Discovery of 318 new risk loci for type 2 diabetes and related vascular outcomes among 1.4 million participants in a multi-ancestry meta-analysis.,Nature Genetics

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Discovery of 318 new risk loci for type 2 diabetes and related vascular outcomes among 1.4 million participants in a multi-ancestry meta-analysis.
Nature Genetics ( IF 31.7 ) Pub Date : 2020-06-15 , DOI: 10.1038/s41588-020-0637-y
Marijana Vujkovic _{1,

2} , Jacob M Keaton _{3,

4,

5,

6} , Julie A Lynch _{7,

8} , Donald R Miller _{9,

10} , Jin Zhou _{11,

12} , Catherine Tcheandjieu _{13,

14,

15} , Jennifer E Huffman ₁₆ , Themistocles L Assimes _{13,

14} , Kimberly Lorenz _{1,

17,

18} , Xiang Zhu _{13,

19} , Austin T Hilliard _{13,

14} , Renae L Judy _{1,

20} , Jie Huang _{16,

21} , Kyung M Lee ₇ , Derek Klarin _{16,

22,

23,

24} , Saiju Pyarajan _{16,

25,

26} , John Danesh ₂₇ , Olle Melander ₂₈ , Asif Rasheed ₂₉ , Nadeem H Mallick ₃₀ , Shahid Hameed ₃₀ , Irshad H Qureshi _{31,

32} , Muhammad Naeem Afzal _{31,

32} , Uzma Malik _{31,

32} , Anjum Jalal ₃₃ , Shahid Abbas ₃₃ , Xin Sheng ₂ , Long Gao ₁₇ , Klaus H Kaestner ₁₇ , Katalin Susztak ₂ , Yan V Sun _{34,

35} , Scott L DuVall _{7,

36} , Kelly Cho _{16,

25} , Jennifer S Lee _{13,

14} , J Michael Gaziano _{16,

25} , Lawrence S Phillips _{34,

37} , James B Meigs _{23,

26,

38} , Peter D Reaven _{11,

39} , Peter W Wilson _{34,

40} , Todd L Edwards _{4,

41} , Daniel J Rader _{2,

17} , Scott M Damrauer _{1,

20} , Christopher J O'Donnell _{16,

25,

26} , Philip S Tsao _{13,

14} , , , , Kyong-Mi Chang _{1,

2,

42} , Benjamin F Voight _{1,

17,

18} , Danish Saleheen _{29,

43,

44}

Affiliation

Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Biomedical Laboratory Research and Development, Tennessee Valley Healthcare System, Nashville, TN, USA.
Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
VA Informatics and Computing Infrastructure, VA Salt Lake City Health Care System, Salt Lake City, UT, USA.
College of Nursing and Health Sciences, University of Massachusetts, Lowell, MA, USA.
Edith Nourse Rogers Memorial VA Hospital, Bedford, MA, USA.
Center for Population Health, University of Massachusetts, Lowell, MA, USA.
Phoenix VA Health Care System, Phoenix, AZ, USA.
Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA.
VA Palo Alto Health Care System, Palo Alto, CA, USA.
Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Department of Pediatric Cardiology, Stanford University School of Medicine, Stanford, CA, USA.
VA Boston Healthcare System, Boston, MA, USA.
Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Department of Statistics, Stanford University, Stanford, CA, USA.
Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Department of Global Health, Peking University School of Public Health, Beijing, China.
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Division of Vascular Surgery and Endovascular Therapy, University of Florida School of Medicine, Gainesville, FL, USA.
Department of Medicine, Brigham Women's Hospital, Boston, MA, USA.
Department of Medicine, Harvard Medical School, Boston, MA, USA.
Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
Center for Non-Communicable Diseases, Karachi, Sindh, Pakistan.
Punjab Institute of Cardiology, Lahore, Punjab, Pakistan.
Department of Medicine, King Edward Medical University, Lahore, Punjab, Pakistan.
Mayo Hospital, Lahore, Punjab, Pakistan.
Department of Cardiology, Faisalabad Institute of Cardiology, Faisalabad, Punjab, Pakistan.
Atlanta VA Medical Center, Decatur, GA, USA.
Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, USA.
Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.
Division of Endocrinology, Emory University School of Medicine, Atlanta, GA, USA.
Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, USA.
College of Medicine, University of Arizona, Phoenix, AZ, USA.
Division of Cardiology, Emory University School of Medicine, Atlanta, GA, USA.
Nashville VA Medical Center, Nashville, TN, USA.
South Texas Veterans Health Care System, San Antonio, TX, USA.
Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
Department of Cardiology, Columbia University Irving Medical Center, New York, NY, USA.

We investigated type 2 diabetes (T2D) genetic susceptibility via multi-ancestry meta-analysis of 228,499 cases and 1,178,783 controls in the Million Veteran Program (MVP), DIAMANTE, Biobank Japan and other studies. We report 568 associations, including 286 autosomal, 7 X-chromosomal and 25 identified in ancestry-specific analyses that were previously unreported. Transcriptome-wide association analysis detected 3,568 T2D associations with genetically predicted gene expression in 687 novel genes; of these, 54 are known to interact with FDA-approved drugs. A polygenic risk score (PRS) was strongly associated with increased risk of T2D-related retinopathy and modestly associated with chronic kidney disease (CKD), peripheral artery disease (PAD) and neuropathy. We investigated the genetic etiology of T2D-related vascular outcomes in the MVP and observed statistical SNP–T2D interactions at 13 variants, including coronary heart disease (CHD), CKD, PAD and neuropathy. These findings may help to identify potential therapeutic targets for T2D and genomic pathways that link T2D to vascular outcomes.

中文翻译：

在一项多血统荟萃分析中，在 140 万参与者中发现了 318 个 2 型糖尿病和相关血管结果的新风险位点。

我们通过对百万老兵计划 (MVP)、DIAMANTE、日本生物银行和其他研究中的 228,499 例病例和 1,178,783 名对照的多血统荟萃分析调查了 2 型糖尿病 (T2D) 的遗传易感性。我们报告了 568 个关联，包括 286 个常染色体、7 个 X 染色体和 25 个在先前未报告的祖先特异性分析中确定的关联。全转录组关联分析在 687 个新基因中检测到 3,568 个 T2D 与遗传预测基因表达的关联；其中，已知有 54 种与 FDA 批准的药物相互作用。多基因风险评分 (PRS) 与 T2D 相关视网膜病变风险增加密切相关，与慢性肾病 (CKD)、外周动脉疾病 (PAD) 和神经病变适度相关。我们调查了 MVP 中 T2D 相关血管结果的遗传病因，并观察了 13 种变异的统计 SNP-T2D 相互作用，包括冠心病 (CHD)、CKD、PAD 和神经病变。这些发现可能有助于确定 T2D 的潜在治疗靶点和将 T2D 与血管结果联系起来的基因组途径。

更新日期：2020-06-15

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