Exploring the genetic architecture of inflammatory bowel disease by whole-genome sequencing identifies association at ADCY7.
Exploring the genetic architecture of inflammatory bowel disease by whole-genome sequencing identifies association at ADCY7.
复制标题
DOI：
10.1038/ng.3761
复制
发表时间：
2017-02
期刊：
影响因子：
30.8
通讯作者：
Anderson CA
中科院分区：
文献类型：
--
作者：
Luo Y;de Lange KM;Jostins L;Moutsianas L;Randall J;Kennedy NA;Lamb CA;McCarthy S;Ahmad T;Edwards C;Serra EG;Hart A;Hawkey C;Mansfield JC;Mowat C;Newman WG;Nichols S;Pollard M;Satsangi J;Simmons A;Tremelling M;Uhlig H;Wilson DC;Lee JC;Prescott NJ;Lees CW;Mathew CG;Parkes M;Barrett JC;Anderson CA
为了进一步解析炎症性肠病、溃疡性结肠炎和克罗恩病的遗传结构，我们对 4,280 名低覆盖率患者的全基因组进行了测序，并将其与 3,652 个先前测序的人群对照（7350 万个变异）进行了比较。然后，我们将这些序列归入新的和现有的 GWAS 队列，并测试了总共 16,432 个病例和 18,843 个对照中约 1200 万个变异的关联性。我们在 ADCY7 中发现了 0.6% 频率的错义变异，它使溃疡性结肠炎的风险加倍。尽管统计能力良好，但我们没有发现任何其他新的低频风险变异，并发现此类变异几乎不能解释遗传性。我们在已知的克罗恩病风险基因中检测到了非常罕见的、具有破坏性的错义变异，这表明更全面的测序研究将继续提高我们对复杂疾病生物学的理解。
To further resolve the genetic architecture of the inflammatory bowel diseases, ulcerative colitis and Crohn’s disease, we sequenced the whole genomes of 4,280 patients at low coverage, and compared them to 3,652 previously sequenced population controls across 73.5 million variants. We then imputed from these sequences into new and existing GWAS cohorts, and tested for association at ~12 million variants in a total of 16,432 cases and 18,843 controls. We discovered a 0.6% frequency missense variant in ADCY7 that doubles risk of ulcerative colitis. Despite good statistical power, we did not identify any other new low-frequency risk variants, and found that such variants explained little heritability. We detected a burden of very rare, damaging missense variants in known Crohn’s disease risk genes, suggesting that more comprehensive sequencing studies will continue to improve our understanding of the biology of complex diseases.