Division of Pediatric Pulmonary Medicine, Allergy and Immunology, Children's Hospital of Pittsburgh of UPMC, 4401 Penn Avenue, Pittsburgh, PA 15224, USA.
Thorax. 2011 Dec;66(12):1085-90. doi: 10.1136/thoraxjnl-2011-200017. Epub 2011 Sep 15.
Traditional genome-wide association studies (GWASs) of large cohorts of subjects with chronic obstructive pulmonary disease (COPD) have successfully identified novel candidate genes, but several other plausible loci do not meet strict criteria for genome-wide significance after correction for multiple testing.
The authors hypothesise that by applying unbiased weights derived from unique populations we can identify additional COPD susceptibility loci. Methods The authors performed a homozygosity haplotype analysis on a group of subjects with and without COPD to identify regions of conserved homozygosity haplotype (RCHHs). Weights were constructed based on the frequency of these RCHHs in case versus controls, and used to adjust the p values from a large collaborative GWAS of COPD.
The authors identified 2318 RCHHs, of which 576 were significantly (p<0.05) over-represented in cases. After applying the weights constructed from these regions to a collaborative GWAS of COPD, the authors identified two single nucleotide polymorphisms (SNPs) in a novel gene (fibroblast growth factor-7 (FGF7)) that gained genome-wide significance by the false discovery rate method. In a follow-up analysis, both SNPs (rs12591300 and rs4480740) were significantly associated with COPD in an independent population (combined p values of 7.9E-7 and 2.8E-6, respectively). In another independent population, increased lung tissue FGF7 expression was associated with worse measures of lung function.
Weights constructed from a homozygosity haplotype analysis of an isolated population successfully identify novel genetic associations from a GWAS on a separate population. This method can be used to identify promising candidate genes that fail to meet strict correction for multiple testing.
对患有慢性阻塞性肺疾病（COPD）的大样本队列进行传统的全基因组关联研究（GWAS）已成功鉴定出一些新的候选基因，但在经过多重检验校正后，还有其他一些合理的基因座不能满足全基因组显著水平的标准。
作者假设，通过应用来自独特人群的无偏权重，我们可以鉴定出更多的 COPD 易感性基因座。
作者对一组 COPD 患者和非 COPD 患者进行了纯合子单体型分析，以鉴定保守纯合子单体型区域（RCHH）。基于这些 RCHH 在病例与对照中的频率构建权重，并用于调整 COPD 大型合作 GWAS 的 p 值。
作者鉴定出 2318 个 RCHH，其中 576 个在病例中显著（p<0.05）过度表达。将这些区域构建的权重应用于 COPD 的合作 GWAS 后，作者在一个新基因（成纤维细胞生长因子-7（FGF7））中鉴定出两个单核苷酸多态性（SNP），这些 SNP 经假发现率法达到了全基因组显著水平。在后续分析中，两个 SNP（rs12591300 和 rs4480740）在一个独立人群中均与 COPD 显著相关（合并 p 值分别为 7.9E-7 和 2.8E-6）。在另一个独立人群中，肺组织 FGF7 表达增加与肺功能测量值恶化相关。
从一个单独人群的 GWAS 中，从一个孤立人群的单体型分析构建的权重成功鉴定出了新的遗传关联。该方法可用于鉴定未能满足严格多重检验校正标准的有前途的候选基因。
