Identification of FGF7 as a novel susceptibility locus for chronic obstructive pulmonary disease.
Identification of FGF7 as a novel susceptibility locus for chronic obstructive pulmonary disease.
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DOI：
10.1136/thoraxjnl-2011-200017
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发表时间：
2011-12
期刊：
影响因子：
10
通讯作者：
Celedón JC
中科院分区：
文献类型：
--
作者：
Brehm JM;Hagiwara K;Tesfaigzi Y;Bruse S;Mariani TJ;Bhattacharya S;Boutaoui N;Ziniti JP;Soto-Quiros ME;Avila L;Cho MH;Himes B;Litonjua AA;Jacobson F;Bakke P;Gulsvik A;Anderson WH;Lomas DA;Forno E;Datta S;Silverman EK;Celedón JC
传统的对大量慢性阻塞性肺疾病(COPD)受试者的全基因组关联研究(GWAS)已经成功地发现了新的候选基因，但在对多重测试进行校正后，其他几个看似合理的基因座并不符合全基因组意义的严格标准。我们假设，通过应用来自独特人群的无偏权重，我们可以识别更多的COPD易感基因座。我们对一组患有和不患有COPD的受试者进行了纯合性单倍型分析，以确定保守纯合性区域(RCHH)。权重是根据病例和对照组中这些RCHH的频率构建的，并用于调整来自COPD大型协作组的P值。我们确定了2318个保守纯合子区域，其中576个区域在病例中显著(P<；0.05)过度表达。在将这些区域构建的权重应用于COPD的协作性GWA后，我们鉴定了一个新基因(Fgf7)中的两个单核苷酸多态，该基因通过错误发现率方法获得了全基因组意义。在后续分析中，两个SNPs(rs12591300和rs4480740)在独立人群中与COPD显著相关(合并P值分别为7.9E-07和2.8E-06)。在另一个独立的人群中，肺组织Fgf7表达的增加与肺功能的较差指标相关。从隔离群体的纯合性单倍型分析中构建的权重成功地识别了来自分离群体的GWA的新的遗传关联。这种方法可以用来识别那些不能满足多次测试的严格校正的有希望的候选基因。
Traditional genome-wide association studies (GWAS) of large cohort 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. We hypothesize that by applying unbiased weights derived from unique populations we can identify additional COPD susceptibility loci. We performed a homozygosity haplotype analysis on a group of subjects with and without COPD to identify regions of conserved homozygosity (RCHH). Weights were constructed based on the frequency of these RCHH in case vs. controls, and used to adjust the P values from a large collaborative GWAS of COPD. We identified 2,318 regions of conserved homozygosity, of which 576 were significantly (P < .05) overrepresented in cases. After applying the weights constructed from these regions to a collaborative GWAS of COPD, we identified two single nucleotide polymorphisms in a novel gene (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-07 and 2.8E-06 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.
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影响因子：
56.9
作者：
Morrow, Eric M.;Yoo, Seung-Yun;Flavell, Steven W.;Kim, Tae-Kyung;Lin, Yingxi;Hill, Robert Sean;Mukaddes, Nahit M.;Balkhy, Soher;Gascon, Generoso;Hashmi, Asif;Al-Saad, Samira;Ware, Janice;Joseph, Robert M.;Greenblatt, Rachel;Gleason, Danielle;Ertelt, Julia A.;Apse, Kira A.;Bodell, Adria;Partlow, Jennifer N.;Barry, Brenda;Yao, Hui;Markianos, Kyriacos;Ferland, Russell J.;Greenberg, Michael E.;Walsh, Christopher A.
通讯作者：
Walsh, Christopher A.
DOI：
10.1165/rcmb.2008-0114oc
发表时间：
2009-03-01
影响因子：
6.4
作者：
Bhattacharya, Soumyaroop;Srisuma, Sorachai;Mariani, Thomas J.
通讯作者：
Mariani, Thomas J.
影响因子：
30.8
作者：
Iafrate, AJ;Feuk, L;Lee, C
通讯作者：
Lee, C
DOI：
10.1073/pnas.86.3.802
发表时间：
1989-02-01
影响因子：
11.1
作者：
RUBIN, JS;OSADA, H;AARONSON, SA
通讯作者：
AARONSON, SA
影响因子：
56.9
作者：
WERNER, S;SMOLA, H;WILLIAMS, LT
通讯作者：
WILLIAMS, LT