Exome array analysis of ischaemic stroke : results from a southern Swedish study

Summary, in English

BACKGROUND AND PURPOSE: 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.

METHODS: 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.

RESULTS: No exome variant or gene was significantly associated with all ischaemic stroke after Bonferroni correction (all P > 1.8 × 10(-6) for single-variant and >4.15 × 10(-6) for 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(-15) and 6 × 10(-3) ).

CONCLUSIONS: 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.

• Författare: M Söderholm; P Almgren; K Jood; T M Stanne; Mats Olsson; A Ilinca; E Lorentzen; B Norrving; G Engström; O Melander; C Jern; Arne Lindgren
• Avdelning/ar: Kardiovaskulär forskning - epidemiologi; Translationell Muskel Forskning; Neurologi, Lund; Kardiovaskulär forskning - hypertoni; Klinisk strokeforskning; EXODIAB: Excellence of Diabetes Research in Sweden; EpiHealth: Epidemiology for Health
• Publiceringsår: 2016-07-29
• Språk: Engelska
• Sidor: 1722-1728
• Publikation/Tidskrift/Serie: European Journal of Neurology
• Volym: 23
• Issue: 12
• Länkar: http://onlinelibrary.wiley.com/doi/10.1111/ene.13086/full; http://dx.doi.org/10.1111/ene.13086
• Dokumenttyp: Artikel i tidskrift
• Förlag: Wiley-Blackwell
• Ämne: Neurosciences
• Nyckelord: stroke; exome array
• Status: Published
• Forskningsgrupp: Cardiovascular Research - Epidemiology; Genomics, Diabetes and Endocrinology; Cardiovascular Research - Hypertension; Clinical Stroke Research Group
• ISBN/ISSN/Övrigt: ISSN: 1351-5101