inflation factor = 1.006). No genome-wide significant association with overall ischaemic stroke risk was found. However, previously reported associations for the PITX2 and ZFHX3 gene loci with cardioembolic stroke subtype were replicated (P = 7 × 10-15and 6 × 10-3).
  
  
  
  This exome array analysis did not identify any single variants or genes reaching the pre-defined significance level for association with ischaemic stroke. Further studies on exome variants should be performed in even larger, well-defined and subtyped samples.
authors.affiliation: Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden.|Department of Neurology and Rehabilitation Medicine, Skåne University Hospital, Lund and Malmö, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Söderholm
authors.affiliation: Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Almgren
authors.affiliation: Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Jood
authors.affiliation: Department of Medical and Clinical Genetics, Institute of Biomedicine, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: T M
authors.initials: TM
authors.lastname: Stanne
authors.affiliation: Department of Medical and Clinical Genetics, Institute of Biomedicine, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Olsson
authors.affiliation: Department of Neurology and Rehabilitation Medicine, Skåne University Hospital, Lund and Malmö, Sweden.|Department of Clinical Sciences Lund, Neurology, Lund University, Lund, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Ilinca
authors.affiliation: Bioinformatics Core Facility, University of Gothenburg, Gothenburg, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Lorentzen
authors.affiliation: Department of Neurology and Rehabilitation Medicine, Skåne University Hospital, Lund and Malmö, Sweden.|Department of Clinical Sciences Lund, Neurology, Lund University, Lund, Sweden.
authors.forename: B
authors.initials: B
authors.lastname: Norrving
authors.affiliation: Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden.
authors.forename: G
authors.initials: G
authors.lastname: Engström
authors.affiliation: Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden.
authors.forename: O
authors.initials: O
authors.lastname: Melander
authors.affiliation: Department of Medical and Clinical Genetics, Institute of Biomedicine, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Jern
authors.affiliation: Department of Neurology and Rehabilitation Medicine, Skåne University Hospital, Lund and Malmö, Sweden.|Department of Clinical Sciences Lund, Neurology, Lund University, Lund, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Lindgren
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002545:Brain Ischemia / Q000235:genetics*; D059472:Exome; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020521:Stroke / Q000235:genetics*; D013548:Sweden
keywords: exome; genome-wide association study; ischaemic stroke; population study