Whole-genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles

VA Million Veteran Program; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

doi:10.1182/blood.2023022596

Whole-genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles

VA Million Veteran Program, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

Preventive Medicine

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

2 Scopus citations

Abstract

Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole-genome sequencing (WGS) data provide better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program (n = 32 572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (n = 131 340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, 4 are driven by common variants of small effect with reported minor allele frequency (MAF) at least 10 percentage points higher in African populations. Three signals (SERPINA1, ZFP36L2, and TLR10) contain predicted deleterious missense variants. Two loci, SOCS3 and HPN, each harbor 2 conditionally distinct, noncoding variants. The gene region encoding the fibrinogen protein chain subunits (FGG;FGB;FGA) contains 7 distinct signals, including 1 novel signal driven by rs28577061, a variant common in African ancestry populations but extremely rare in Europeans (MAF_AFR = 0.180; MAF_EUR = 0.008). Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation.

Original language	English (US)
Pages (from-to)	2248-2265
Number of pages	18
Journal	Blood
Volume	144
Issue number	21
DOIs	https://doi.org/10.1182/blood.2023022596
State	Published - Nov 21 2024

Funding

The authors gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. Molecular data for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI). See the TOPMed Omics Support Table in the supplemental Data for study-specific omics support information. Core support, including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering, was provided by the TOPMed Informatics Research Center (NIH, NHLBI grant 3R01HL-117626-02S1; contract HHSN268201800002I). Core support, including phenotype harmonization, data management, sample-identity quality control, and general program coordination, was provided by the TOPMed Data Coordinating Center (NIH, NHLBI grants R01HL-120393; U01HL-120393; contract HHSN268201800001I). CHARGE is supported by NIH, NHLBI grant R01HL-105756, and the CHARGE and TOPMed Hemostasis Working Groups by NIH, NHLBI grants R01HL-134894, R01HL-139553, and R01HL-141291. This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by award I01-BX004821. The study was supported by the Novo Nordisk Foundation (grant NNF18CC0034900). D.-A.T. was supported by the EPIDEMIOM-VT Senior Chair of Excellence from the University of Bordeaux initiative of Excellence. M.S.-L. is supported by a Miguel Servet contract from the ISCIII Spanish Health Institute (CPII22/00007) and cofinanced by the European Social Fund. Additional study-specific funding and acknowledgments can be found in the supplemental Data. The Genotype-Tissue Expression Project was supported by the Common Fund of the NIH Office of the Director, and by the NIH, National Cancer Institute, NIH, National Human Genome Research Institute, NIH, NHLBI, NIH, National Institute on Drug Abuse, NIH, National Institute of Mental Health, and NIH, National Institute of Neurological Disorders and Stroke. This publication does not represent the views of the Department of Veteran Affairs, the US National Institutes of Health, the National Heart, Lung, and Blood Institute, the US Department of Health and Human Services, or the US government. Contribution: L.M.R. J.A.B. L.A. D.I.C. M.-H.C. J.P.L. O. Polasek, J.I.R. E.d.G. J.-F.D. L.E. N.F. M.G. A.L. S.S.R. F.R.R. I.R. J.C.S. L.C.B. A.B. H.C. K.C. J.E.C. M.D. P.E. M.N. V.O. B.M.P. J.M.S. D.J.S. A.v.H. H.W. W.F.W. Y.B.-S. J.B. D.B. S.R.C. J.G.E. E.F. C.H. M.A.I. J.W.J. S.L.R.K. L.A.L. R.A.M. B.D.M. D.O.M.-K. P.-E.M. P.P.P. A.R. P.M.R. T.D.S. N.J.W. J.F.W. D.-A.T. A.D.J. P.S.d.V. A.C.M. and N.L.S. participated in the design and/or funding of the contributing studies; J.E.H. L.M.R. L.R.Y. L.A. L.F.B. R.P.B. G.D.C. J.L. J.P.L. R.L.-G. M.M. O. Polasek, M.S. P.S. M.H.C. P.C. E.d.G. N.F. M.G. A.G. H.G. T.H. T.K. J.L. A.L. S.N. F.R.R. I.R. K.A.R. J.C.S. F.J.A.v.R. H.W. W.Z.A.B. B.E.C. K.C. J.D.C. M.P.M.d.M. M.D. P.E. C.F. N.G. S.H.E. I.K. M.N. J.R.O. V.O. B.M.P. K.R. J.A.S. D.J.S. A.v.H. G.W. Y.B.-S. J.B. D.B. S.R.C. J.G.E. E.F. T.H. S.L.R.K. L.A.L. B.D.M. P.-E.M. O. Pedersen, S.R. P.M.R. E.K.S. N.J.W. J.F.W. P.S.d.V. M.S.-L. A.C.M. and N.L.S. participated in phenotype data acquisition and/or quality control; L.R.Y. L.A. G.D.C. D.I.C. M.-H.C. D.B.E. J.H. J.-J.H. M.E.K. N.-Q.L. J.L. R.L.-G. M.M. A.M.-P. A.R. B.A.T.R. M.S. P.S. S.T. S.W. M.Z. P.A. M.H.C. G.D. E.d.G. J.-F.D. H.G. T.O.K. J.L. A.L. S.N. F.P.-V. F.R.R. K.A.R. F.J.A.v.R. H.W. W.Z. B.E.C. J.E.C. C.F. N.G. S.H.E. C.M. J.R.O. V.O. B.M.P. K.R. J.A.S. G.W. J.B. D.B. A.D. J.G.E. E.F. M.F. T.H. C.H. J.W.J. S.L.R.K. R.A.M. B.D.M. D.O.M.-K. P.-E.M. O. Pedersen, S.R. P.M.R. E.K.S. U.V. J.F.W. D.-A.T. A.D.J. M.S.-L. and A.C.M. participated in genotype data acquisition and/or quality control; J.E.H. J.N. J.H. A.S.H. L.R.Y. J.A.B. F.T. L.F.B. G.D.C. M.-H.C. D.B.E. M.G. J.-J.H. M.E.K. N.-Q.L. J.P.L. R.L.-G. J.L. A.M. M.M. R.E.M. A.M.-P. A.R. B.A.T.R. M.S. P.S. S.T. S.W. M.Z. P.A. G.D. G.E.D. M.G. P.K.J. S.N. R.N. F.P.-V. K.A.R. M.R.B. J.S.F. C.F. X.G. C.K. J.R.O. D.B. A.D. C.H. R.A.M. B.D.M. A.R. U.V. J.Y. D.-A.T. A.D.J. P.S.d.V. M.S.-L. A.C.M. and N.L.S. participated in data analysis and/or interpretation; and J.E.H. J.N. J.H. P.S.d.V. M.S.-L. A.C.M. and N.L.S. participated in drafting the initial manuscript; and all authors participated in critical review of the manuscript. Molecular data for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Institutes of Health (NIH), National Heart, Lung, and Blood Institute ( NHLBI ). See the TOPMed Omics Support Table in the supplemental Data for study-specific omics support information. Core support, including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering, was provided by the TOPMed Informatics Research Center (NHLBI grant 3R01HL-117626-02S1; contract HHSN268201800002I). Core support, including phenotype harmonization, data management, sample-identity quality control, and general program coordination, was provided by the TOPMed Data Coordinating Center (NHLBI grants R01HL-120393; U01HL-120393; contract HHSN268201800001I). CHARGE is supported by NHLBI grant R01HL-105756, and the CHARGE and TOPMed Hemostasis Working Groups by NHLBI grants R01HL-134894, R01HL-139553, and R01HL-141291. This research is based on data from the Million Veteran Program, Office of Research and Development , Veterans Health Administration, and was supported by award I01-BX004821. The study was supported by the Novo Nordisk Foundation (grant NNF18CC0034900). D.-A.T. was supported by the EPIDEMIOM-VT Senior Chair of Excellence from the University of Bordeaux initiative of Excellence. M.S.-L. is supported by a Miguel Servet contract from the ISCIII Spanish Health Institute (CPII22/00007) and cofinanced by the European Social Fund. Additional study-specific funding and acknowledgements can be found in the supplemental Data. The Genotype-Tissue Expression Project was supported by the Common Fund of the NIH Office of the Director, and by the NIH, National Cancer Institute, NIH, National Human Genome Research Institute, NIH, NHLBI , NIH, National Institute on Drug Abuse, NIH, National Institute of Mental Health, and NIH, National Institute of Neurological Disorders and Stroke.

ASJC Scopus subject areas

Biochemistry
Immunology
Hematology
Cell Biology

Access to Document

10.1182/blood.2023022596

Cite this

@article{419d3885a74a4e8a920201347dc027e2,

title = "Whole-genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles",

abstract = "Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole-genome sequencing (WGS) data provide better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program (n = 32 572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (n = 131 340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, 4 are driven by common variants of small effect with reported minor allele frequency (MAF) at least 10 percentage points higher in African populations. Three signals (SERPINA1, ZFP36L2, and TLR10) contain predicted deleterious missense variants. Two loci, SOCS3 and HPN, each harbor 2 conditionally distinct, noncoding variants. The gene region encoding the fibrinogen protein chain subunits (FGG;FGB;FGA) contains 7 distinct signals, including 1 novel signal driven by rs28577061, a variant common in African ancestry populations but extremely rare in Europeans (MAFAFR = 0.180; MAFEUR = 0.008). Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation.",

author = "{VA Million Veteran Program} and {NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium} and Huffman, {Jennifer E.} and Jayna Nicholas and Julie Hahn and Heath, {Adam S.} and Raffield, {Laura M.} and Yanek, {Lisa R.} and Brody, {Jennifer A.} and Florian Thibord and Laura Almasy and Bartz, {Traci M.} and Bielak, {Lawrence F.} and Bowler, {Russell P.} and Carrasquilla, {Germ{\'a}n D.} and Chasman, {Daniel I.} and Chen, {Ming Huei} and Emmert, {David B.} and Mohsen Ghanbari and Jeffrey Haessler and Hottenga, {Jouke Jan} and Kleber, {Marcus E.} and Le, {Ngoc Quynh} and Jiwon Lee and Lewis, {Joshua P.} and Ruifang Li-Gao and Jian'an Luan and Anni Malmberg and Massimo Mangino and Marioni, {Riccardo E.} and Angel Martinez-Perez and Nathan Pankratz and Ozren Polasek and Anne Richmond and Rodriguez, {Benjamin A.T.} and Rotter, {Jerome I.} and Maristella Steri and Pierre Suchon and Stella Trompet and Stefan Weiss and Marjan Zare and Paul Auer and Cho, {Michael H.} and Paraskevi Christofidou and Gail Davies and {de Geus}, Eco and Deleuze, {Jean Fran{\c c}ois} and Delgado, {Graciela E.} and Lynette Ekunwe and Nauder Faraday and Martin G{\"o}gele and Lifang Hou",

note = "Publisher Copyright: {\textcopyright} 2024",

year = "2024",

month = nov,

day = "21",

doi = "10.1182/blood.2023022596",

language = "English (US)",

volume = "144",

pages = "2248--2265",

journal = "Blood",

issn = "0006-4971",

publisher = "Elsevier B.V.",

number = "21",

}

TY - JOUR

T1 - Whole-genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles

AU - VA Million Veteran Program

AU - NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

AU - Huffman, Jennifer E.

AU - Nicholas, Jayna

AU - Hahn, Julie

AU - Heath, Adam S.

AU - Raffield, Laura M.

AU - Yanek, Lisa R.

AU - Brody, Jennifer A.

AU - Thibord, Florian

AU - Almasy, Laura

AU - Bartz, Traci M.

AU - Bielak, Lawrence F.

AU - Bowler, Russell P.

AU - Carrasquilla, Germán D.

AU - Chasman, Daniel I.

AU - Chen, Ming Huei

AU - Emmert, David B.

AU - Ghanbari, Mohsen

AU - Haessler, Jeffrey

AU - Hottenga, Jouke Jan

AU - Kleber, Marcus E.

AU - Le, Ngoc Quynh

AU - Lee, Jiwon

AU - Lewis, Joshua P.

AU - Li-Gao, Ruifang

AU - Luan, Jian'an

AU - Malmberg, Anni

AU - Mangino, Massimo

AU - Marioni, Riccardo E.

AU - Martinez-Perez, Angel

AU - Pankratz, Nathan

AU - Polasek, Ozren

AU - Richmond, Anne

AU - Rodriguez, Benjamin A.T.

AU - Rotter, Jerome I.

AU - Steri, Maristella

AU - Suchon, Pierre

AU - Trompet, Stella

AU - Weiss, Stefan

AU - Zare, Marjan

AU - Auer, Paul

AU - Cho, Michael H.

AU - Christofidou, Paraskevi

AU - Davies, Gail

AU - de Geus, Eco

AU - Deleuze, Jean François

AU - Delgado, Graciela E.

AU - Ekunwe, Lynette

AU - Faraday, Nauder

AU - Gögele, Martin

AU - Hou, Lifang

PY - 2024/11/21

Y1 - 2024/11/21

N2 - Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole-genome sequencing (WGS) data provide better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program (n = 32 572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (n = 131 340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, 4 are driven by common variants of small effect with reported minor allele frequency (MAF) at least 10 percentage points higher in African populations. Three signals (SERPINA1, ZFP36L2, and TLR10) contain predicted deleterious missense variants. Two loci, SOCS3 and HPN, each harbor 2 conditionally distinct, noncoding variants. The gene region encoding the fibrinogen protein chain subunits (FGG;FGB;FGA) contains 7 distinct signals, including 1 novel signal driven by rs28577061, a variant common in African ancestry populations but extremely rare in Europeans (MAFAFR = 0.180; MAFEUR = 0.008). Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation.

AB - Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole-genome sequencing (WGS) data provide better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program (n = 32 572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (n = 131 340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, 4 are driven by common variants of small effect with reported minor allele frequency (MAF) at least 10 percentage points higher in African populations. Three signals (SERPINA1, ZFP36L2, and TLR10) contain predicted deleterious missense variants. Two loci, SOCS3 and HPN, each harbor 2 conditionally distinct, noncoding variants. The gene region encoding the fibrinogen protein chain subunits (FGG;FGB;FGA) contains 7 distinct signals, including 1 novel signal driven by rs28577061, a variant common in African ancestry populations but extremely rare in Europeans (MAFAFR = 0.180; MAFEUR = 0.008). Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation.

UR - http://www.scopus.com/inward/record.url?scp=85207137131&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85207137131&partnerID=8YFLogxK

U2 - 10.1182/blood.2023022596

DO - 10.1182/blood.2023022596

M3 - Article

C2 - 39226462

AN - SCOPUS:85207137131

SN - 0006-4971

VL - 144

SP - 2248

EP - 2265

JO - Blood

JF - Blood

IS - 21

ER -

Whole-genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles

Abstract

Funding

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this