Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF

Jennifer E Huffman, Paul S de Vries, Alanna C Morrison, Maria Sabater-Lleal, Tim Kacprowski, Paul L Auer, Jennifer A Brody, Daniel I Chasman, Ming-Huei Chen, Xiuqing Guo, Li-An Lin, Riccardo E Marioni, Martina Müller-Nurasyid, Lisa R Yanek, Nathan Pankratz, Megan L Grove, Moniek P M de Maat, Mary Cushman, Kerri L Wiggins, Lihong Qi, Bengt Sennblad, Sarah E Harris, Ozren Polasek, Helene Riess, Fernando Rivadeneira, Lynda M Rose, Anuj Goel, Kent D Taylor, Alexander Teumer, André G Uitterlinden, Dhananjay Vaidya, Jie Yao, Weihong Tang, Daniel Levy, Melanie Waldenberger, Diane M Becker, Aaron R Folsom, Franco Giulianini, Andreas Greinacher, Albert Hofman, Chiang-Ching Huang, Charles Kooperberg, Angela Silveira, John M Starr, Konstantin Strauch, Rona J Strawbridge, Alan F Wright, Barbara McKnight, Oscar H Franco, Neil Zakai, Rasika A Mathias, Bruce M Psaty, Paul M Ridker, Geoffrey H Tofler, Uwe Völker, Hugh Watkins, Myriam Fornage, Anders Hamsten, Ian J Deary, Eric Boerwinkle, Wolfgang Koenig, Jerome I Rotter, Caroline Hayward, Abbas Dehghan, Alex P Reiner, Christopher J O'Donnell, Nicholas L Smith

Fibrinogen, coagulation factor VII (FVII), 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 variation 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 identify 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 to understanding individual variation in hemostasis pathways.