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

dc.rights.licenseopenen_US
dc.contributor.authorHUFFMAN, Jennifer
dc.contributor.authorNICOLAS, Jayna
dc.contributor.authorHAHN, Julie
dc.contributor.authorHEATH, Adam
dc.contributor.authorRAFFIELD, Laura
dc.contributor.authorYANEK, Lisa
dc.contributor.authorBRODY, Jennifer
dc.contributor.authorTHIBORD, Florian
dc.contributor.authorALMASY, Laura
dc.contributor.authorBARTZ, Traci
dc.contributor.authorBIELAK, Lawrence
dc.contributor.authorBOWLER, Russell
dc.contributor.authorCARRASQUILLA, Germán
dc.contributor.authorCHASMAN, Daniel
dc.contributor.authorCHEN, Ming-Huei
dc.contributor.authorEMMERT, David
dc.contributor.authorGHANBARI, Mohsen
dc.contributor.authorHAESSLE, Jeffery
dc.contributor.authorHOTTENGA, Jouke-Jan
dc.contributor.authorKLEBER, Marcus
dc.contributor.authorLE, Ngoc-Quynh
dc.contributor.authorLEE, Jiwon
dc.contributor.authorLEWIS, Joshua
dc.contributor.authorLI-GAO, Ruifang
dc.contributor.authorLUAN, Jian'an
dc.contributor.authorMALMBERG, Anni
dc.contributor.authorMANGINO, Massimo
dc.contributor.authorMARIONI, Riccardo
dc.contributor.authorMARTINEZ-PEREZ, Angel
dc.contributor.authorPANKRATZ, Nathan
dc.contributor.authorPOLASEK, Ozren
dc.contributor.authorRICHMOND, Anne
dc.contributor.authorRODRIGUEZ, Benjamin At
dc.contributor.authorROTTER, Jerome
dc.contributor.authorSTERI, Maristella
dc.contributor.authorSUCHON, Pierre
dc.contributor.authorTROMPET, Stella
dc.contributor.authorWEISS, Stefan
dc.contributor.authorZARE, Marjan
dc.contributor.authorAUER, Paul
dc.contributor.authorCHO, Michael
dc.contributor.authorCHRISTOFIDOU, Paraskevi
dc.contributor.authorDAVIES, Gail
dc.contributor.authorDE GEUS, Eco
dc.contributor.authorDELEUZE, Jean-François
dc.contributor.authorDELGADO, Graciela
dc.contributor.authorEKUNWE, Lynette
dc.contributor.authorFARADAY, Nauder
dc.contributor.authorGÖGELE, Martin
dc.contributor.authorGREINACHER, Andreas
dc.contributor.authorHE, Gao
dc.contributor.authorHOWARD, Tom
dc.contributor.authorJOSHI, Peter
dc.contributor.authorKILPELÄINEN, Tuomas
dc.contributor.authorLAHTI, Jari
dc.contributor.authorLINNEBERG, Allan
dc.contributor.authorNAITZA, Silvia
dc.contributor.authorNOORDAM, Raymond
dc.contributor.authorPAÜLS-VERGÉS, Ferran
dc.contributor.authorRICH, Stephen
dc.contributor.authorROSENDAAL, Frits
dc.contributor.authorRUDAN, Igor
dc.contributor.authorRYAN, Kathleen
dc.contributor.authorSOUTO, Juan Carlos
dc.contributor.authorVAN ROOIJ, Frank Ja
dc.contributor.authorWANG, Heming
dc.contributor.authorZHAO, Wei
dc.contributor.authorBECKER, Lewis
dc.contributor.authorBESWICK, Andrew
dc.contributor.authorBROWN, Michael
dc.contributor.authorCADE, Brian
dc.contributor.authorCAMPBELL, Harry
dc.contributor.authorCHO, Kelly
dc.contributor.authorCRAPO, James
dc.contributor.authorCURRAN, Joanne
dc.contributor.authorDE MAAT, Moniek Pm
dc.contributor.authorDOYLE, Margaret
dc.contributor.authorELLIOTT, Paul
dc.contributor.authorFLOYD, James
dc.contributor.authorFUCHSBERGER, Christian
dc.contributor.authorGRARUP, Niels
dc.contributor.authorGUO, Xiuqing
dc.contributor.authorHARRIS, Sarah
dc.contributor.authorHOU, Lifang
dc.contributor.authorKOLCIC, Ivana
dc.contributor.authorKOOPERBERG, Charles
dc.contributor.authorMENNI, Cristina
dc.contributor.authorNAUCK, Matthias
dc.contributor.authorO'CONNELL, Jeffrey
dc.contributor.authorORRÙ, Valeria
dc.contributor.authorPSATY, Bruce
dc.contributor.authorRÄIKKÖNEN, Katri
dc.contributor.authorSMITH, Jennifer
dc.contributor.authorSORIA, Jose Manuel
dc.contributor.authorSTOTT, David
dc.contributor.authorVAN HYLCKAMA VLIEG, Astrid
dc.contributor.authorWATKINS, Hugh
dc.contributor.authorWILLEMSEN, Gonneke
dc.contributor.authorWILSON, Peter
dc.contributor.authorBEN-SHLOMO, Yoav
dc.contributor.authorBLANGERO, John
dc.contributor.authorBOOMSMA, Dorret
dc.contributor.authorCOX, Simon
dc.contributor.authorDEHGHAN, Abbas
dc.contributor.authorERIKSSON, Johan
dc.contributor.authorFIORILLO, Edoardo
dc.contributor.authorFORNAGE, Myriam
dc.contributor.authorHANSEN, Torben
dc.contributor.authorHAYWARD, Caroline
dc.contributor.authorIKRAM, M. Arfan
dc.contributor.authorJUKEMA, J Wouter
dc.contributor.authorKARDIA, Sharon Lr
dc.contributor.authorLANGE, Leslie
dc.contributor.authorMÄRZ, Winfried
dc.contributor.authorMATHIAS, Rasika
dc.contributor.authorMITCHELL, Braxton
dc.contributor.authorMOOK-KANAMORI, Dennis
dc.contributor.authorMORANGE, Pierre-Emmanuel
dc.contributor.authorPEDERSEN, Oluf
dc.contributor.authorPRAMSTALLER, Peter
dc.contributor.authorREDLINE, Susan
dc.contributor.authorREINER, Alexander
dc.contributor.authorRIDKER, Paul
dc.contributor.authorSILVERMAN, Edwin
dc.contributor.authorSPECTOR, Tim
dc.contributor.authorVÖLKER, Uwe
dc.contributor.authorWAREHAM, Nick
dc.contributor.authorWILSON, James
dc.contributor.authorYAO, Jie
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorTREGOUET, David-Alexandre
dc.contributor.authorJOHNSON, Andrew
dc.contributor.authorWOLBERG, Alisa
dc.contributor.authorDE VRIES, Paul
dc.contributor.authorSABATER-LLEAL, Maria
dc.contributor.authorMORRISON, Alanna
dc.contributor.authorSMITH, Nicholas
dc.date.accessioned2024-09-09T12:44:27Z
dc.date.available2024-09-09T12:44:27Z
dc.date.created2023-06-12
dc.date.issued2023-12
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/201496
dc.description.abstractEnGenetic 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% higher in African populations. Three ( SERPINA1, ZFP36L2 , and TLR10) signals contain predicted deleterious missense variants. Two loci, SOCS3 and HPN , each harbor two conditionally distinct, non-coding variants. The gene region encoding the protein chain subunits ( FGG;FGB;FGA ), contains 7 distinct signals, including one novel signal driven by rs28577061, a variant common (MAF=0.180) in African reference panels but extremely rare (MAF=0.008) in Europeans. 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. Key Points Largest and most diverse genetic study of plasma fibrinogen identifies 54 regions (18 novel), housing 69 conditionally distinct variants (20 novel). Sufficient power achieved to identify signal driven by African population variant. Links to (1) liver enzyme, blood cell and lipid genetic signals, (2) liver regulatory elements, and (3) thrombotic and inflammatory disease.
dc.language.isoENen_US
dc.title.enWhole genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles
dc.typeDocument de travail - Pré-publicationen_US
dc.identifier.doi10.1101/2023.06.07.23291095en_US
dc.subject.halSciences du Vivant [q-bio]/Santé publique et épidémiologieen_US
dc.identifier.pubmed37398003en_US
bordeaux.hal.laboratoriesBordeaux Population Health Research Center (BPH) - UMR 1219en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.institutionINSERMen_US
bordeaux.teamELEANOR_BPHen_US
bordeaux.identifier.funderIDNational Heart, Lung, and Blood Instituteen_US
hal.popularnonen_US
hal.audienceInternationaleen_US
hal.exportfalse
dc.rights.ccPas de Licence CCen_US
bordeaux.subtypePrepublication/Preprinten_US
bordeaux.COinSctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.date=2023-12&rft.au=HUFFMAN,%20Jennifer&NICOLAS,%20Jayna&HAHN,%20Julie&HEATH,%20Adam&RAFFIELD,%20Laura&rft.genre=preprint


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