Genome-wide association analysis of self-reported events in 6135 individuals and 252 827 controls identifies 8 loci associated with thrombosis
Por:
Hinds, DA, Buil, A, Ziemek, D, Martinez-Perez, A, Malik, R, Folkersen, L, Germain, M, Malarstig, A, Brown, A, Soria, JM, Dichgans, M, Bing, N, Franco-Cereceda, A, Souto, JC, Dermitzakis, ET, Hamsten, A, Worrall, BB, Tung, JY, Sabater-Lleal, M
Publicada:
1 may 2016
Resumen:
Thrombotic diseases are among the leading causes of morbidity and mortality in the world. To add insights into the genetic regulation of thrombotic disease, we conducted a genome-wide association study (GWAS) of 6135 self-reported blood clots events and 252 827 controls of European ancestry belonging to the 23andMe cohort of research participants. Eight loci exceeded genome-wide significance. Among the genome-wide significant results, our study replicated previously known venous thromboembolism (VTE) loci near the F5, FGA-FGG, F11, F2, PROCR and ABO genes, and the more recently discovered locus near SLC44A2. In addition, our study reports for the first time a genome-wide significant association between rs114209171, located upstream of the F8 structural gene, and thrombosis risk. Analyses of expression profiles and expression quantitative trait loci across different tissues suggested SLC44A2, ILF3 and AP1M2 as the three most plausible candidate genes for the chromosome 19 locus, our only genome-wide significant thrombosis-related locus that does not harbor likely coagulation-related genes. In addition, we present data showing that this locus also acts as a novel risk factor for stroke and coronary artery disease ( CAD). In conclusion, our study reveals novel common genetic risk factors for VTE, stroke and CAD and provides evidence that self-reported data on blood clots used in a GWAS yield results that are comparable with those obtained using clinically diagnosed VTE. This observation opens up the potential for larger meta-analyses, which will enable elucidation of the genetics of thrombotic diseases, and serves as an example for the genetic study of other diseases.
Filiaciones:
Hinds, DA:
23andMe Inc, Mountain View, CA USA
Buil, A:
Univ Geneva, Sch Med, Dept Genet Med & Dev, Geneva, Switzerland
Ziemek, D:
Pfizer Worldwide R&D, New York, NY USA
Karolinska Inst, Dept Med, Cardiovasc Med Unit, S-17176 Stockholm, Sweden
Martinez-Perez, A:
IIB St Pau, UGMC, Inst Recerca Hosp Santa Creu & St Pau, Barcelona, Spain
Malik, R:
Univ Munich, Klinikum Univ Munchen, Inst Stroke & Dementia Res, Munich, Germany
Folkersen, L:
Karolinska Inst, Dept Med, Cardiovasc Med Unit, S-17176 Stockholm, Sweden
Tech Univ Denmark, Ctr Biol Sequence Anal, Dept Syst Biol, Bldg 208, DK-2800 Lyngby, Denmark
Germain, M:
Univ Paris 06, Sorbonne Univ, INSERM, Team Genom & Pathophysiol Cardiovasc Dis,UMR S 11, Paris, France
ICAN, Paris, France
Malarstig, A:
Pfizer Worldwide R&D, New York, NY USA
Karolinska Inst, Dept Med, Cardiovasc Med Unit, S-17176 Stockholm, Sweden
Brown, A:
Univ Geneva, Sch Med, Dept Genet Med & Dev, Geneva, Switzerland
Soria, JM:
IIB St Pau, UGMC, Inst Recerca Hosp Santa Creu & St Pau, Barcelona, Spain
Dichgans, M:
Univ Munich, Inst Stroke & Dementia Res, Klinikum Univ Munchen, Munich, Germany
Munich Cluster Syst Neurol SyNergy, Munich, Germany
Bing, N:
Pfizer Worldwide R&D, New York, NY USA
Franco-Cereceda, A:
Karolinska Inst, Cardiothorac Surg Unit, Dept Mol Med & Surg, Karolinska Univ Hosp Solna, Stockholm, Sweden
Souto, JC:
IIB St Pau, Hosp Santa Creu & St Pau, Unitat Hemostasia & Trombosi, Barcelona, Spain
Dermitzakis, ET:
Univ Geneva, Sch Med, Dept Genet Med & Dev, Geneva, Switzerland
Hamsten, A:
Karolinska Inst, Dept Med, Cardiovasc Med Unit, S-17176 Stockholm, Sweden
Worrall, BB:
Univ Virginia Hlth Syst, Dept Neurol, Charlottesville, VA USA
Tung, JY:
23andMe Inc, Mountain View, CA USA
Sabater-Lleal, M:
Karolinska Inst, Dept Med, Cardiovasc Med Unit, S-17176 Stockholm, Sweden
Green Published, Bronze
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