Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF.
Huffman JE., de Vries PS., Morrison AC., Sabater-Lleal M., Kacprowski T., Auer PL., Brody JA., Chasman DI., Chen MH., Guo X., Lin LA., Marioni RE., Müller-Nurasyid M., Yanek LR., Pankratz N., Grove ML., de Maat MP., Cushman M., Wiggins KL., Qi L., Sennblad B., Harris SE., Polasek O., Riess H., Rivadeneira F., Rose LM., Goel A., Taylor KD., Teumer A., Uitterlinden AG., Vaidya D., Yao J., Tang W., Levy D., Waldenberger M., Becker DM., Folsom AR., Giulianini F., Greinacher A., Hofman A., Huang CC., Kooperberg C., Silveira A., Starr JM., Strauch K., Strawbridge RJ., Wright AF., McKnight B., Franco OH., Zakai N., Mathias RA., Psaty BM., Ridker PM., Tofler GH., Völker U., Watkins H., Fornage M., Hamsten A., Deary IJ., Boerwinkle E., Koenig W., Rotter JI., Hayward C., Dehghan A., Reiner AP., O'Donnell CJ., Smith NL.
Fibrinogen, coagulation factor VII (FVII), and factor VIII (FVIII) and its carrier von Willebrand factor (vWF) play key roles in hemostasis. Previously identified common variants explain only a small fraction of the trait heritabilities, and additional variations may be explained by associations with rarer variants with larger effects. The aim of this study was to identify low-frequency (minor allele frequency [MAF] ≥0.01 and <0.05) and rare (MAF <0.01) variants that influence plasma concentrations of these 4 hemostatic factors by meta-analyzing exome chip data from up to 76,000 participants of 4 ancestries. We identified 12 novel associations of low-frequency (n = 2) and rare (n = 10) variants across the fibrinogen, FVII, FVIII, and vWF traits that were independent of previously identified associations. Novel loci were found within previously reported genes and had effect sizes much larger than and independent of previously identified common variants. In addition, associations at KCNT1, HID1, and KATNB1 identified new candidate genes related to hemostasis for follow-up replication and functional genomic analysis. Newly identified low-frequency and rare-variant associations accounted for modest amounts of trait variance and therefore are unlikely to increase predicted trait heritability but provide new information for understanding individual variation in hemostasis pathways.