M Söderholm1,2, P Almgren1, K Jood3, T M Stanne4, M Olsson4, A Ilinca2,5, E Lorentzen6, B Norrving2,5, G Engström1, O Melander1, C Jern4, A Lindgren2,5. 1. Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden. 2. Department of Neurology and Rehabilitation Medicine, Skåne University Hospital, Lund and Malmö, Sweden. 3. Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden. 4. Department of Medical and Clinical Genetics, Institute of Biomedicine, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden. 5. Department of Clinical Sciences Lund, Neurology, Lund University, Lund, Sweden. 6. Bioinformatics Core Facility, University of Gothenburg, Gothenburg, Sweden.
Abstract
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.
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.
Authors: Candelaria Vergara; Samantha M Bomotti; Cristian Valencia; Barbara E K Klein; Kristine E Lee; Ronald Klein; Alison P Klein; Priya Duggal Journal: Hum Mutat Date: 2018-09-11 Impact factor: 4.878
Authors: Debby Ngo; Mark D Benson; Jonathan Z Long; Zsu-Zsu Chen; Ruiqi Wang; Anjali K Nath; Michelle J Keyes; Dongxiao Shen; Sumita Sinha; Eric Kuhn; Jordan E Morningstar; Xu Shi; Bennet D Peterson; Christopher Chan; Daniel H Katz; Usman A Tahir; Laurie A Farrell; Olle Melander; Jonathan D Mosley; Steven A Carr; Ramachandran S Vasan; Martin G Larson; J Gustav Smith; Thomas J Wang; Qiong Yang; Robert E Gerszten Journal: JCI Insight Date: 2021-03-08
Authors: Tara M Stanne; Maja Olsson; Erik Lorentzen; Annie Pedersen; Anders Gummesson; Ann Gils; Katarina Jood; Gunnar Engström; Olle Melander; Paul J Declerck; Christina Jern Journal: Thromb Haemost Date: 2018-01-29 Impact factor: 5.249
Authors: M Olsson; T M Stanne; A Pedersen; E Lorentzen; E Kara; A Martinez-Palacian; N P Rønnow Sand; A F Jacobsen; P M Sandset; J J Sidelmann; G Engström; O Melander; S M Kanse; C Jern Journal: J Thromb Haemost Date: 2018-08-24 Impact factor: 5.824