Journal
NATURE GENETICS
Volume 43, Issue 8, Pages 801-U114Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.871
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Funding
- Sigrid Juselius foundation
- Folkhalsan foundation
- Swedish Research Council
- Novartis
- US National Institutes of Health (NIH)
- US National Heart, Lung, and Blood Institute [R01 HL087676]
- Doris Duke Charitable Foundation
- NIH
- Department of Medicine and Cardiovascular Research Center at Massachusetts General Hospital
- US National Human Genome Research Institute
- Broad Institute
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Noncoding variants at human chromosome 9p21 near CDKN2A and CDKN2B are associated with type 2 diabetes(1-4), myocardial infarction(5-7), aneurysm(8), vertical cup disc ratio(9) and at least five cancers(10-16). Here we compare approaches to more comprehensively assess genetic variation in the region. We carried out targeted sequencing at high coverage in 47 individuals and compared the results to pilot data from the 1000 Genomes Project. We imputed variants into type 2 diabetes and myocardial infarction cohorts directly from targeted sequencing, from a genotyped reference panel derived from sequencing and from 1000 Genomes Project low-coverage data. Polymorphisms with frequency >5% were captured well by all strategies. Imputation of intermediate-frequency polymorphisms required a higher density of tag SNPs in disease samples than is available on first-generation genome-wide association study (GWAS) arrays. Our association analyses identified more comprehensive sets of variants showing equivalent statistical association with type 2 diabetes or myocardial infarction, but did not identify stronger associations than the original GWAS signals.
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