Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism

Sara Lindström; Lu Wang; Erin N. Smith; William Gordon; Astrid Van Hylckama Vlieg; Mariza De Andrade; Jennifer A. Brody; Jack W. Pattee; Jeffrey Haessler; Ben M. Brumpton; Daniel I. Chasman; Pierre Suchon; Ming Huei Chen; Constance Turman; Marine Germain; Kerri L. Wiggins; James MacDonald; Sigrid K. Braekkan; Sebastian M. Armasu; Nathan Pankratz; Rebecca D. Jackson; Jonas B. Nielsen; Franco Giulianini; Marja K. Puurunen; Manal Ibrahim; Susan R. Heckbert; Scott M. Damrauer; Pradeep Natarajan; Derek Klarin; Paul S. De Vries; Maria Sabater-Lleal; Jennifer E. Huffman; Theo K. Bammler; Kelly A. Frazer; Bryan M. McCauley; Kent Taylor; James S. Pankow; Alexander P. Reiner; Maiken E. Gabrielsen; Jean François Deleuze; Chris J. O'Donnell; Jihye Kim; Barbara McKnight; Peter Kraft; John Bjarne Hansen; Frits R. Rosendaal; John A. Heit; Bruce M. Psaty; Weihong Tang; Charles Kooperberg; Kristian Hveem; Paul M. Ridker; Pierre Emmanuel Morange; Andrew D. Johnson; Christopher Kabrhel; David Alexandre Trégouët; Nicholas L. Smith

doi:10.1182/blood.2019000435

Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism

Sara Lindström, Lu Wang, Erin N. Smith, William Gordon, Astrid Van Hylckama Vlieg, Mariza De Andrade, Jennifer A. Brody, Jack W. Pattee, Jeffrey Haessler, Ben M. Brumpton, Daniel I. Chasman, Pierre Suchon, Ming Huei Chen, Constance Turman, Marine Germain, Kerri L. Wiggins, James MacDonald, Sigrid K. Braekkan, Sebastian M. Armasu, Nathan PankratzRebecca D. Jackson, Jonas B. Nielsen, Franco Giulianini, Marja K. Puurunen, Manal Ibrahim, Susan R. Heckbert, Scott M. Damrauer, Pradeep Natarajan, Derek Klarin, Paul S. De Vries, Maria Sabater-Lleal, Jennifer E. Huffman, Theo K. Bammler, Kelly A. Frazer, Bryan M. McCauley, Kent Taylor, James S. Pankow, Alexander P. Reiner, Maiken E. Gabrielsen, Jean François Deleuze, Chris J. O'Donnell, Jihye Kim, Barbara McKnight, Peter Kraft, John Bjarne Hansen, Frits R. Rosendaal, John A. Heit, Bruce M. Psaty, Weihong Tang, Charles Kooperberg, Kristian Hveem, Paul M. Ridker, Pierre Emmanuel Morange, Andrew D. Johnson, Christopher Kabrhel, David Alexandre Trégouët, Nicholas L. Smith

Quantitative Health Sciences

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

Abstract

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE,we conducted a genome-wide association study (GWAS) of VTE and a transcriptomewide association study (TWAS) based on imputed gene expression from whole blood and liver.Wemeta-analyzedGWAS data from18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci.We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude,we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.

Original language	English (US)
Pages (from-to)	1645-1657
Number of pages	13
Journal	Blood
Volume	134
Issue number	19
DOIs	https://doi.org/10.1182/blood.2019000435
State	Published - Nov 7 2019

ASJC Scopus subject areas

Biochemistry
Immunology
Hematology
Cell Biology

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Lindström, S., Wang, L., Smith, E. N., Gordon, W., Van Hylckama Vlieg, A., De Andrade, M., Brody, J. A., Pattee, J. W., Haessler, J., Brumpton, B. M., Chasman, D. I., Suchon, P., Chen, M. H., Turman, C., Germain, M., Wiggins, K. L., MacDonald, J., Braekkan, S. K., Armasu, S. M., ... Smith, N. L. (2019). Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism. Blood, 134(19), 1645-1657. https://doi.org/10.1182/blood.2019000435

Lindström, S, Wang, L, Smith, EN, Gordon, W, Van Hylckama Vlieg, A, De Andrade, M, Brody, JA, Pattee, JW, Haessler, J, Brumpton, BM, Chasman, DI, Suchon, P, Chen, MH, Turman, C, Germain, M, Wiggins, KL, MacDonald, J, Braekkan, SK, Armasu, SM, Pankratz, N, Jackson, RD, Nielsen, JB, Giulianini, F, Puurunen, MK, Ibrahim, M, Heckbert, SR, Damrauer, SM, Natarajan, P, Klarin, D, De Vries, PS, Sabater-Lleal, M, Huffman, JE, Bammler, TK, Frazer, KA, McCauley, BM, Taylor, K, Pankow, JS, Reiner, AP, Gabrielsen, ME, Deleuze, JF, O'Donnell, CJ, Kim, J, McKnight, B, Kraft, P, Hansen, JB, Rosendaal, FR, Heit, JA, Psaty, BM, Tang, W, Kooperberg, C, Hveem, K, Ridker, PM, Morange, PE, Johnson, AD, Kabrhel, C, Trégouët, DA & Smith, NL 2019, 'Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism', Blood, vol. 134, no. 19, pp. 1645-1657. https://doi.org/10.1182/blood.2019000435

@article{2ac2a440c2e848c1b24ac556e44a1cc2,

title = "Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism",

abstract = "Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE,we conducted a genome-wide association study (GWAS) of VTE and a transcriptomewide association study (TWAS) based on imputed gene expression from whole blood and liver.Wemeta-analyzedGWAS data from18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci.We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude,we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.",

author = "Sara Lindstr{\"o}m and Lu Wang and Smith, {Erin N.} and William Gordon and {Van Hylckama Vlieg}, Astrid and {De Andrade}, Mariza and Brody, {Jennifer A.} and Pattee, {Jack W.} and Jeffrey Haessler and Brumpton, {Ben M.} and Chasman, {Daniel I.} and Pierre Suchon and Chen, {Ming Huei} and Constance Turman and Marine Germain and Wiggins, {Kerri L.} and James MacDonald and Braekkan, {Sigrid K.} and Armasu, {Sebastian M.} and Nathan Pankratz and Jackson, {Rebecca D.} and Nielsen, {Jonas B.} and Franco Giulianini and Puurunen, {Marja K.} and Manal Ibrahim and Heckbert, {Susan R.} and Damrauer, {Scott M.} and Pradeep Natarajan and Derek Klarin and {De Vries}, {Paul S.} and Maria Sabater-Lleal and Huffman, {Jennifer E.} and Bammler, {Theo K.} and Frazer, {Kelly A.} and McCauley, {Bryan M.} and Kent Taylor and Pankow, {James S.} and Reiner, {Alexander P.} and Gabrielsen, {Maiken E.} and Deleuze, {Jean Fran{\c c}ois} and O'Donnell, {Chris J.} and Jihye Kim and Barbara McKnight and Peter Kraft and Hansen, {John Bjarne} and Rosendaal, {Frits R.} and Heit, {John A.} and Psaty, {Bruce M.} and Weihong Tang and Charles Kooperberg and Kristian Hveem and Ridker, {Paul M.} and Morange, {Pierre Emmanuel} and Johnson, {Andrew D.} and Christopher Kabrhel and Tr{\'e}gou{\"e}t, {David Alexandre} and Smith, {Nicholas L.}",

note = "Funding Information: Conflict-of-interest disclosures: B.M.P. serves on the Steering Committee of the Yale Open Data Access project funded by Johnson & Johnson. Funding Information: P.N. has received grant support from Amgen, Apple, and Boston Scientific and is a scientific advisor to Apple. S.M.D. receives institutional funding from CytoVas LLC and RenalytixAI. The remaining authors declare no competing financial interests. Funding Information: This work was supported in part by National Institutes of Health, National Heart, Lung, and Blood Institute grants HL134894, HL139553, and HL141791 (N.L.S.). The K.G. Jebsen Thombosis Research and Expertise Center is supported by an independent grant from Stiftelsen Kristian Gerhard Jebsen (J.H.) and HL116854 (C. Kabrhel). Sources of funding for the specific cohorts can be found in the supplemental Materials. Publisher Copyright: {\textcopyright} 2019 American Society of Hematology. All rights reserved.",

year = "2019",

month = nov,

day = "7",

doi = "10.1182/blood.2019000435",

language = "English (US)",

volume = "134",

pages = "1645--1657",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

number = "19",

}

TY - JOUR

T1 - Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism

AU - Lindström, Sara

AU - Wang, Lu

AU - Smith, Erin N.

AU - Gordon, William

AU - Van Hylckama Vlieg, Astrid

AU - De Andrade, Mariza

AU - Brody, Jennifer A.

AU - Pattee, Jack W.

AU - Haessler, Jeffrey

AU - Brumpton, Ben M.

AU - Chasman, Daniel I.

AU - Suchon, Pierre

AU - Chen, Ming Huei

AU - Turman, Constance

AU - Germain, Marine

AU - Wiggins, Kerri L.

AU - MacDonald, James

AU - Braekkan, Sigrid K.

AU - Armasu, Sebastian M.

AU - Pankratz, Nathan

AU - Jackson, Rebecca D.

AU - Nielsen, Jonas B.

AU - Giulianini, Franco

AU - Puurunen, Marja K.

AU - Ibrahim, Manal

AU - Heckbert, Susan R.

AU - Damrauer, Scott M.

AU - Natarajan, Pradeep

AU - Klarin, Derek

AU - De Vries, Paul S.

AU - Sabater-Lleal, Maria

AU - Huffman, Jennifer E.

AU - Bammler, Theo K.

AU - Frazer, Kelly A.

AU - McCauley, Bryan M.

AU - Taylor, Kent

AU - Pankow, James S.

AU - Reiner, Alexander P.

AU - Gabrielsen, Maiken E.

AU - Deleuze, Jean François

AU - O'Donnell, Chris J.

AU - Kim, Jihye

AU - McKnight, Barbara

AU - Kraft, Peter

AU - Hansen, John Bjarne

AU - Rosendaal, Frits R.

AU - Heit, John A.

AU - Psaty, Bruce M.

AU - Tang, Weihong

AU - Kooperberg, Charles

AU - Hveem, Kristian

AU - Ridker, Paul M.

AU - Morange, Pierre Emmanuel

AU - Johnson, Andrew D.

AU - Kabrhel, Christopher

AU - Trégouët, David Alexandre

AU - Smith, Nicholas L.

N1 - Funding Information: Conflict-of-interest disclosures: B.M.P. serves on the Steering Committee of the Yale Open Data Access project funded by Johnson & Johnson. Funding Information: P.N. has received grant support from Amgen, Apple, and Boston Scientific and is a scientific advisor to Apple. S.M.D. receives institutional funding from CytoVas LLC and RenalytixAI. The remaining authors declare no competing financial interests. Funding Information: This work was supported in part by National Institutes of Health, National Heart, Lung, and Blood Institute grants HL134894, HL139553, and HL141791 (N.L.S.). The K.G. Jebsen Thombosis Research and Expertise Center is supported by an independent grant from Stiftelsen Kristian Gerhard Jebsen (J.H.) and HL116854 (C. Kabrhel). Sources of funding for the specific cohorts can be found in the supplemental Materials. Publisher Copyright: © 2019 American Society of Hematology. All rights reserved.

PY - 2019/11/7

Y1 - 2019/11/7

N2 - Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE,we conducted a genome-wide association study (GWAS) of VTE and a transcriptomewide association study (TWAS) based on imputed gene expression from whole blood and liver.Wemeta-analyzedGWAS data from18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci.We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude,we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.

AB - Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE,we conducted a genome-wide association study (GWAS) of VTE and a transcriptomewide association study (TWAS) based on imputed gene expression from whole blood and liver.Wemeta-analyzedGWAS data from18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci.We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude,we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.

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U2 - 10.1182/blood.2019000435

DO - 10.1182/blood.2019000435

M3 - Article

C2 - 31420334

AN - SCOPUS:85074331473

VL - 134

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EP - 1657

JO - Blood

JF - Blood

SN - 0006-4971

IS - 19

ER -

Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism

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