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

Shea, Jessica; Agarwala, Vineeta; Philippakis, Anthony A.; Maguire, Jared; Banks, Eric; DePristo, Mark; Thomson, Brian; Guiducci, Candace; Onofrio, Robert C. and Kathiresan, Sekar, et al. (2011) In Nature Genetics 43(8). p.114-801
Abstract
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... (More)
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. (Less)
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Nature Genetics
volume
43
issue
8
pages
114 - 801
publisher
Nature Publishing Group
external identifiers
  • wos:000293178300018
  • scopus:79960930495
ISSN
1546-1718
DOI
10.1038/ng.871
language
English
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yes
id
6bad232f-f2d9-4973-862b-832617506639 (old id 2071980)
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2011-09-02 08:30:17
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2017-09-03 04:09:08
@article{6bad232f-f2d9-4973-862b-832617506639,
  abstract     = {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       = {Shea, Jessica and Agarwala, Vineeta and Philippakis, Anthony A. and Maguire, Jared and Banks, Eric and DePristo, Mark and Thomson, Brian and Guiducci, Candace and Onofrio, Robert C. and Kathiresan, Sekar and Gabriel, Stacey and Burtt, Noel P. and Daly, Mark J. and Groop, Leif and Altshuler, David},
  issn         = {1546-1718},
  language     = {eng},
  number       = {8},
  pages        = {114--801},
  publisher    = {Nature Publishing Group},
  series       = {Nature Genetics},
  title        = {Comparing strategies to fine-map the association of common SNPs at chromosome 9p21 with type 2 diabetes and myocardial infarction},
  url          = {http://dx.doi.org/10.1038/ng.871},
  volume       = {43},
  year         = {2011},
}