Meta-analysis of 65,734 individuals identifies TSPAN15 and SLC44A2 as two susceptibility loci for venous thromboembolism

Marine Germain; Daniel I. Chasman; Hugoline De Haan; Weihong Tang; Sara Lindström; Lu Chen Weng; Mariza De Andrade; Marieke C H De Visser; Kerri L. Wiggins; Pierre Suchon; Noémie Saut; David M. Smadja; Grégoire Le Gal; Astrid Van Hylckama Vlieg; Antonio Di Narzo; Ke Hao; Christopher P. Nelson; Ares Rocanin-Arjo; Lasse Folkersen; Ramin Monajemi; Lynda M. Rose; Jennifer A. Brody; Eline Slagboom; Dylan Aïssi; France Gagnon; Jean Francois Deleuze; Panos Deloukas; Christophe Tzourio; Jean Francois Dartigues; Claudine Berr; Kent D. Taylor; Mete Civelek; Per Eriksson; Bruce M. Psaty; Jeanine Houwing-Duitermaat; Alison H. Goodall; François Cambien; Peter Kraft; Philippe Amouyel; Nilesh J. Samani; Saonli Basu; Paul M. Ridker; Frits R. Rosendaal; Christopher Kabrhel; Aaron R. Folsom; John Heit; Pieter H. Reitsma; David Alexandre Trégouët; Nicholas L. Smith; Pierre Emmanuel Morange

doi:10.1016/j.ajhg.2015.01.019

Meta-analysis of 65,734 individuals identifies TSPAN15 and SLC44A2 as two susceptibility loci for venous thromboembolism

Marine Germain, Daniel I. Chasman, Hugoline De Haan, Weihong Tang, Sara Lindström, Lu Chen Weng, Mariza De Andrade, Marieke C H De Visser, Kerri L. Wiggins, Pierre Suchon, Noémie Saut, David M. Smadja, Grégoire Le Gal, Astrid Van Hylckama Vlieg, Antonio Di Narzo, Ke Hao, Christopher P. Nelson, Ares Rocanin-Arjo, Lasse Folkersen, Ramin MonajemiLynda M. Rose, Jennifer A. Brody, Eline Slagboom, Dylan Aïssi, France Gagnon, Jean Francois Deleuze, Panos Deloukas, Christophe Tzourio, Jean Francois Dartigues, Claudine Berr, Kent D. Taylor, Mete Civelek, Per Eriksson, Bruce M. Psaty, Jeanine Houwing-Duitermaat, Alison H. Goodall, François Cambien, Peter Kraft, Philippe Amouyel, Nilesh J. Samani, Saonli Basu, Paul M. Ridker, Frits R. Rosendaal, Christopher Kabrhel, Aaron R. Folsom, John Heit, Pieter H. Reitsma, David Alexandre Trégouët, Nicholas L. Smith, Pierre Emmanuel Morange

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Abstract

Venous thromboembolism (VTE), the third leading cause of cardiovascular mortality, is a complex thrombotic disorder with environmental and genetic determinants. Although several genetic variants have been found associated with VTE, they explain a minor proportion of VTE risk in cases. We undertook a meta-analysis of genome-wide association studies (GWASs) to identify additional VTE susceptibility genes. Twelve GWASs totaling 7,507 VTE case subjects and 52,632 control subjects formed our discovery stage where 6,751,884 SNPs were tested for association with VTE. Nine loci reached the genome-wide significance level of 5 × 10^-8 including six already known to associate with VTE (ABO, F2, F5, F11, FGG, and PROCR) and three unsuspected loci. SNPs mapping to these latter were selected for replication in three independent case-control studies totaling 3,009 VTE-affected individuals and 2,586 control subjects. This strategy led to the identification and replication of two VTE-associated loci, TSPAN15 and SLC44A2, with lead risk alleles associated with odds ratio for disease of 1.31 (p = 1.67 × 10^-16) and 1.21 (p = 2.75 × 10^-15), respectively. The lead SNP at the TSPAN15 locus is the intronic rs78707713 and the lead SLC44A2 SNP is the non-synonymous rs2288904 previously shown to associate with transfusion-related acute lung injury. We further showed that these two variants did not associate with known hemostatic plasma markers. TSPAN15 and SLC44A2 do not belong to conventional pathways for thrombosis and have not been associated to other cardiovascular diseases nor related quantitative biomarkers. Our findings uncovered unexpected actors of VTE etiology and pave the way for novel mechanistic concepts of VTE pathophysiology.

Original language	English (US)
Pages (from-to)	532-542
Number of pages	11
Journal	American Journal of Human Genetics
Volume	96
Issue number	4
DOIs	https://doi.org/10.1016/j.ajhg.2015.01.019
State	Published - Apr 2 2015

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Publisher Copyright:
© 2015 The American Society of Human Genetics.

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Germain, M., Chasman, D. I., De Haan, H., Tang, W., Lindström, S., Weng, L. C., De Andrade, M., De Visser, M. C. H., Wiggins, K. L., Suchon, P., Saut, N., Smadja, D. M., Le Gal, G., Van Hylckama Vlieg, A., Di Narzo, A., Hao, K., Nelson, C. P., Rocanin-Arjo, A., Folkersen, L., ... Morange, P. E. (2015). Meta-analysis of 65,734 individuals identifies TSPAN15 and SLC44A2 as two susceptibility loci for venous thromboembolism. American Journal of Human Genetics, 96(4), 532-542. https://doi.org/10.1016/j.ajhg.2015.01.019

Germain, M, Chasman, DI, De Haan, H, Tang, W, Lindström, S, Weng, LC, De Andrade, M, De Visser, MCH, Wiggins, KL, Suchon, P, Saut, N, Smadja, DM, Le Gal, G, Van Hylckama Vlieg, A, Di Narzo, A, Hao, K, Nelson, CP, Rocanin-Arjo, A, Folkersen, L, Monajemi, R, Rose, LM, Brody, JA, Slagboom, E, Aïssi, D, Gagnon, F, Deleuze, JF, Deloukas, P, Tzourio, C, Dartigues, JF, Berr, C, Taylor, KD, Civelek, M, Eriksson, P, Psaty, BM, Houwing-Duitermaat, J, Goodall, AH, Cambien, F, Kraft, P, Amouyel, P, Samani, NJ, Basu, S, Ridker, PM, Rosendaal, FR, Kabrhel, C, Folsom, AR, Heit, J, Reitsma, PH, Trégouët, DA, Smith, NL & Morange, PE 2015, 'Meta-analysis of 65,734 individuals identifies TSPAN15 and SLC44A2 as two susceptibility loci for venous thromboembolism', American Journal of Human Genetics, vol. 96, no. 4, pp. 532-542. https://doi.org/10.1016/j.ajhg.2015.01.019

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title = "Meta-analysis of 65,734 individuals identifies TSPAN15 and SLC44A2 as two susceptibility loci for venous thromboembolism",

abstract = "Venous thromboembolism (VTE), the third leading cause of cardiovascular mortality, is a complex thrombotic disorder with environmental and genetic determinants. Although several genetic variants have been found associated with VTE, they explain a minor proportion of VTE risk in cases. We undertook a meta-analysis of genome-wide association studies (GWASs) to identify additional VTE susceptibility genes. Twelve GWASs totaling 7,507 VTE case subjects and 52,632 control subjects formed our discovery stage where 6,751,884 SNPs were tested for association with VTE. Nine loci reached the genome-wide significance level of 5 × 10-8 including six already known to associate with VTE (ABO, F2, F5, F11, FGG, and PROCR) and three unsuspected loci. SNPs mapping to these latter were selected for replication in three independent case-control studies totaling 3,009 VTE-affected individuals and 2,586 control subjects. This strategy led to the identification and replication of two VTE-associated loci, TSPAN15 and SLC44A2, with lead risk alleles associated with odds ratio for disease of 1.31 (p = 1.67 × 10-16) and 1.21 (p = 2.75 × 10-15), respectively. The lead SNP at the TSPAN15 locus is the intronic rs78707713 and the lead SLC44A2 SNP is the non-synonymous rs2288904 previously shown to associate with transfusion-related acute lung injury. We further showed that these two variants did not associate with known hemostatic plasma markers. TSPAN15 and SLC44A2 do not belong to conventional pathways for thrombosis and have not been associated to other cardiovascular diseases nor related quantitative biomarkers. Our findings uncovered unexpected actors of VTE etiology and pave the way for novel mechanistic concepts of VTE pathophysiology.",

author = "Marine Germain and Chasman, {Daniel I.} and {De Haan}, Hugoline and Weihong Tang and Sara Lindstr{\"o}m and Weng, {Lu Chen} and {De Andrade}, Mariza and {De Visser}, {Marieke C H} and Wiggins, {Kerri L.} and Pierre Suchon and No{\'e}mie Saut and Smadja, {David M.} and {Le Gal}, Gr{\'e}goire and {Van Hylckama Vlieg}, Astrid and {Di Narzo}, Antonio and Ke Hao and Nelson, {Christopher P.} and Ares Rocanin-Arjo and Lasse Folkersen and Ramin Monajemi and Rose, {Lynda M.} and Brody, {Jennifer A.} and Eline Slagboom and Dylan A{\"i}ssi and France Gagnon and Deleuze, {Jean Francois} and Panos Deloukas and Christophe Tzourio and Dartigues, {Jean Francois} and Claudine Berr and Taylor, {Kent D.} and Mete Civelek and Per Eriksson and Psaty, {Bruce M.} and Jeanine Houwing-Duitermaat and Goodall, {Alison H.} and Fran{\c c}ois Cambien and Peter Kraft and Philippe Amouyel and Samani, {Nilesh J.} and Saonli Basu and Ridker, {Paul M.} and Rosendaal, {Frits R.} and Christopher Kabrhel and Folsom, {Aaron R.} and John Heit and Reitsma, {Pieter H.} and Tr{\'e}gou{\"e}t, {David Alexandre} and Smith, {Nicholas L.} and Morange, {Pierre Emmanuel}",

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doi = "10.1016/j.ajhg.2015.01.019",

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T1 - Meta-analysis of 65,734 individuals identifies TSPAN15 and SLC44A2 as two susceptibility loci for venous thromboembolism

AU - Germain, Marine

AU - Chasman, Daniel I.

AU - De Haan, Hugoline

AU - Tang, Weihong

AU - Lindström, Sara

AU - Weng, Lu Chen

AU - De Andrade, Mariza

AU - De Visser, Marieke C H

AU - Wiggins, Kerri L.

AU - Suchon, Pierre

AU - Saut, Noémie

AU - Smadja, David M.

AU - Le Gal, Grégoire

AU - Van Hylckama Vlieg, Astrid

AU - Di Narzo, Antonio

AU - Hao, Ke

AU - Nelson, Christopher P.

AU - Rocanin-Arjo, Ares

AU - Folkersen, Lasse

AU - Monajemi, Ramin

AU - Rose, Lynda M.

AU - Brody, Jennifer A.

AU - Slagboom, Eline

AU - Aïssi, Dylan

AU - Gagnon, France

AU - Deleuze, Jean Francois

AU - Deloukas, Panos

AU - Tzourio, Christophe

AU - Dartigues, Jean Francois

AU - Berr, Claudine

AU - Taylor, Kent D.

AU - Civelek, Mete

AU - Eriksson, Per

AU - Psaty, Bruce M.

AU - Houwing-Duitermaat, Jeanine

AU - Goodall, Alison H.

AU - Cambien, François

AU - Kraft, Peter

AU - Amouyel, Philippe

AU - Samani, Nilesh J.

AU - Basu, Saonli

AU - Ridker, Paul M.

AU - Rosendaal, Frits R.

AU - Kabrhel, Christopher

AU - Folsom, Aaron R.

AU - Heit, John

AU - Reitsma, Pieter H.

AU - Trégouët, David Alexandre

AU - Smith, Nicholas L.

AU - Morange, Pierre Emmanuel

PY - 2015/4/2

Y1 - 2015/4/2

N2 - Venous thromboembolism (VTE), the third leading cause of cardiovascular mortality, is a complex thrombotic disorder with environmental and genetic determinants. Although several genetic variants have been found associated with VTE, they explain a minor proportion of VTE risk in cases. We undertook a meta-analysis of genome-wide association studies (GWASs) to identify additional VTE susceptibility genes. Twelve GWASs totaling 7,507 VTE case subjects and 52,632 control subjects formed our discovery stage where 6,751,884 SNPs were tested for association with VTE. Nine loci reached the genome-wide significance level of 5 × 10-8 including six already known to associate with VTE (ABO, F2, F5, F11, FGG, and PROCR) and three unsuspected loci. SNPs mapping to these latter were selected for replication in three independent case-control studies totaling 3,009 VTE-affected individuals and 2,586 control subjects. This strategy led to the identification and replication of two VTE-associated loci, TSPAN15 and SLC44A2, with lead risk alleles associated with odds ratio for disease of 1.31 (p = 1.67 × 10-16) and 1.21 (p = 2.75 × 10-15), respectively. The lead SNP at the TSPAN15 locus is the intronic rs78707713 and the lead SLC44A2 SNP is the non-synonymous rs2288904 previously shown to associate with transfusion-related acute lung injury. We further showed that these two variants did not associate with known hemostatic plasma markers. TSPAN15 and SLC44A2 do not belong to conventional pathways for thrombosis and have not been associated to other cardiovascular diseases nor related quantitative biomarkers. Our findings uncovered unexpected actors of VTE etiology and pave the way for novel mechanistic concepts of VTE pathophysiology.

AB - Venous thromboembolism (VTE), the third leading cause of cardiovascular mortality, is a complex thrombotic disorder with environmental and genetic determinants. Although several genetic variants have been found associated with VTE, they explain a minor proportion of VTE risk in cases. We undertook a meta-analysis of genome-wide association studies (GWASs) to identify additional VTE susceptibility genes. Twelve GWASs totaling 7,507 VTE case subjects and 52,632 control subjects formed our discovery stage where 6,751,884 SNPs were tested for association with VTE. Nine loci reached the genome-wide significance level of 5 × 10-8 including six already known to associate with VTE (ABO, F2, F5, F11, FGG, and PROCR) and three unsuspected loci. SNPs mapping to these latter were selected for replication in three independent case-control studies totaling 3,009 VTE-affected individuals and 2,586 control subjects. This strategy led to the identification and replication of two VTE-associated loci, TSPAN15 and SLC44A2, with lead risk alleles associated with odds ratio for disease of 1.31 (p = 1.67 × 10-16) and 1.21 (p = 2.75 × 10-15), respectively. The lead SNP at the TSPAN15 locus is the intronic rs78707713 and the lead SLC44A2 SNP is the non-synonymous rs2288904 previously shown to associate with transfusion-related acute lung injury. We further showed that these two variants did not associate with known hemostatic plasma markers. TSPAN15 and SLC44A2 do not belong to conventional pathways for thrombosis and have not been associated to other cardiovascular diseases nor related quantitative biomarkers. Our findings uncovered unexpected actors of VTE etiology and pave the way for novel mechanistic concepts of VTE pathophysiology.

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Meta-analysis of 65,734 individuals identifies TSPAN15 and SLC44A2 as two susceptibility loci for venous thromboembolism

Abstract

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