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 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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Blood |
| Vol/bind | 144 |
| Udgave nummer | 21 |
| Sider (fra-til) | 2248–2265 |
| ISSN | 0006-4971 |
| DOI | |
| Status | Udgivet - 2024 |
Bibliografisk note
Copyright © 2024 American Society of Hematology.Adgang til dokumentet
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Whole-genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles. / Huffman, Jennifer E; Nicholas, Jayna; Hahn, Julie; Heath, Adam S; Raffield, Laura M; Yanek, Lisa R; Brody, Jennifer A; Thibord, Florian; Almasy, Laura; Bartz, Traci M; Bielak, Lawrence F; Bowler, Russell P; Carrasquilla, German D; Chasman, Daniel I; Chen, Ming-Huei; Emmert, David B; Ghanbari, Mohsen; Haessler, Jeffrey; Hottenga, Jouke J; Kleber, Marcus E; Le, Ngoc-Quynh; Lee, Jiwon; Lewis, Joshua P; Li-Gao, Ruifang; Luan, Jian'an; Malmberg, Anni Liisi; Mangino, Massimo; Marioni, Riccardo; Martinez-Perez, Angel; Pankratz, Nathan; Polasek, Ozren; Richmond, Anne; Rodriguez, Benjamin A T; Rotter, Jerome I; Steri, Maristella; Suchon, Pierre; Trompet, Stella; Weiss, Stefan; Zare, Marjan; Auer, Paul L; Cho, Michael; Christofidou, Paraskevi; Davies, Gail; de Geus, Eco Jc; Deleuze, Jean-François; Delgado, Graciela E; Ekunwe, Lynette; Faraday, Nauder; Gogele, Martin; Greinacher, Andreas; Gao, He; Howard, Tom E; Joshi, Peter K; Kilpeläinen, Tuomas O; Lahti, Jari; Linneberg, Allan; Naitza, Silvia; Noordam, Raymond; Vergés, Ferran Paüls; Rich, Stephen S; Rosendaal, Frits R; Rudan, Igor; Ryan, Kathleen A; Souto, Juan Carlos Carlos; van Rooij, Frank J A; Wang, Heming; Zhao, Wei; Becker, Lewis; Beswick, Andrew; Brown, Michael R; Cade, Brian; Campbell, Harry; Cho, Kelly; Crapo, James; Curran, Joanne; de Maat, Moniek P M; Doyle, Margaret F; Elliott, Paul; Floyd, James S; Fuchsberger, Christian; Grarup, Niels; Guo, Xiuqing; Harris, Sarah; Hou, Lifang; Kolcic, Ivana; Kooperberg, Charles; Menni, Cristina; Nauck, Matthias; O'Connell, Jeffrey R; Orru, Valeria; Psaty, Bruce M; Räikkönen, Katri; Smith, Jennifer A; Soria, Jose Manuel; Stott, David; van Hylckama Vlieg, Astrid; Watkins, Hugh; Willemsen, Gonneke; Wilson, Peter Wf; Ben-Shlomo, Yoav; Blangero, John; Boomsma, Dorret; Cox, Simon R; Dehghan, Abbas; Eriksson, Johan G; Fiorillo, Edoardo; Fornage, Myriam; Hansen, Torben; Hayward, Caroline; Ikram, Mohammad Arfan; Jukema, J Wouter; Kardia, Sharon; Lange, Leslie; Maerz, Winfried; Mathias, Rasika; Mitchell, Braxton D; Mook-Kanamori, Dennis O; Morange, Pierre-Emmanuel; Pedersen, Oluf; Pramstaller, Peter P; Redline, Susan; Reiner, Alex P; Ridker, Paul M; Silverman, Edwin K; Spector, Tim D; Volker, Uwe; Wareham, Nick; Wilson, James; Yao, Jie; Tregouet, David-Alexandre; Johnson, Andrew D; Wolberg, Alisa S; de Vries, Paul S; Sabater-Lleal, Maria; Morrison, Alanna; Smith, Nicholas L.
I: Blood, Bind 144, Nr. 21, 2024, s. 2248–2265.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review
}
TY - JOUR
T1 - Whole-genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles
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, German D
AU - Chasman, Daniel I
AU - Chen, Ming-Huei
AU - Emmert, David B
AU - Ghanbari, Mohsen
AU - Haessler, Jeffrey
AU - Hottenga, Jouke J
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 Liisi
AU - Mangino, Massimo
AU - Marioni, Riccardo
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 L
AU - Cho, Michael
AU - Christofidou, Paraskevi
AU - Davies, Gail
AU - de Geus, Eco Jc
AU - Deleuze, Jean-François
AU - Delgado, Graciela E
AU - Ekunwe, Lynette
AU - Faraday, Nauder
AU - Gogele, Martin
AU - Greinacher, Andreas
AU - Gao, He
AU - Howard, Tom E
AU - Joshi, Peter K
AU - Kilpeläinen, Tuomas O
AU - Lahti, Jari
AU - Linneberg, Allan
AU - Naitza, Silvia
AU - Noordam, Raymond
AU - Vergés, Ferran Paüls
AU - Rich, Stephen S
AU - Rosendaal, Frits R
AU - Rudan, Igor
AU - Ryan, Kathleen A
AU - Souto, Juan Carlos Carlos
AU - van Rooij, Frank J A
AU - Wang, Heming
AU - Zhao, Wei
AU - Becker, Lewis
AU - Beswick, Andrew
AU - Brown, Michael R
AU - Cade, Brian
AU - Campbell, Harry
AU - Cho, Kelly
AU - Crapo, James
AU - Curran, Joanne
AU - de Maat, Moniek P M
AU - Doyle, Margaret F
AU - Elliott, Paul
AU - Floyd, James S
AU - Fuchsberger, Christian
AU - Grarup, Niels
AU - Guo, Xiuqing
AU - Harris, Sarah
AU - Hou, Lifang
AU - Kolcic, Ivana
AU - Kooperberg, Charles
AU - Menni, Cristina
AU - Nauck, Matthias
AU - O'Connell, Jeffrey R
AU - Orru, Valeria
AU - Psaty, Bruce M
AU - Räikkönen, Katri
AU - Smith, Jennifer A
AU - Soria, Jose Manuel
AU - Stott, David
AU - van Hylckama Vlieg, Astrid
AU - Watkins, Hugh
AU - Willemsen, Gonneke
AU - Wilson, Peter Wf
AU - Ben-Shlomo, Yoav
AU - Blangero, John
AU - Boomsma, Dorret
AU - Cox, Simon R
AU - Dehghan, Abbas
AU - Eriksson, Johan G
AU - Fiorillo, Edoardo
AU - Fornage, Myriam
AU - Hansen, Torben
AU - Hayward, Caroline
AU - Ikram, Mohammad Arfan
AU - Jukema, J Wouter
AU - Kardia, Sharon
AU - Lange, Leslie
AU - Maerz, Winfried
AU - Mathias, Rasika
AU - Mitchell, Braxton D
AU - Mook-Kanamori, Dennis O
AU - Morange, Pierre-Emmanuel
AU - Pedersen, Oluf
AU - Pramstaller, Peter P
AU - Redline, Susan
AU - Reiner, Alex P
AU - Ridker, Paul M
AU - Silverman, Edwin K
AU - Spector, Tim D
AU - Volker, Uwe
AU - Wareham, Nick
AU - Wilson, James
AU - Yao, Jie
AU - Tregouet, David-Alexandre
AU - Johnson, Andrew D
AU - Wolberg, Alisa S
AU - de Vries, Paul S
AU - Sabater-Lleal, Maria
AU - Morrison, Alanna
AU - Smith, Nicholas L
N1 - Copyright © 2024 American Society of Hematology.
PY - 2024
Y1 - 2024
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 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.
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 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.
U2 - 10.1182/blood.2023022596
DO - 10.1182/blood.2023022596
M3 - Journal article
C2 - 39226462
VL - 144
SP - 2248
EP - 2265
JO - Blood
JF - Blood
SN - 0006-4971
IS - 21
ER -