Einzeltreffer — DigiBib

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.

Titel:	Whole genome sequence analysis of platelet traits in the NHLBI Trans-Omics for Precision Medicine (TOPMed) initiative.
Autor/in / Beteiligte Person:	Little, A ; Hu, Y ; Sun, Q ; Jain, D ; Broome, J ; Chen, MH ; Thibord, F ; McHugh, C ; Surendran, P ; Blackwell, TW ; Brody, JA ; Bhan, A ; Chami, N ; de Vries PS ; Ekunwe, L ; Heard-Costa, N ; Hobbs, BD ; Manichaikul, A ; Moon, JY ; Preuss, MH ; Ryan, K ; Wang, Z ; Wheeler, M ; Yanek, LR ; Abecasis, GR ; Almasy, L ; Beaty, TH ; Becker, LC ; Blangero, J ; Boerwinkle, E ; Butterworth, AS ; Choquet, H ; Correa, A ; Curran, JE ; Faraday, N ; Fornage, M ; Glahn, DC ; Hou, L ; Jorgenson, E ; Kooperberg, C ; Lewis, JP ; Lloyd-Jones, DM ; Loos, RJF ; Min, YI ; Mitchell, BD ; Morrison, AC ; Nickerson, DA ; North, KE ; O'Connell, JR ; Pankratz, N ; Psaty, BM ; Vasan, RS ; Rich, SS ; Rotter, JI ; Smith, AV ; Smith, NL ; Tang, H ; Tracy, RP ; Conomos, MP ; Laurie, CA ; Mathias, RA ; Li, Y ; Auer, PL ; Thornton, T ; Reiner, AP ; Johnson, AD ; Raffield, LM
Link:	Full Text Finder (Volltext)
Zeitschrift:	Human molecular genetics, Jg. 31 (2022-02-03), Heft 3, S. 347-361
Veröffentlichung:	Oxford, England ; New York : IRL Press at Oxford University Press, c1992-, 2022
Medientyp:	academicJournal
ISSN:	1460-2083 (electronic)
DOI:	10.1093/hmg/ddab252
Schlagwort:	Blood Platelets Humans National Heart, Lung, and Blood Institute (U.S.) Phenotype Polymorphism, Single Nucleotide United States Genome-Wide Association Study Precision Medicine methods
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Corporate Authors: NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Language: English [Hum Mol Genet] 2022 Feb 03; Vol. 31 (3), pp. 347-361. MeSH Terms: Genome-Wide Association Study* ; Precision Medicine* / methods ; Blood Platelets ; Humans ; National Heart, Lung, and Blood Institute (U.S.) ; Phenotype ; Polymorphism, Single Nucleotide ; United States References: Curr Opin Hematol. 2013 Sep;20(5):457-63. (PMID: 23892572) ; Genetics. 2015 Aug;200(4):1285-95. (PMID: 26092716) ; PLoS Genet. 2017 Apr 28;13(4):e1006760. (PMID: 28453575) ; Nature. 2010 Aug 26;466(7310):1129-33. (PMID: 20639862) ; Blood. 2017 Jun 29;129(26):3407-3418. (PMID: 28465343) ; Biomed Res Int. 2015;2015:914965. (PMID: 26064965) ; Nat Commun. 2018 Jun 21;9(1):2427. (PMID: 29930244) ; Nat Protoc. 2016 Jan;11(1):1-9. 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(PMID: 23103231) Grant Information: HHSN268201800005I United States HL NHLBI NIH HHS; U01HL137162 United States HB NHLBI NIH HHS; HHSN268201800015I United States HB NHLBI NIH HHS; MR/L003120/1 United Kingdom MRC_ Medical Research Council; HHSN268201300049C United States HL NHLBI NIH HHS; HHSN268201800003I United States HL NHLBI NIH HHS; N01HC85080 United States HL NHLBI NIH HHS; R01 HL113323 United States HL NHLBI NIH HHS; N01HC95169 United States HL NHLBI NIH HHS; HHSN268201300046C United States HL NHLBI NIH HHS; UM1 HG008898 United States HG NHGRI NIH HHS; 75N92020D00007 United States HL NHLBI NIH HHS; N01HC65236 United States HL NHLBI NIH HHS; HHSN268201800006I United States HL NHLBI NIH HHS; R01 HL120393 United States HL NHLBI NIH HHS; R01 HL071251 United States HL NHLBI NIH HHS; R01 AG023629 United States AG NIA NIH HHS; U01 HL080295 United States HL NHLBI NIH HHS; N01HC95161 United States HL NHLBI NIH HHS; 75N92020D00001 United States HL NHLBI NIH HHS; UL1 TR001881 United States TR NCATS NIH HHS; HHSN268201200036C United States HL NHLBI NIH HHS; R01 HL139553 United States HL NHLBI NIH HHS; P50 HD105351 United States HD NICHD NIH HHS; 206194 United Kingdom WT_ Wellcome Trust; 75N92020D00005 United States HL NHLBI NIH HHS; HHSN268201700001I United States HL NHLBI NIH HHS; R01 HL071259 United States HL NHLBI NIH HHS; N01HC95168 United States HL NHLBI NIH HHS; 75N92021D00006 United States HL NHLBI NIH HHS; U01 HL120393 United States HL NHLBI NIH HHS; N01HC65237 United States HL NHLBI NIH HHS; N01HC65234 United States HL NHLBI NIH HHS; United Kingdom DH_ Department of Health; HHSN268201300047C United States HL NHLBI NIH HHS; RG/18/13/33946 United Kingdom BHF_ British Heart Foundation; R01 EY027004 United States EY NEI NIH HHS; HHSN268201700004I United States HL NHLBI NIH HHS; N01HC95162 United States HL NHLBI NIH HHS; R01 HL071051 United States HL NHLBI NIH HHS; 75N92020D00004 United States HL NHLBI NIH HHS; N01HC85082 United States HL NHLBI NIH HHS; UL1 TR001420 United States TR NCATS NIH HHS; N02 HL64278 United States HL NHLBI NIH HHS; R01 HL071205 United States HL NHLBI NIH HHS; HHSN268201500001I United States HL NHLBI NIH HHS; HHSN268201800007I United States HL NHLBI NIH HHS; N01HC65235 United States HL NHLBI NIH HHS; U01 HL089856 United States HL NHLBI NIH HHS; N01HC95165 United States HL NHLBI NIH HHS; N01HC65233 United States HL NHLBI NIH HHS; N01HC55222 United States HL NHLBI NIH HHS; N01HC85079 United States HL NHLBI NIH HHS; R01 HL059367 United States HL NHLBI NIH HHS; R01 HL071258 United States HL NHLBI NIH HHS; N01HC95167 United States HL NHLBI NIH HHS; N01HC85083 United States HL NHLBI NIH HHS; HHSN268201800001C United States HL NHLBI NIH HHS; U01 HG007417 United States HG NHGRI NIH HHS; HHSN268201700002I United States HL NHLBI NIH HHS; N01HC95159 United States HL NHLBI NIH HHS; U24 HG008956 United States HG NHGRI NIH HHS; N01HC95163 United States HL NHLBI NIH HHS; N01HC85086 United States HL NHLBI NIH HHS; U54 DK110805 United States DK NIDDK NIH HHS; HHSN268201300048C United States HL NHLBI NIH HHS; U01 DK085524 United States DK NIDDK NIH HHS; 75N92020D00002 United States HL NHLBI NIH HHS; R01 HL121007 United States HL NHLBI NIH HHS; HHSN268201700005I United States HL NHLBI NIH HHS; R01CA2416323 United States CA NCI NIH HHS; RC2 AG036607 United States AG NIA NIH HHS; 75N92020D00003 United States HL NHLBI NIH HHS; N01HC25195 United States HL NHLBI NIH HHS; P01 HL045522 United States HL NHLBI NIH HHS; HHSN268201700003I United States HL NHLBI NIH HHS; UL1 RR033176 United States RR NCRR NIH HHS; M01 RR000052 United States RR NCRR NIH HHS; HHSN268201500003I United States HL NHLBI NIH HHS; K08 HL136928 United States HL NHLBI NIH HHS; R01 HL092577 United States HL NHLBI NIH HHS; N01HC95164 United States HL NHLBI NIH HHS; R01 HL146500 United States HL NHLBI NIH HHS; U01 GM074518 United States GM NIGMS NIH HHS; 75N92020D00006 United States HL NHLBI NIH HHS; UL1 TR001079 United States TR NCATS NIH HHS; U01 HL130114 United States HL NHLBI NIH HHS; N01HC95166 United States HL NHLBI NIH HHS; U01 HL072515 United States HL NHLBI NIH HHS; HHSN268200800007C United States HL NHLBI NIH HHS; R01 HL117626 United States HL NHLBI NIH HHS; United Kingdom CSO_ Chief Scientist Office; R01 DK116738 United States DK NIDDK NIH HHS; UL1 TR000040 United States TR NCATS NIH HHS; N01HC85081 United States HL NHLBI NIH HHS; HHSN268201300050C United States HL NHLBI NIH HHS; T32 HL129982 United States HL NHLBI NIH HHS; R01 HL071250 United States HL NHLBI NIH HHS; N01HC95160 United States HL NHLBI NIH HHS; RG/13/13/30194 United Kingdom BHF_ British Heart Foundation; U01 HL089897 United States HL NHLBI NIH HHS; CH/12/2/29428 United Kingdom BHF_ British Heart Foundation; HHSN268201800004I United States HL NHLBI NIH HHS; SP/09/002 United Kingdom BHF_ British Heart Foundation Entry Date(s): Date Created: 20210923 Date Completed: 20220427 Latest Revision: 20240420 Update Code: 20240420 PubMed Central ID: PMC8825339

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