Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Nat Genet. 2011 Jul 24;43(8):801-5. doi: 10.1038/ng.871.
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.
非编码变异在人类 9p21 染色体附近的 CDKN2A 和 CDKN2B 与 2 型糖尿病、心肌梗死、动脉瘤、垂直杯盘比和至少五种癌症有关。在这里，我们比较了更全面评估该区域遗传变异的方法。我们在 47 个人中进行了高覆盖率的靶向测序，并将结果与 1000 基因组计划的试点数据进行了比较。我们直接从靶向测序、从测序衍生的基因分型参考面板和 1000 基因组计划低覆盖率数据中对 2 型糖尿病和心肌梗死队列进行了变体推断。所有策略都能很好地捕获频率>5%的多态性。中间频率多态性的推断需要在疾病样本中具有比第一代全基因组关联研究 (GWAS) 阵列更高密度的标记 SNP。我们的关联分析确定了更全面的显示与 2 型糖尿病或心肌梗死等效统计关联的变体集，但没有发现比原始 GWAS 信号更强的关联。
