Comparing strategies to fine-map the association of common SNPs at chromosome 9p21 with type 2 diabetes and myocardial infarction

Summary, in English

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.

• Author: Jessica Shea; Vineeta Agarwala; Anthony A. Philippakis; Jared Maguire; Eric Banks; Mark DePristo; Brian Thomson; Candace Guiducci; Robert C. Onofrio; Sekar Kathiresan; Stacey Gabriel; Noel P. Burtt; Mark J. Daly; Leif Groop; David Altshuler
• Department/s: Translational Muscle Research; EXODIAB: Excellence of Diabetes Research in Sweden
• Publishing year: 2011
• Language: English
• Pages: 114-801
• Publication/Series: Nature Genetics
• Volume: 43
• Issue: 8
• Links: http://dx.doi.org/10.1038/ng.871
• Document type: Journal article
• Publisher: Nature Publishing Group
• Topic: Endocrinology and Diabetes
• Status: Published
• Research group: Translational Muscle Research
• ISBN/ISSN/Other: ISSN: 1546-1718