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No large-effect low-frequency coding variation found for myocardial infarction
Holmen, Oddger L. Zhang, He Zhou, Wei Schmidt, Ellen Hovelson, Daniel H. Langhammer, Arnulf Loechen, Maja-Lisa Ganesh, Santhi K. Mathiesen, E. B. Vatten, L.
Holmen, Oddger L.
Zhang, He
Zhou, Wei
Schmidt, Ellen
Hovelson, Daniel H.
Langhammer, Arnulf
Loechen, Maja-Lisa
Ganesh, Santhi K.
Mathiesen, E. B.
Vatten, L.
Author
Holmen, Oddger L.
Zhang, He
Zhou, Wei
Schmidt, Ellen
Hovelson, Daniel H.
Langhammer, Arnulf
Loechen, Maja-Lisa
Ganesh, Santhi K.
Mathiesen, E. B.
Vatten, L.
Platou, Carl
Wilsgaard, Tom
Chen, Jin
Skorpen, Frank
Dalen, Havard
Boehnke, Michael
Abecasis, Goncalo R.
Njolstad, I.
Hveem, Kristian
Willer, Cristen J.
Zhang, He
Zhou, Wei
Schmidt, Ellen
Hovelson, Daniel H.
Langhammer, Arnulf
Loechen, Maja-Lisa
Ganesh, Santhi K.
Mathiesen, E. B.
Vatten, L.
Platou, Carl
Wilsgaard, Tom
Chen, Jin
Skorpen, Frank
Dalen, Havard
Boehnke, Michael
Abecasis, Goncalo R.
Njolstad, I.
Hveem, Kristian
Willer, Cristen J.
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.
Keywords
myocardial infarction, coronary arteriosclerosis, gene frequency, genes, genome, norway, single nucleotide, polymorphism, genotype determination, genome-wide association study, exome, norwegian, whole exome sequencing
Date
2014
Type
Journal article
Journal
Human Molecular Genetics
Book
Volume
23
Issue
17
Page Range
4721-4728
Article Number
ACU Department
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Event URL
Open Access Status
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File Access
Controlled