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通过全基因组测序探索炎症性肠病的遗传结构,发现ADCY7存在关联。

Exploring the genetic architecture of inflammatory bowel disease by whole-genome sequencing identifies association at ADCY7.

作者信息

Luo Yang, de Lange Katrina M, Jostins Luke, Moutsianas Loukas, Randall Joshua, Kennedy Nicholas A, Lamb Christopher A, McCarthy Shane, Ahmad Tariq, Edwards Cathryn, Serra Eva Goncalves, Hart Ailsa, Hawkey Chris, Mansfield John C, Mowat Craig, Newman William G, Nichols Sam, Pollard Martin, Satsangi Jack, Simmons Alison, Tremelling Mark, Uhlig Holm, Wilson David C, Lee James C, Prescott Natalie J, Lees Charlie W, Mathew Christopher G, Parkes Miles, Barrett Jeffrey C, Anderson Carl A

机构信息

Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.

Division of Genetics and Rheumatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

出版信息

Nat Genet. 2017 Feb;49(2):186-192. doi: 10.1038/ng.3761. Epub 2017 Jan 9.

Abstract

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 genome-wide association study 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 the 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 understanding of the biology of complex diseases.

摘要

为了进一步解析炎性肠病(溃疡性结肠炎和克罗恩病)的遗传结构,我们对4280例患者的全基因组进行了低覆盖度测序,并将其与3652例先前测序的人群对照在7350万个变异位点上进行比较。然后,我们将这些序列推断到新的和现有的全基因组关联研究队列中,并在总共16432例病例和18843例对照中对约1200万个变异位点进行关联测试。我们在ADCY7基因中发现了一个频率为0.6%的错义变异,该变异使溃疡性结肠炎的风险增加了一倍。尽管有良好的统计效力,但我们未识别出任何其他新的低频风险变异,且发现此类变异对遗传度的解释作用很小。我们在已知的克罗恩病风险基因中检测到大量非常罕见的、有害的错义变异,这表明更全面的测序研究将继续增进对复杂疾病生物学机制的理解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ee6/5289625/3c50a87257f7/emss-70680-f001.jpg

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