Whole genome sequence analysis of platelet traits in the NHLBI Trans-Omics for Precision Medicine (TOPMed) initiative.,Human Molecular Genetics

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Whole genome sequence analysis of platelet traits in the NHLBI Trans-Omics for Precision Medicine (TOPMed) initiative.
Human Molecular Genetics ( IF 3.5 ) Pub Date : 2022-02-03 , DOI: 10.1093/hmg/ddab252
Amarise Little ₁ , Yao Hu ₂ , Quan Sun ₃ , Deepti Jain ₁ , Jai Broome ₁ , Ming-Huei Chen _{4,

5} , Florian Thibord _{4,

5} , Caitlin McHugh ₁ , Praveen Surendran _{6,

7,

8,

9} , Thomas W Blackwell ₁₀ , Jennifer A Brody ₁₁ , Arunoday Bhan ₁₂ , Nathalie Chami ₁₃ , Paul S de Vries ₁₄ , Lynette Ekunwe ₁₅ , Nancy Heard-Costa _{5,

16} , Brian D Hobbs ₁₇ , Ani Manichaikul ₁₈ , Jee-Young Moon ₁₉ , Michael H Preuss ₁₃ , Kathleen Ryan ₂₀ , Zhe Wang ₁₃ , Marsha Wheeler ₂₁ , Lisa R Yanek ₂₂ , Goncalo R Abecasis ₁₀ , Laura Almasy _{23,

24} , Terri H Beaty ₂₅ , Lewis C Becker ₂₆ , John Blangero ₂₇ , Eric Boerwinkle ₁₄ , Adam S Butterworth _{6,

7,

8,

28,

29} , Hélène Choquet ₃₀ , Adolfo Correa ₁₅ , Joanne E Curran ₂₇ , Nauder Faraday ₃₁ , Myriam Fornage ₃₂ , David C Glahn ₃₃ , Lifang Hou ₃₄ , Eric Jorgenson ₃₀ , Charles Kooperberg ₂ , Joshua P Lewis ₂₀ , Donald M Lloyd-Jones ₃₄ , Ruth J F Loos ₁₃ , Yuan-I Min ₁₅ , Braxton D Mitchell ₂₀ , Alanna C Morrison ₁₄ , Deborah A Nickerson ₂₁ , Kari E North ₃₅ , Jeffrey R O'Connell ₂₀ , Nathan Pankratz ₃₆ , Bruce M Psaty _{11,

37,

38} , Ramachandran S Vasan _{5,

39,

40} , Stephen S Rich ₁₈ , Jerome I Rotter ₄₁ , Albert V Smith ₁₀ , Nicholas L Smith _{37,

38,

42} , Hua Tang ₄₃ , Russell P Tracy ₄₄ , Matthew P Conomos ₁ , Cecelia A Laurie ₁ , Rasika A Mathias ₄₅ , Yun Li ₄₆ , Paul L Auer ₄₇ , Timothy Thornton ₁ , Alexander P Reiner ₃₇ , Andrew D Johnson _{4,

5} , Laura M Raffield ₄₈ ,

Affiliation

Department of Biostatistics, University of Washington, Seattle, WA 98105, USA
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, MD 20892, USA
National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA 01702, USA
British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge CB1 8RN, UK
Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge CB1 8RN, UK
Rutherford Fund Fellow, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
TOPMed Informatics Research Center, University of Michigan, Department of Biostatistics, Ann Arbor, MI 48109, USA
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA
Boston Children’s Hospital, Boston, MA 02644, USA
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York City, NY 10029, USA
Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA
Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA
Channing Division of Network Medicine and Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA
Department of Medicine, Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
School of Public Health, Baltimore, MD 21205, USA
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Department of Human Genetics and South Texas Diabetes and Obesity Institute, School of Medicine, University of Texas Rio Grande Valley, Brownsville, TX 78520, USA
National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge CB1 8RN, UK
National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals, Cambridge CB1 8RN, UK
Division of Research, Kaiser Permanente Northern California, Oakland, CA 94612, USA
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Department of Psychiatry, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA
Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27599, USA
Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
Department of Epidemiology, University of Washington, Seattle, WA 98195, USA
Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle WA 98101, USA
Departments of Cardiology and Preventive Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA
Department of Epidemiology, Boston University School of Public Health, Boston, MA 02118, USA
Department of Pediatrics, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA 90502, USA
Department of Veterans Affairs Office of Research and Development, Seattle Epidemiologic Research and Information Center, Seattle, WA 98108, USA
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
Department of Pathology and Laboratory Medicine and Biochemistry, University of Vermont Larner College of Medicine, Colchester, VT 05446, USA
Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Departments of Biostatistics, Genetics, Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA
Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA

Platelets play a key role in thrombosis and hemostasis. Platelet count (PLT) and mean platelet volume (MPV) are highly heritable quantitative traits, with hundreds of genetic signals previously identified, mostly in European ancestry populations. We here utilize whole genome sequencing (WGS) from NHLBI's Trans-Omics for Precision Medicine initiative (TOPMed) in a large multi-ethnic sample to further explore common and rare variation contributing to PLT (n = 61 200) and MPV (n = 23 485). We identified and replicated secondary signals at MPL (rs532784633) and PECAM1 (rs73345162), both more common in African ancestry populations. We also observed rare variation in Mendelian platelet-related disorder genes influencing variation in platelet traits in TOPMed cohorts (not enriched for blood disorders). For example, association of GP9 with lower PLT and higher MPV was partly driven by a pathogenic Bernard-Soulier syndrome variant (rs5030764, p.Asn61Ser), and the signals at TUBB1 and CD36 were partly driven by loss of function variants not annotated as pathogenic in ClinVar (rs199948010 and rs571975065). However, residual signal remained for these gene-based signals after adjusting for lead variants, suggesting that additional variants in Mendelian genes with impacts in general population cohorts remain to be identified. Gene-based signals were also identified at several genome-wide association study identified loci for genes not annotated for Mendelian platelet disorders (PTPRH, TET2, CHEK2), with somatic variation driving the result at TET2. These results highlight the value of WGS in populations of diverse genetic ancestry to identify novel regulatory and coding signals, even for well-studied traits like platelet traits.

中文翻译：

NHLBI Trans-Omics for Precision Medicine (TOPMed) 计划中血小板特性的全基因组序列分析。

血小板在血栓形成和止血中起关键作用。血小板计数 (PLT) 和平均血小板体积 (MPV) 是高度可遗传的数量性状，之前已鉴定出数百种遗传信号，主要发生在欧洲血统人群中。我们在这里利用来自 NHLBI 的跨组学精准医学计划 (TOPMed) 的全基因组测序 (WGS) 在一个大型多种族样本中进一步探索导致 PLT (n = 61 200) 和 MPV (n = 23) 的常见和罕见变异485). 我们在 MPL (rs532784633) 和 PECAM1 (rs73345162) 处识别并复制了次级信号，这两种信号在非洲血统人群中更为常见。我们还观察到影响 TOPMed 队列中血小板特征变异的孟德尔血小板相关疾病基因的罕见变异（未针对血液疾病进行富集）。例如，GP9 与较低 PLT 和较高 MPV 的关联部分是由致病性 Bernard-Soulier 综合征变异（rs5030764，p.Asn61Ser）驱动的，而 TUBB1 和 CD36 的信号部分是由 ClinVar 中未注释为致病性的功能丧失变异驱动的（ rs199948010 和 rs571975065）。然而，在针对先导变异进行调整后，这些基于基因的信号仍然存在残余信号，这表明孟德尔基因中对一般人群有影响的其他变异仍有待确定。在几项全基因组关联研究中也确定了基于基因的信号，这些研究确定了未注释孟德尔血小板疾病（PTPRH、TET2、CHEK2）的基因位点，体细胞变异驱动了 TET2 的结果。

更新日期：2021-09-06

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