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

Amarise Little, Yao Hu, Quan Sun, Deepti Jain, Jai Broome, Ming Huei Chen, Florian Thibord, Caitlin Mchugh, Praveen Surendran, Thomas W. Blackwell, Jennifer A. Brody, Arunoday Bhan, Nathalie Chami, Paul S. De Vries, Lynette Ekunwe, Nancy Heard-Costa, Brian D. Hobbs, Ani Manichaikul, Jee Young Moon, Michael H. PreussKathleen Ryan, Zhe Wang, Marsha Wheeler, Lisa R. Yanek, Goncalo R. Abecasis, Laura Almasy, Terri H. Beaty, Lewis C. Becker, John Blangero, Eric Boerwinkle, Adam S. Butterworth, Hélène Choquet, Adolfo Correa, Joanne E. Curran, Nauder Faraday, Myriam Fornage, David C. Glahn, Lifang Hou, Eric Jorgenson, Charles Kooperberg, Joshua P. Lewis, Donald M. Lloyd-Jones, Ruth J.F. Loos, Yuan I. Min, Braxton D. Mitchell, Alanna C. Morrison, Deborah A. Nickerson, Kari E. North, Jeffrey R. O'connell, Nathan Pankratz, Bruce M. Psaty, Ramachandran S. Vasan, Stephen S. Rich, Jerome I. Rotter, Albert V. Smith, Nicholas L. Smith, Hua Tang, Russell P. Tracy, Matthew P. Conomos, Cecelia A. Laurie, Rasika A. Mathias, Yun Li, Paul L. Auer, Timothy Thornton, Alexander P. Reiner, Andrew D. Johnson, Laura M. Raffield

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)347-361
Number of pages15
JournalHuman molecular genetics
Issue number3
StatePublished - Feb 1 2022

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© 2021 The Author(s) 2021. Published by Oxford University Press. All rights reserved.


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