TY - JOUR
T1 - A Genome-Wide Association Study for Venous Thromboembolism
T2 - The Extended Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium
AU - Tang, Weihong
AU - Teichert, Martina
AU - Chasman, Daniel I.
AU - Heit, John A.
AU - Morange, Pierre Emmanuel
AU - Li, Guo
AU - Pankratz, Nathan
AU - Leebeek, Frank W.
AU - Paré, Guillaume
AU - de Andrade, Mariza
AU - Tzourio, Christophe
AU - Psaty, Bruce M.
AU - Basu, Saonli
AU - Ruiter, Rikje
AU - Rose, Lynda
AU - Armasu, Sebastian M.
AU - Lumley, Thomas
AU - Heckbert, Susan R.
AU - Uitterlinden, André G.
AU - Lathrop, Mark
AU - Rice, Kenneth M.
AU - Cushman, Mary
AU - Hofman, Albert
AU - Lambert, Jean Charles
AU - Glazer, Nicole L.
AU - Pankow, James S.
AU - Witteman, Jacqueline C.
AU - Amouyel, Philippe
AU - Bis, Joshua C.
AU - Bovill, Edwin G.
AU - Kong, Xiaoxiao
AU - Tracy, Russell P.
AU - Boerwinkle, Eric
AU - Rotter, Jerome I.
AU - Trégouët, David Alexandre
AU - Loth, Daan W.
AU - Stricker, Bruno H.Ch
AU - Ridker, Paul M.
AU - Folsom, Aaron R.
AU - Smith, Nicholas L.
PY - 2013/7
Y1 - 2013/7
N2 - Venous thromboembolism (VTE) is a common, heritable disease resulting in high rates of hospitalization and mortality. Yet few associations between VTE and genetic variants, all in the coagulation pathway, have been established. To identify additional genetic determinants of VTE, we conducted a two-stage genome-wide association study (GWAS) among individuals of European ancestry in the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) VTE consortium. The discovery GWAS comprised 1,618 incident VTE cases out of 44,499 participants from six community-based studies. Genotypes for genome-wide single-nucleotide polymorphisms (SNPs) were imputed to approximately 2.5 million SNPs in HapMap and association with VTE assessed using study-design appropriate regression methods. Meta-analysis of these results identified two known loci, in F5 and ABO. Top 1,047 tag SNPs (P ≤ 0.0016) from the discovery GWAS were tested for association in an additional 3,231 cases and 3,536 controls from three case-control studies. In the combined data from these two stages, additional genome-wide significant associations were observed on 4q35 at F11 (top SNP rs4253399, intronic to F11) and on 4q28 at FGG (rs6536024, 9.7 kb from FGG; P < 5.0 × 10-13 for both). The associations at the FGG locus were not completely explained by previously reported variants. Loci at or near SUSD1 and OTUD7A showed borderline yet novel associations (P < 5.0 × 10-6) and constitute new candidate genes. In conclusion, this large GWAS replicated key genetic associations in F5 and ABO, and confirmed the importance of F11 and FGG loci for VTE. Future studies are warranted to better characterize the associations with F11 and FGG and to replicate the new candidate associations.
AB - Venous thromboembolism (VTE) is a common, heritable disease resulting in high rates of hospitalization and mortality. Yet few associations between VTE and genetic variants, all in the coagulation pathway, have been established. To identify additional genetic determinants of VTE, we conducted a two-stage genome-wide association study (GWAS) among individuals of European ancestry in the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) VTE consortium. The discovery GWAS comprised 1,618 incident VTE cases out of 44,499 participants from six community-based studies. Genotypes for genome-wide single-nucleotide polymorphisms (SNPs) were imputed to approximately 2.5 million SNPs in HapMap and association with VTE assessed using study-design appropriate regression methods. Meta-analysis of these results identified two known loci, in F5 and ABO. Top 1,047 tag SNPs (P ≤ 0.0016) from the discovery GWAS were tested for association in an additional 3,231 cases and 3,536 controls from three case-control studies. In the combined data from these two stages, additional genome-wide significant associations were observed on 4q35 at F11 (top SNP rs4253399, intronic to F11) and on 4q28 at FGG (rs6536024, 9.7 kb from FGG; P < 5.0 × 10-13 for both). The associations at the FGG locus were not completely explained by previously reported variants. Loci at or near SUSD1 and OTUD7A showed borderline yet novel associations (P < 5.0 × 10-6) and constitute new candidate genes. In conclusion, this large GWAS replicated key genetic associations in F5 and ABO, and confirmed the importance of F11 and FGG loci for VTE. Future studies are warranted to better characterize the associations with F11 and FGG and to replicate the new candidate associations.
KW - Genetic epidemiology
KW - Genetics
KW - Genome-wide association
KW - Venous thrombosis
UR - http://www.scopus.com/inward/record.url?scp=84879176226&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84879176226&partnerID=8YFLogxK
U2 - 10.1002/gepi.21731
DO - 10.1002/gepi.21731
M3 - Article
C2 - 23650146
AN - SCOPUS:84879176226
SN - 0741-0395
VL - 37
SP - 512
EP - 521
JO - Genetic epidemiology
JF - Genetic epidemiology
IS - 5
ER -