title: No large-effect low-frequency coding variation found for myocardial infarction.
abstract: Genome-wide association studies have identified variants, primarily common, that are associated with coronary artery disease or myocardial infarction (MI), but have not tested the majority of the low frequency and rare variation in the genome. We explored the hypothesis that previously untested low frequency (1-5% minor allele frequency) and rare (<1% minor allele frequency) coding variants are associated with MI. We genotyped 2906 MI cases and 6738 non-MI controls from Norway using the Illumina HumanExome Beadchip, allowing for direct genotyping of 85 972 polymorphic coding variants as well as 48 known GWAS SNPs. We followed-up 34 coding variants in an additional 2350 MI cases and 2318 controls from Norway. We evaluated exome array coverage in a subset of these samples using whole exome sequencing (N = 151). The exome array provided successful genotyping for an estimated 72.5% of Norwegian loss-of-function or missense variants with frequency >1% and 66.2% of variants <1% frequency observed more than once. Despite 80% power in the two-stage study (N = 14 312) to detect association with low-frequency variants with high effect sizes [odds ratio (OR) >1.86 and >1.36 for 1 and 5% frequency, respectively], we did not identify any novel genes or single variants that reached significance. This suggests that low-frequency coding variants with large effect sizes (OR >2) may not exist for MI. Larger sample sizes may identify coding variants with more moderate effects.
authors.affiliation: HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, 7600 Levanger, Norway St. Olav Hospital, Trondheim University Hospital, Trondheim, Norway.
authors.forename: Oddgeir L
authors.initials: OL
authors.lastname: Holmen
authors.affiliation: Department of Internal Medicine, Division of Cardiology.
authors.forename: He
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine, Division of Cardiology.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Internal Medicine, Division of Cardiology, Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Schmidt
authors.affiliation: Department of Internal Medicine, Division of Cardiology, Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Hovelson
authors.affiliation: HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, 7600 Levanger, Norway.
authors.forename: Arnulf
authors.initials: A
authors.lastname: Langhammer
authors.affiliation: Epidemiology of Chronic Diseases Research Group, Department of Community Medicine, Faculty of Health Sciences.
authors.forename: Maja-Lisa
authors.initials: ML
authors.lastname: Løchen
authors.affiliation: Department of Internal Medicine, Division of Cardiology.
authors.forename: Santhi K
authors.initials: SK
authors.lastname: Ganesh
authors.affiliation: Brain and Circulation Research Group, Department of Clinical Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, 9037 Tromsø, Norway Department of Neurology and Neurophysiology, University Hospital of North Norway, 9037 Tromsø, Norway.
authors.forename: Ellisiv B
authors.initials: EB
authors.lastname: Mathiesen
authors.affiliation: Department of Public Health.
authors.forename: Lars
authors.initials: L
authors.lastname: Vatten
authors.affiliation: HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, 7600 Levanger, Norway.
authors.forename: Carl
authors.initials: C
authors.lastname: Platou
authors.affiliation: Epidemiology of Chronic Diseases Research Group, Department of Community Medicine, Faculty of Health Sciences.
authors.forename: Tom
authors.initials: T
authors.lastname: Wilsgaard
authors.affiliation: Department of Internal Medicine, Division of Cardiology.
authors.forename: Jin
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Laboratory Medicine, Children's and Women's Health Faculty of Medicine.
authors.forename: Frank
authors.initials: F
authors.lastname: Skorpen
authors.affiliation: Medical Imaging Laboratory for Innovative Future Healthcare, Lab and Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, 7030 Trondheim, Norway Department of Medicine, Levanger Hospital, Nord-Trøndelag Health Trust, 7600 Levanger, Norway.
authors.forename: Håvard
authors.initials: H
authors.lastname: Dalen
authors.affiliation: Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Boehnke
authors.affiliation: Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA.
authors.forename: Goncalo R
authors.initials: GR
authors.lastname: Abecasis
authors.affiliation: Epidemiology of Chronic Diseases Research Group, Department of Community Medicine, Faculty of Health Sciences.
authors.forename: Inger
authors.initials: I
authors.lastname: Njølstad
authors.affiliation: HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, 7600 Levanger, Norway Department of Medicine, Levanger Hospital, Nord-Trøndelag Health Trust, 7600 Levanger, Norway.
authors.forename: Kristian
authors.initials: K
authors.lastname: Hveem
authors.affiliation: Department of Internal Medicine, Division of Cardiology, Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA cristen@umich.edu.
authors.forename: Cristen J
authors.initials: CJ
authors.lastname: Willer
mesh_terms: D059472:Exome / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D008297:Male; D009203:Myocardial Infarction / Q000235:genetics*; D016366:Open Reading Frames / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
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