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. Preuss; Kathleen 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

doi:10.1093/hmg/ddab252

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

Epidemiology & Population Health

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

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.

Original language	English (US)
Pages (from-to)	347-361
Number of pages	15
Journal	Human molecular genetics
Volume	31
Issue number	3
DOIs	https://doi.org/10.1093/hmg/ddab252
State	Published - Feb 1 2022

ASJC Scopus subject areas

Molecular Biology
Genetics
Genetics(clinical)

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10.1093/hmg/ddab252

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Little, A., Hu, Y., Sun, Q., Jain, D., Broome, J., Chen, M. H., Thibord, F., Mchugh, C., Surendran, P., Blackwell, T. W., Brody, J. A., Bhan, A., Chami, N., De Vries, P. S., Ekunwe, L., Heard-Costa, N., Hobbs, B. D., Manichaikul, A., Moon, J. Y., ... Raffield, L. M. (2022). Whole genome sequence analysis of platelet traits in the NHLBI Trans-Omics for Precision Medicine (TOPMed) initiative. Human molecular genetics, 31(3), 347-361. https://doi.org/10.1093/hmg/ddab252

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 2022, 'Whole genome sequence analysis of platelet traits in the NHLBI Trans-Omics for Precision Medicine (TOPMed) initiative', Human molecular genetics, vol. 31, no. 3, pp. 347-361. https://doi.org/10.1093/hmg/ddab252

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

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.",

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

year = "2022",

month = feb,

day = "1",

doi = "10.1093/hmg/ddab252",

language = "English (US)",

volume = "31",

pages = "347--361",

journal = "Human molecular genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "3",

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TY - JOUR

T1 - Whole genome sequence analysis of platelet traits in the NHLBI Trans-Omics for Precision Medicine (TOPMed) initiative

AU - Little, Amarise

AU - Hu, Yao

AU - Sun, Quan

AU - Jain, Deepti

AU - Broome, Jai

AU - Chen, Ming Huei

AU - Thibord, Florian

AU - Mchugh, Caitlin

AU - Surendran, Praveen

AU - Blackwell, Thomas W.

AU - Brody, Jennifer A.

AU - Bhan, Arunoday

AU - Chami, Nathalie

AU - De Vries, Paul S.

AU - Ekunwe, Lynette

AU - Heard-Costa, Nancy

AU - Hobbs, Brian D.

AU - Manichaikul, Ani

AU - Moon, Jee Young

AU - Preuss, Michael H.

AU - Ryan, Kathleen

AU - Wang, Zhe

AU - Wheeler, Marsha

AU - Yanek, Lisa R.

AU - Abecasis, Goncalo R.

AU - Almasy, Laura

AU - Beaty, Terri H.

AU - Becker, Lewis C.

AU - Blangero, John

AU - Boerwinkle, Eric

AU - Butterworth, Adam S.

AU - Choquet, Hélène

AU - Correa, Adolfo

AU - Curran, Joanne E.

AU - Faraday, Nauder

AU - Fornage, Myriam

AU - Glahn, David C.

AU - Hou, Lifang

AU - Jorgenson, Eric

AU - Kooperberg, Charles

AU - Lewis, Joshua P.

AU - Lloyd-Jones, Donald M.

AU - Loos, Ruth J.F.

AU - Min, Yuan I.

AU - Mitchell, Braxton D.

AU - Morrison, Alanna C.

AU - Nickerson, Deborah A.

AU - North, Kari E.

AU - O'connell, Jeffrey R.

AU - Pankratz, Nathan

AU - Psaty, Bruce M.

AU - Vasan, Ramachandran S.

AU - Rich, Stephen S.

AU - Rotter, Jerome I.

AU - Smith, Albert V.

AU - Smith, Nicholas L.

AU - Tang, Hua

AU - Tracy, Russell P.

AU - Conomos, Matthew P.

AU - Laurie, Cecelia A.

AU - Mathias, Rasika A.

AU - Li, Yun

AU - Auer, Paul L.

AU - Thornton, Timothy

AU - Reiner, Alexander P.

AU - Johnson, Andrew D.

AU - Raffield, Laura M.

PY - 2022/2/1

Y1 - 2022/2/1

N2 - 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.

AB - 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.

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DO - 10.1093/hmg/ddab252

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AN - SCOPUS:85124433263

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JO - Human molecular genetics

JF - Human molecular genetics

IS - 3

ER -

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

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