原发性硬化性胆管炎的全基因组关联研究确定了新的风险位点并量化了与炎症性肠病的遗传关系。
Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease.
作者信息
Ji Sun-Gou, Juran Brian D, Mucha Sören, Folseraas Trine, Jostins Luke, Melum Espen, Kumasaka Natsuhiko, Atkinson Elizabeth J, Schlicht Erik M, Liu Jimmy Z, Shah Tejas, Gutierrez-Achury Javier, Boberg Kirsten M, Bergquist Annika, Vermeire Severine, Eksteen Bertus, Durie Peter R, Farkkila Martti, Müller Tobias, Schramm Christoph, Sterneck Martina, Weismüller Tobias J, Gotthardt Daniel N, Ellinghaus David, Braun Felix, Teufel Andreas, Laudes Mattias, Lieb Wolfgang, Jacobs Gunnar, Beuers Ulrich, Weersma Rinse K, Wijmenga Cisca, Marschall Hanns-Ulrich, Milkiewicz Piotr, Pares Albert, Kontula Kimmo, Chazouillères Olivier, Invernizzi Pietro, Goode Elizabeth, Spiess Kelly, Moore Carmel, Sambrook Jennifer, Ouwehand Willem H, Roberts David J, Danesh John, Floreani Annarosa, Gulamhusein Aliya F, Eaton John E, Schreiber Stefan, Coltescu Catalina, Bowlus Christopher L, Luketic Velimir A, Odin Joseph A, Chopra Kapil B, Kowdley Kris V, Chalasani Naga, Manns Michael P, Srivastava Brijesh, Mells George, Sandford Richard N, Alexander Graeme, Gaffney Daniel J, Chapman Roger W, Hirschfield Gideon M, de Andrade Mariza, Rushbrook Simon M, Franke Andre, Karlsen Tom H, Lazaridis Konstantinos N, Anderson Carl A
机构信息
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
出版信息
Nat Genet. 2017 Feb;49(2):269-273. doi: 10.1038/ng.3745. Epub 2016 Dec 19.
Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; ∼75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (r) between PSC and ulcerative colitis (UC) (r = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (r = 0.04) (P = 2.55 × 10). UC and CD were genetically more similar to each other (r = 0.56) than either was to PSC (P < 1.0 × 10). Our study represents a substantial advance in understanding of the genetics of PSC.
原发性硬化性胆管炎（PSC）是一种导致胆管破坏的罕见进行性疾病；约75%的患者合并有炎症性肠病（IBD）。我们开展了最大规模的PSC全基因组关联研究（4796例病例和19955名人群对照），并确定了4个新的全基因组显著位点。其中一个位点最相关的单核苷酸多态性（SNP）影响UBASH3A的剪接和表达，其保护性等位基因（C）预计会导致无义介导的mRNA降解并降低UBASH3A的表达。基于常见变异的进一步分析表明，PSC与溃疡性结肠炎（UC）之间的全基因组遗传相关性（r = 0.29）显著大于PSC与克罗恩病（CD）之间的遗传相关性（r = 0.04）（P = 2.55×10）。UC和CD之间的遗传相似性（r = 0.56）高于它们与PSC之间的遗传相似性（P < 1.0×10）。我们的研究在理解PSC遗传学方面取得了重大进展。
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