Whole genome sequence analysis of platelet traits in the NHLBI Trans-Omics for Precision Medicine (TOPMed) initiative.
Authors
Little, Amarise
Hu, Yao
Sun, Quan
Jain, Deepti
Broome, Jai
Chen, Ming-Huei
Thibord, Florian
McHugh, Caitlin
Surendran, Praveen
Blackwell, Thomas W
Brody, Jennifer A
Bhan, Arunoday
Chami, Nathalie
de Vries, Paul S
Ekunwe, Lynette
Heard-Costa, Nancy
Hobbs, Brian D
Manichaikul, Ani
Moon, Jee-Young
Preuss, Michael H
Ryan, Kathleen
Wang, Zhe
Wheeler, Marsha
Yanek, Lisa R
Abecasis, Goncalo R
Almasy, Laura
Beaty, Terri H
Becker, Lewis C
Blangero, John
Boerwinkle, Eric
Butterworth, Adam S
Choquet, Hélène
Correa, Adolfo
Curran, Joanne E
Faraday, Nauder
Fornage, Myriam
Glahn, David C
Hou, Lifang
Jorgenson, Eric
Kooperberg, Charles
Lewis, Joshua P
Lloyd-Jones, Donald M
Loos, Ruth JF
Min, Yuan-I
Mitchell, Braxton D
Morrison, Alanna C
Nickerson, Deborah A
North, Kari E
O'Connell, Jeffrey R
Pankratz, Nathan
Psaty, Bruce M
Vasan, Ramachandran S
Rich, Stephen S
Rotter, Jerome I
Smith, Albert V
Smith, Nicholas L
Tang, Hua
Tracy, Russell P
Conomos, Matthew P
Laurie, Cecelia A
Mathias, Rasika A
Li, Yun
Auer, Paul L
NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
Thornton, Timothy
Reiner, Alexander P
Johnson, Andrew D
Raffield, Laura M
Publication Date
2022-02-03Journal Title
Hum Mol Genet
ISSN
0964-6906
Publisher
Oxford University Press (OUP)
Type
Article
This Version
AM
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Little, A., Hu, Y., Sun, Q., Jain, D., Broome, J., Chen, M., Thibord, F., et al. (2022). Whole genome sequence analysis of platelet traits in the NHLBI Trans-Omics for Precision Medicine (TOPMed) initiative.. Hum Mol Genet https://doi.org/10.1093/hmg/ddab252
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.
Keywords
NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
Sponsorship
Medical Research Council (MR/L003120/1)
British Heart Foundation (None)
British Heart Foundation (RG/18/13/33946)
British Heart Foundation (CH/12/2/29428)
Identifiers
External DOI: https://doi.org/10.1093/hmg/ddab252
This record's URL: https://www.repository.cam.ac.uk/handle/1810/332821
Rights
Publisher's own licence
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