Whole-genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles.
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 M-H., Emmert DB., Ghanbari M., Haessler J., Hottenga JJ., Kleber ME., Le N-Q., 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 J-F., 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 P-E., Pedersen O., Pramstaller PP., Redline S., Reiner AP., Ridker PM., Silverman EK., Spector TD., Volker U., Wareham N., Wilson J., Yao J., Tregouet D-A., Johnson AD., Wolberg AS., de Vries PS., Sabater-Lleal M., Morrison A., Smith NL.
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.