| Title: |
Whole genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles. |
| Authors: |
Huffman JE, Nicolas 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, Haessle J, Hottenga JJ, Kleber ME, Le NQ, Lee J, Lewis JP, Li-Gao R, Luan J, Malmberg A, Mangino M, Marioni RE, Martinez-Perez A, Pankratz N, Polasek O, Richmond A, Rodriguez BA, Rotter JI, Steri M, Suchon P, Trompet S, Weiss S, Zare M, Auer P, Cho MH, Christofidou P, Davies G, de Geus E, Deleuze JF, Delgado GE, Ekunwe L, Faraday N, Gögele M, Greinacher A, He G, Howard T, Joshi PK, Kilpeläinen TO, Lahti J, Linneberg A, Naitza S, Noordam R, Paüls-Vergés F, Rich SS, Rosendaal FR, Rudan I, Ryan KA, Souto JC, van Rooij FJ, Wang H, Zhao W, Becker LC, Beswick A, Brown MR, Cade BE, Campbell H, Cho K, Crapo JD, Curran JE, de Maat MP, Doyle M, Elliott P, Floyd JS, Fuchsberger C, Grarup N, Guo X, Harris SE, Hou L, Kolcic I, Kooperberg C, Menni C, Nauck M, O'Connell JR, Orrù V, Psaty BM, Räikkönen K, Smith JA, Soria JM, Stott DJ, van Hylckama Vlieg A, Watkins H, Willemsen G, Wilson P, 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 SL, Lange LA, März W, Mathias RA, Mitchell BD, Mook-Kanamori DO, Morange PE, Pedersen O, Pramstaller PP, Redline S, Reiner A, Ridker PM, Silverman EK, Spector TD, Völker U, Wareham N, Wilson JF, Yao J; VA Million Veteran Program; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; Trégouët DA, Johnson AD, Wolberg AS, de Vries PS, Sabater-Lleal M, Morrison AC, Smith NL. |
| Source: |
2023. |
| Publication Year: |
2023 |
| Collection: |
PUMAlab (ISTI CNR - Consiglio Nazionale delle Ricerche / National Research Council) |
| Subject Terms: |
genetic study; fibrinogen; blood cells; lipids; inflammatory disease; thrombotic disease |
| Description: |
Scientific study published on medRxiv 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% 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. |
| Document Type: |
other/unknown material |
| Language: |
English |
| Relation: |
info:cnr-pdr/author/matricola:14542/FIORILLO/EDOARDO; info:cnr-pdr/author/matricola:14543/ORRU'/VALERIA; http://www.cnr.it/prodotto/i/492181; https://publications.cnr.it/doc/492181 |
| Availability: |
http://www.cnr.it/prodotto/i/492181; https://publications.cnr.it/doc/492181 |
| Rights: |
info:eu-repo/semantics/restrictedAccess |
| Accession Number: |
edsbas.659AEAF6 |
| Database: |
BASE |