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

JE Huffman; J Nicholas; J Hahn; AS Heath; LM Raffield; LR Yanek; JA Brody; F Thibord; L Almasy; TM Bartz; LF Bielak; RP Bowler; GD Carrasquilla; DI Chasman; MH Chen; David Bruce Emmert; M Ghanbari; J Haessler; JJ Hottenga; ME Kleber; NQ Le; J Lee; JP Lewis; R Li-Gao; J Luan; AL Malmberg; M Mangino; R Marioni; A Martinez-Perez; N Pankratz; O Polasek; A Richmond; BAT Rodriguez; JI Rotter; M Steri; P Suchon; S Trompet; S Weiss; M Zare; PL Auer; M Cho; P Christofidou; G Davies; EJ de Geus; JF Deleuze; GE Delgado; L Ekunwe; N Faraday; Martin Gögele; A Greinacher; H Gao; TE Howard; PK Joshi; TO Kilpeläinen; J Lahti; A Linneberg; S Naitza; R Noordam; FP Vergés; SS Rich; FR Rosendaal; I Rudan; KA Ryan; JCC Souto; FJA van Rooij; H Wang; W Zhao; L Becker; A Beswick; MR Brown; B Cade; H Campbell; K Cho; J Crapo; J Curran; MPM de Maat; MF Doyle; P Elliott; JS Floyd; Christian Fuchsberger; N Grarup; X Guo; S Harris; L Hou; I Kolcic; C Kooperberg; C Menni; M Nauck; JR O'Connell; V Orru; BM Psaty; K Räikkönen; JA Smith; JM Soria; D Stott; A van Hylckama Vlieg; H Watkins; G Willemsen; PW Wilson; Y Ben-Shlomo; J Blangero; D Boomsma; SR Cox; A Dehghan; JG Eriksson; E Fiorillo; M Fornage; T Hansen; C Hayward; MA Ikram; JW Jukema; S Kardia; L Lange; W Maerz; R Mathias; BD Mitchell; DO Mook-Kanamori; PE Morange; O Pedersen; Peter P. Pramstaller; S Redline; AP Reiner; PM Ridker; EK Silverman; TD Spector; U Volker; N Wareham; J Wilson; J Yao; DA Tregouet; AD Johnson; AS Wolberg; PS de Vries; M Sabater-Lleal; A Morrison; NL Smith

doi:10.1182/blood.2023022596

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

Journal article

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

JE Huffman, J Nicholas, J Hahn, AS Heath, LM Raffield, LR Yanek, JA Brody, F Thibord, L Almasy, TM Bartz, …

Blood, Vol.144(21)

144

03/09/2024

DOI: https://doi.org/10.1182/blood.2023022596

Handle:

https://hdl.handle.net/10863/44671

PMID: 39226462

Abstract

CHRIS study

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 provides 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 NHLBI'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 (CHARGE) 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, four are driven by common variants of small effect with reported 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 two conditionally distinct, non-coding variants. The gene region encoding the fibrinogen protein chain subunits (FGG;FGB;FGA), contains 7 distinct signals, including one 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.

Details

Title: Whole-genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles
Creators: JE Huffman - VA Boston Healthcare System
J Nicholas
J Hahn - The University of Texas Health Science Center at Houston
AS Heath - The University of Texas Health Science Center at Houston
LM Raffield - Karolinska Institutet
LR Yanek - Johns Hopkins University
JA Brody - University of Washington
F Thibord - Karolinska Institutet
L Almasy - Children's Hospital of Philadelphia
TM Bartz - University of Washington
LF Bielak - University of Michigan–Ann Arbor
RP Bowler - National Jewish Health
GD Carrasquilla - University of Copenhagen
DI Chasman - Brigham and Women's Hospital
MH Chen - National Heart Lung and Blood Institute
David Bruce Emmert - Eurac Research
M Ghanbari - Erasmus MC
J Haessler - Fred Hutch Cancer Center
JJ Hottenga - Vrije Universiteit Amsterdam
ME Kleber - University Medical Centre Mannheim
NQ Le
J Lee - Brigham and Women's Hospital
JP Lewis - University of Maryland, Baltimore
R Li-Gao - Leiden University Medical Center
J Luan - MRC Epidemiology Unit
AL Malmberg - University of Helsinki
M Mangino - King's College London
R Marioni - Edinburgh Cancer Research
A Martinez-Perez - Hospital de Sant Pau
N Pankratz - University of Minnesota Medical Center
O Polasek - University of Split
A Richmond - Medical Research Council
BAT Rodriguez
JI Rotter - Ronald Reagan UCLA Medical Center
M Steri - Institute of Genetic and Biomedical Research
P Suchon - Aix-Marseille Université
S Trompet - Leiden University Medical Center
S Weiss
M Zare - Imperial College London
PL Auer - Framingham Heart Study
M Cho - Harvard University
P Christofidou - King's College London
G Davies - University of Edinburgh
EJ de Geus - Karolinska Institutet
JF Deleuze - Université Paris-Saclay
GE Delgado - University Medical Centre Mannheim
L Ekunwe - University of Mississippi Medical Center
N Faraday - Johns Hopkins University
Martin Gögele - Eurac Research
A Greinacher - Universitätsmedizin Greifswald
H Gao - Public Health England
TE Howard - The University of Texas Rio Grande Valley
PK Joshi - Centre for Global Health Research
TO Kilpeläinen - University of Copenhagen
J Lahti - University of Helsinki
A Linneberg - Frederiksberg Hospital
S Naitza - Institute of Genetic and Biomedical Research
R Noordam - Leiden University Medical Center
FP Vergés
SS Rich - University of Virginia
FR Rosendaal - Leiden University Medical Center
I Rudan - University of Edinburgh
KA Ryan - University of Maryland, Baltimore
JCC Souto
FJA van Rooij
H Wang - Brigham and Women's Hospital
W Zhao - University of Michigan–Ann Arbor
L Becker - Johns Hopkins University
A Beswick
MR Brown - The University of Texas Health Science Center at Houston
B Cade - Brigham and Women's Hospital
H Campbell - University of Edinburgh
K Cho - VA Boston Healthcare System
J Crapo - National Jewish Health
J Curran - The University of Texas Rio Grande Valley
MPM de Maat
MF Doyle - University of Vermont
P Elliott - Public Health England
JS Floyd - University of Washington
Christian Fuchsberger - Eurac Research
N Grarup - Novo Nordisk Foundation
X Guo - UCLA Medical Center
S Harris - Karolinska Institutet
L Hou - Northwestern University
I Kolcic - University of Split
C Kooperberg - Fred Hutch Cancer Center
C Menni - King's College London
M Nauck - Universitätsmedizin Greifswald
JR O'Connell
V Orru - Institute of Genetic and Biomedical Research
BM Psaty - University of Washington
K Räikkönen - University of Helsinki
JA Smith - University of Michigan–Ann Arbor
JM Soria - Centre for Biomedical Network Research on Rare Diseases
D Stott - University of Glasgow
A van Hylckama Vlieg - Leiden University Medical Center
H Watkins - University of Oxford
G Willemsen - Vrije Universiteit Amsterdam
PW Wilson - Emory University
Y Ben-Shlomo - University of Bristol
J Blangero - The University of Texas Rio Grande Valley
D Boomsma - Vrije Universiteit Amsterdam
SR Cox - University of Edinburgh
A Dehghan - Public Health England
JG Eriksson - National University of Singapore
E Fiorillo - Institute of Genetic and Biomedical Research
M Fornage - Brown Foundation
T Hansen - Novo Nordisk Foundation
C Hayward - MRC Institute of Genetics and Molecular Medicine
MA Ikram - Erasmus MC
JW Jukema - Leiden University Medical Center
S Kardia
L Lange - University of Colorado Anschutz Medical Campus
W Maerz
R Mathias - Johns Hopkins University
BD Mitchell - University of Maryland, Baltimore
DO Mook-Kanamori - Leiden University Medical Center
PE Morange - Inserm
O Pedersen - Novo Nordisk Foundation
Peter P. Pramstaller - Eurac Research
S Redline - Brigham and Women's Hospital
AP Reiner - Fred Hutch Cancer Center
PM Ridker - Brigham and Women's Hospital
EK Silverman - Brigham and Women's Hospital
TD Spector - King's College London
U Volker - Universitätsmedizin Greifswald
N Wareham - MRC Epidemiology Unit
J Wilson - MRC Institute of Genetics and Molecular Medicine
J Yao - Ronald Reagan UCLA Medical Center
DA Tregouet - Université de Bordeaux
AD Johnson - Framingham Heart Study
AS Wolberg - University of North Carolina at Chapel Hill
PS de Vries - The University of Texas Health Science Center at Houston
M Sabater-Lleal - Hospital de Sant Pau
A Morrison - The University of Texas Health Science Center at Houston
NL Smith - Kaiser Permanente Washington Health Research Institute
Publication Details: Blood, Vol.144(21)
ISSN: 0006-4971
EISSN: 1528-0020
Series / Volume: 144
Publisher: American Society of Hematology
Identifiers: (EURAC)28651991
991006916926301241
Web of Science ID: WOS:001381370500001
Academic Unit: Institute for Biomedicine
Language: English
Resource Type: Journal article
Description coverage: international
Description audience: Scientific
Local Fields: Scientific
Author Names String: Huffman JE, Nicholas J, Hahn J, Heath AS, Raffield LM, Yanek LR, Brody JA, Thibord F, Almasy L, Bartz TM, Bielak LF, Bowler RP, Carrasquilla GD, Chasman DI, Chen MH, Emmert DB, Ghanbari M, Haessler J, Hottenga JJ, Kleber ME, Le NQ, Lee J, Lewis JP, Li-Gao R, Luan J, Malmberg AL, Mangino M, Marioni R, Martinez-Perez A, Pankratz N, Polasek O, Richmond A, Rodriguez BAT, Rotter JI, Steri M, Suchon P, Trompet S, Weiss S, Zare M, Auer PL, Cho M, Christofidou P, Davies G, de Geus EJ, Deleuze JF, Delgado GE, Ekunwe L, Faraday N, Gogele M, Greinacher A, Gao H, Howard TE, Joshi PK, Kilpeläinen TO, Lahti J, Linneberg A, Naitza S, Noordam R, Vergés FP, Rich SS, Rosendaal FR, Rudan I, Ryan KA, Souto JCC, van Rooij FJA, Wang H, Zhao W, Becker L, Beswick A, Brown MR, Cade B, Campbell H, Cho K, Crapo J, Curran J, de Maat MPM, Doyle MF, Elliott P, Floyd JS, Fuchsberger C, Grarup N, Guo X, Harris S, Hou L, Kolcic I, Kooperberg C, Menni C, Nauck M, O'Connell JR, Orru V, Psaty BM, Räikkönen K, Smith JA, Soria JM, Stott D, van Hylckama Vlieg A, Watkins H, Willemsen G, Wilson PW, Ben-Shlomo Y, Blangero J, Boomsma D, Cox SR, Dehghan A, Eriksson JG, Fiorillo E, Fornage M, Hansen T, Hayward C, Ikram MA, Jukema JW, Kardia S, Lange L, Maerz W, Mathias R, Mitchell BD, Mook-Kanamori DO, Morange PE, Pedersen O, Pramstaller PP, Redline S, Reiner AP, Ridker PM, Silverman EK, Spector TD, Volker U, Wareham N, Wilson J, Yao J, Tregouet DA, Johnson AD, Wolberg AS, de Vries PS, Sabater-Lleal M, Morrison A, Smith NL

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

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