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

Author:

Little Amarise1,Hu Yao2,Sun Quan3,Jain Deepti1,Broome Jai1,Chen Ming-Huei45,Thibord Florian45,McHugh Caitlin1,Surendran Praveen6789,Blackwell Thomas W10,Brody Jennifer A11,Bhan Arunoday12,Chami Nathalie13,de Vries Paul S14,Ekunwe Lynette15,Heard-Costa Nancy165,Hobbs Brian D17,Manichaikul Ani18,Moon Jee-Young19,Preuss Michael H13,Ryan Kathleen20,Wang Zhe13,Wheeler Marsha21,Yanek Lisa R22,Abecasis Goncalo R10,Almasy Laura2324,Beaty Terri H25,Becker Lewis C26,Blangero John27,Boerwinkle Eric14,Butterworth Adam S6782829,Choquet Hélène30,Correa Adolfo15,Curran Joanne E27,Faraday Nauder31,Fornage Myriam32,Glahn David C33,Hou Lifang34,Jorgenson Eric30,Kooperberg Charles2,Lewis Joshua P20,Lloyd-Jones Donald M34,Loos Ruth J F13,Min Yuan-I15,Mitchell Braxton D20,Morrison Alanna C14,Nickerson Deborah A21,North Kari E35,O'Connell Jeffrey R20,Pankratz Nathan36,Psaty Bruce M113738,Vasan Ramachandran S53940,Rich Stephen S18,Rotter Jerome I41,Smith Albert V10,Smith Nicholas L373842,Tang Hua43,Tracy Russell P44,Conomos Matthew P1,Laurie Cecelia A1,Mathias Rasika A45,Li Yun46,Auer Paul L47,Thornton Timothy1,Reiner Alexander P37,Johnson Andrew D45,Raffield Laura M48,

Affiliation:

1. Department of Biostatistics, University of Washington, Seattle, WA 98105, USA

2. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA

3. Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

4. Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, MD 20892, USA

5. National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA 01702, USA

6. British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK

7. British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge CB1 8RN, UK

8. Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge CB1 8RN, UK

9. Rutherford Fund Fellow, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK

10. TOPMed Informatics Research Center, University of Michigan, Department of Biostatistics, Ann Arbor, MI 48109, USA

11. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA

12. Boston Children’s Hospital, Boston, MA 02644, USA

13. The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York City, NY 10029, USA

14. 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

15. Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA

16. Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA

17. 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

18. Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA

19. Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA

20. Department of Medicine, Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA

21. Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA

22. Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

23. Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA

24. Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA

25. School of Public Health, Baltimore, MD 21205, USA

26. Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

27. Department of Human Genetics and South Texas Diabetes and Obesity Institute, School of Medicine, University of Texas Rio Grande Valley, Brownsville, TX 78520, USA

28. National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge CB1 8RN, UK

29. National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals, Cambridge CB1 8RN, UK

30. Division of Research, Kaiser Permanente Northern California, Oakland, CA 94612, USA

31. Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

32. University of Texas Health Science Center at Houston, Houston, TX 77030, USA

33. Department of Psychiatry, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA

34. Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA

35. Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27599, USA

36. Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 55455, USA

37. Department of Epidemiology, University of Washington, Seattle, WA 98195, USA

38. Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle WA 98101, USA

39. Departments of Cardiology and Preventive Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA

40. Department of Epidemiology, Boston University School of Public Health, Boston, MA 02118, USA

41. 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

42. Department of Veterans Affairs Office of Research and Development, Seattle Epidemiologic Research and Information Center, Seattle, WA 98108, USA

43. Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA

44. Department of Pathology and Laboratory Medicine and Biochemistry, University of Vermont Larner College of Medicine, Colchester, VT 05446, USA

45. Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

46. Departments of Biostatistics, Genetics, Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

47. Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA

48. Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA

Abstract

Abstract 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.

Funder

American Heart Association

National Eye Institute

National Institute of Diabetes and Digestive and Kidney Diseases

National Cancer Institute

NHLBI

Canadian Institutes of Health Research

National Blood Foundation/American Association of Blood Banks

NRSA Joint Program in Transfusion Medicine

Publisher

Oxford University Press (OUP)

Subject

Genetics (clinical),Genetics,Molecular Biology,General Medicine

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