title: Comparing strategies to fine-map the association of common SNPs at chromosome 9p21 with type 2 diabetes and myocardial infarction.
abstract: Noncoding variants at human chromosome 9p21 near CDKN2A and CDKN2B are associated with type 2 diabetes, myocardial infarction, aneurysm, vertical cup disc ratio and at least five cancers. 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.
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Shea
authors.forename: Vineeta
authors.initials: V
authors.lastname: Agarwala
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Philippakis
authors.forename: Jared
authors.initials: J
authors.lastname: Maguire
authors.forename: Eric
authors.initials: E
authors.lastname: Banks
authors.forename: Mark
authors.initials: M
authors.lastname: Depristo
authors.forename: Brian
authors.initials: B
authors.lastname: Thomson
authors.forename: Candace
authors.initials: C
authors.lastname: Guiducci
authors.forename: Robert C
authors.initials: RC
authors.lastname: Onofrio
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
authors.forename: Stacey
authors.initials: S
authors.lastname: Gabriel
authors.forename: Noël P
authors.initials: NP
authors.lastname: Burtt
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
mesh_terms: D002874:Chromosome Mapping; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D009203:Myocardial Infarction / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*