eQTL Set-Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma

Xiaoyu Wang; Puya Gharahkhani; David M. Levine; Rebecca C. Fitzgerald; Ines Gockel; Douglas A. Corley; Harvey A. Risch; Leslie Bernstein; Wong Ho Chow; Lynn Onstad; Nicholas J. Shaheen; Jesper Lagergren; Laura J. Hardie; Anna H. Wu; Paul D.P. Pharoah; Geoffrey Liu; Lesley A. Anderson; Prasad G. Iyer; Marilie D. Gammon; Carlos Caldas; Weimin Ye; Hugh Barr; Paul Moayyedi; Rebecca Harrison; R. G.Peter Watson; Stephen Attwood; Laura Chegwidden; Sharon B. Love; David MacDonald; John deCaestecker; Hans Prenen; Katja Ott; Susanne Moebus; Marino Venerito; Hauke Lang; Rupert Mayershofer; Michael Knapp; Lothar Veits; Christian Gerges; Josef Weismüller; Matthias Reeh; Markus M. Nöthen; Jakob R. Izbicki; Hendrik Manner; Horst Neuhaus; Thomas Rösch; Anne C. Böhmer; Arnulf H. Hölscher; Mario Anders; Oliver Pech; Brigitte Schumacher; Claudia Schmidt; Thomas Schmidt; Tania Noder; Dietmar Lorenz; Michael Vieth; Andrea May; Timo Hess; Nicole Kreuser; Jessica Becker; Christian Ell; Ian Tomlinson; Claire Palles; Janusz A. Jankowski; David C. Whiteman; Stuart MacGregor; Johannes Schumacher; Thomas L. Vaughan; Matthew F. Buas; James Y. Dai

doi:10.1158/1055-9965.EPI-22-0096

eQTL Set-Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma

Xiaoyu Wang, Puya Gharahkhani, David M. Levine, Rebecca C. Fitzgerald, Ines Gockel, Douglas A. Corley, Harvey A. Risch, Leslie Bernstein, Wong Ho Chow, Lynn Onstad, Nicholas J. Shaheen, Jesper Lagergren, Laura J. Hardie, Anna H. Wu, Paul D.P. Pharoah, Geoffrey Liu, Lesley A. Anderson, Prasad G. Iyer, Marilie D. Gammon, Carlos CaldasWeimin Ye, Hugh Barr, Paul Moayyedi, Rebecca Harrison, R. G.Peter Watson, Stephen Attwood, Laura Chegwidden, Sharon B. Love, David MacDonald, John deCaestecker, Hans Prenen, Katja Ott, Susanne Moebus, Marino Venerito, Hauke Lang, Rupert Mayershofer, Michael Knapp, Lothar Veits, Christian Gerges, Josef Weismüller, Matthias Reeh, Markus M. Nöthen, Jakob R. Izbicki, Hendrik Manner, Horst Neuhaus, Thomas Rösch, Anne C. Böhmer, Arnulf H. Hölscher, Mario Anders, Oliver Pech, Brigitte Schumacher, Claudia Schmidt, Thomas Schmidt, Tania Noder, Dietmar Lorenz, Michael Vieth, Andrea May, Timo Hess, Nicole Kreuser, Jessica Becker, Christian Ell, Ian Tomlinson, Claire Palles, Janusz A. Jankowski, David C. Whiteman, Stuart MacGregor, Johannes Schumacher, Thomas L. Vaughan, Matthew F. Buas, James Y. Dai

Comprehensive Cancer Centre

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4 Citations (Scopus)

Abstract

BACKGROUND: Over 20 susceptibility single-nucleotide polymorphisms (SNP) have been identified for esophageal adenocarcinoma (EAC) and its precursor, Barrett esophagus (BE), explaining a small portion of heritability. METHODS: Using genetic data from 4,323 BE and 4,116 EAC patients aggregated by international consortia including the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON), we conducted a comprehensive transcriptome-wide association study (TWAS) for BE/EAC, leveraging Genotype Tissue Expression (GTEx) gene-expression data from six tissue types of plausible relevance to EAC etiology: mucosa and muscularis from the esophagus, gastroesophageal (GE) junction, stomach, whole blood, and visceral adipose. Two analytical approaches were taken: standard TWAS using the predicted gene expression from local expression quantitative trait loci (eQTL), and set-based SKAT association using selected eQTLs that predict the gene expression. RESULTS: Although the standard approach did not identify significant signals, the eQTL set-based approach identified eight novel associations, three of which were validated in independent external data (eQTL SNP sets for EXOC3, ZNF641, and HSP90AA1). CONCLUSIONS: This study identified novel genetic susceptibility loci for EAC and BE using an eQTL set-based genetic association approach. IMPACT: This study expanded the pool of genetic susceptibility loci for EAC and BE, suggesting the potential of the eQTL set-based genetic association approach as an alternative method for TWAS analysis.

Original language	English
Pages (from-to)	1735-1745
Number of pages	11
Journal	Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume	31
Issue number	9
DOIs	https://doi.org/10.1158/1055-9965.EPI-22-0096
Publication status	Published - 2 Sept 2022

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10.1158/1055-9965.EPI-22-0096

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Wang, X., Gharahkhani, P., Levine, D. M., Fitzgerald, R. C., Gockel, I., Corley, D. A., Risch, H. A., Bernstein, L., Chow, W. H., Onstad, L., Shaheen, N. J., Lagergren, J., Hardie, L. J., Wu, A. H., Pharoah, P. D. P., Liu, G., Anderson, L. A., Iyer, P. G., Gammon, M. D., ... Dai, J. Y. (2022). eQTL Set-Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 31(9), 1735-1745. https://doi.org/10.1158/1055-9965.EPI-22-0096

Wang, Xiaoyu ; Gharahkhani, Puya ; Levine, David M. et al. / eQTL Set-Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma. In: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2022 ; Vol. 31, No. 9. pp. 1735-1745.

@article{3f1e8b4a501c48aa8624684d19414fbb,

title = "eQTL Set-Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma",

abstract = "BACKGROUND: Over 20 susceptibility single-nucleotide polymorphisms (SNP) have been identified for esophageal adenocarcinoma (EAC) and its precursor, Barrett esophagus (BE), explaining a small portion of heritability. METHODS: Using genetic data from 4,323 BE and 4,116 EAC patients aggregated by international consortia including the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON), we conducted a comprehensive transcriptome-wide association study (TWAS) for BE/EAC, leveraging Genotype Tissue Expression (GTEx) gene-expression data from six tissue types of plausible relevance to EAC etiology: mucosa and muscularis from the esophagus, gastroesophageal (GE) junction, stomach, whole blood, and visceral adipose. Two analytical approaches were taken: standard TWAS using the predicted gene expression from local expression quantitative trait loci (eQTL), and set-based SKAT association using selected eQTLs that predict the gene expression. RESULTS: Although the standard approach did not identify significant signals, the eQTL set-based approach identified eight novel associations, three of which were validated in independent external data (eQTL SNP sets for EXOC3, ZNF641, and HSP90AA1). CONCLUSIONS: This study identified novel genetic susceptibility loci for EAC and BE using an eQTL set-based genetic association approach. IMPACT: This study expanded the pool of genetic susceptibility loci for EAC and BE, suggesting the potential of the eQTL set-based genetic association approach as an alternative method for TWAS analysis.",

author = "Xiaoyu Wang and Puya Gharahkhani and Levine, {David M.} and Fitzgerald, {Rebecca C.} and Ines Gockel and Corley, {Douglas A.} and Risch, {Harvey A.} and Leslie Bernstein and Chow, {Wong Ho} and Lynn Onstad and Shaheen, {Nicholas J.} and Jesper Lagergren and Hardie, {Laura J.} and Wu, {Anna H.} and Pharoah, {Paul D.P.} and Geoffrey Liu and Anderson, {Lesley A.} and Iyer, {Prasad G.} and Gammon, {Marilie D.} and Carlos Caldas and Weimin Ye and Hugh Barr and Paul Moayyedi and Rebecca Harrison and Watson, {R. G.Peter} and Stephen Attwood and Laura Chegwidden and Love, {Sharon B.} and David MacDonald and John deCaestecker and Hans Prenen and Katja Ott and Susanne Moebus and Marino Venerito and Hauke Lang and Rupert Mayershofer and Michael Knapp and Lothar Veits and Christian Gerges and Josef Weism{\"u}ller and Matthias Reeh and N{\"o}then, {Markus M.} and Izbicki, {Jakob R.} and Hendrik Manner and Horst Neuhaus and Thomas R{\"o}sch and B{\"o}hmer, {Anne C.} and H{\"o}lscher, {Arnulf H.} and Mario Anders and Oliver Pech and Brigitte Schumacher and Claudia Schmidt and Thomas Schmidt and Tania Noder and Dietmar Lorenz and Michael Vieth and Andrea May and Timo Hess and Nicole Kreuser and Jessica Becker and Christian Ell and Ian Tomlinson and Claire Palles and Jankowski, {Janusz A.} and Whiteman, {David C.} and Stuart MacGregor and Johannes Schumacher and Vaughan, {Thomas L.} and Buas, {Matthew F.} and Dai, {James Y.}",

note = "Funding Information: conduct of the study. N.J. Shaheen reports grants from NIH during the conduct of the study; grants from Lucid, Steris, Medtronic, Pentax, CDx Medical, Interpace Diagnostics, and Phathom, personal fees from Aqua, Cook Medical, Castle, Exact outside the submitted work. P.D. Pharoah reports grants from Cancer Research UK during the conduct of the study. P.G. Iyer reports grants from Exact Sciences, Pentax Medical, Cernostics, other support from Exact Sciences, CDx Medical, Ambu, and Cernostics outside the submitted work. M. Venerito reports personal fees from Nordic Pharma, Merck Serono, Bayer Vital, Lilly, grants and personal fees from Sirtex, Ipsen, BMS, MSD, Eisai, Amgen, and AstraZeneca outside the submitted work. M.M. Nothen reports grants from Deutsche Forschungsgemeinschaft during the conduct of the study; personal fees from Life&Brain GmbH outside the submitted work. H. Manner reports grants from Erbe Elektromedizin, Germany outside the submitted work. D.C. Whiteman reports grants from the National Health and Medical Research Council of Australia during the conduct of the study. S. MacGregor reports grants from the Australian National Health and Medical Research Council during the conduct of the study. T.L. Vaughan reports grants from the Fred Hutch Cancer Center during the conduct of the study. No disclosures were reported by the other authors. Funding Information: J.Y. Dai and X. Wang were supported by the NCI grant R01 CA222833. M.F. Buas was supported by NCI grant R03CA223731. Computation is in part supported by NIH grant S10OD028685 to Fred Hutch Cancer Research Center. A full list of acknowledgments for consortia data used for this study is provided in the Supplementary Data. Publisher Copyright: {\textcopyright} 2022 American Association for Cancer Research.",

year = "2022",

month = sep,

day = "2",

doi = "10.1158/1055-9965.EPI-22-0096",

language = "English",

volume = "31",

pages = "1735--1745",

journal = "Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology",

issn = "1055-9965",

publisher = "American Association for Cancer Research",

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Wang, X, Gharahkhani, P, Levine, DM, Fitzgerald, RC, Gockel, I, Corley, DA, Risch, HA, Bernstein, L, Chow, WH, Onstad, L, Shaheen, NJ, Lagergren, J, Hardie, LJ, Wu, AH, Pharoah, PDP, Liu, G, Anderson, LA, Iyer, PG, Gammon, MD, Caldas, C, Ye, W, Barr, H, Moayyedi, P, Harrison, R, Watson, RGP, Attwood, S, Chegwidden, L, Love, SB, MacDonald, D, deCaestecker, J, Prenen, H, Ott, K, Moebus, S, Venerito, M, Lang, H, Mayershofer, R, Knapp, M, Veits, L, Gerges, C, Weismüller, J, Reeh, M, Nöthen, MM, Izbicki, JR, Manner, H, Neuhaus, H, Rösch, T, Böhmer, AC, Hölscher, AH, Anders, M, Pech, O, Schumacher, B, Schmidt, C, Schmidt, T, Noder, T, Lorenz, D, Vieth, M, May, A, Hess, T, Kreuser, N, Becker, J, Ell, C, Tomlinson, I, Palles, C, Jankowski, JA, Whiteman, DC, MacGregor, S, Schumacher, J, Vaughan, TL, Buas, MF & Dai, JY 2022, 'eQTL Set-Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma', Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, vol. 31, no. 9, pp. 1735-1745. https://doi.org/10.1158/1055-9965.EPI-22-0096

eQTL Set-Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma. / Wang, Xiaoyu; Gharahkhani, Puya; Levine, David M. et al.
In: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, Vol. 31, No. 9, 02.09.2022, p. 1735-1745.

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

TY - JOUR

T1 - eQTL Set-Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma

AU - Wang, Xiaoyu

AU - Gharahkhani, Puya

AU - Levine, David M.

AU - Fitzgerald, Rebecca C.

AU - Gockel, Ines

AU - Corley, Douglas A.

AU - Risch, Harvey A.

AU - Bernstein, Leslie

AU - Chow, Wong Ho

AU - Onstad, Lynn

AU - Shaheen, Nicholas J.

AU - Lagergren, Jesper

AU - Hardie, Laura J.

AU - Wu, Anna H.

AU - Pharoah, Paul D.P.

AU - Liu, Geoffrey

AU - Anderson, Lesley A.

AU - Iyer, Prasad G.

AU - Gammon, Marilie D.

AU - Caldas, Carlos

AU - Ye, Weimin

AU - Barr, Hugh

AU - Moayyedi, Paul

AU - Harrison, Rebecca

AU - Watson, R. G.Peter

AU - Attwood, Stephen

AU - Chegwidden, Laura

AU - Love, Sharon B.

AU - MacDonald, David

AU - deCaestecker, John

AU - Prenen, Hans

AU - Ott, Katja

AU - Moebus, Susanne

AU - Venerito, Marino

AU - Lang, Hauke

AU - Mayershofer, Rupert

AU - Knapp, Michael

AU - Veits, Lothar

AU - Gerges, Christian

AU - Weismüller, Josef

AU - Reeh, Matthias

AU - Nöthen, Markus M.

AU - Izbicki, Jakob R.

AU - Manner, Hendrik

AU - Neuhaus, Horst

AU - Rösch, Thomas

AU - Böhmer, Anne C.

AU - Hölscher, Arnulf H.

AU - Anders, Mario

AU - Pech, Oliver

AU - Schumacher, Brigitte

AU - Schmidt, Claudia

AU - Schmidt, Thomas

AU - Noder, Tania

AU - Lorenz, Dietmar

AU - Vieth, Michael

AU - May, Andrea

AU - Hess, Timo

AU - Kreuser, Nicole

AU - Becker, Jessica

AU - Ell, Christian

AU - Tomlinson, Ian

AU - Palles, Claire

AU - Jankowski, Janusz A.

AU - Whiteman, David C.

AU - MacGregor, Stuart

AU - Schumacher, Johannes

AU - Vaughan, Thomas L.

AU - Buas, Matthew F.

AU - Dai, James Y.

N1 - Funding Information: conduct of the study. N.J. Shaheen reports grants from NIH during the conduct of the study; grants from Lucid, Steris, Medtronic, Pentax, CDx Medical, Interpace Diagnostics, and Phathom, personal fees from Aqua, Cook Medical, Castle, Exact outside the submitted work. P.D. Pharoah reports grants from Cancer Research UK during the conduct of the study. P.G. Iyer reports grants from Exact Sciences, Pentax Medical, Cernostics, other support from Exact Sciences, CDx Medical, Ambu, and Cernostics outside the submitted work. M. Venerito reports personal fees from Nordic Pharma, Merck Serono, Bayer Vital, Lilly, grants and personal fees from Sirtex, Ipsen, BMS, MSD, Eisai, Amgen, and AstraZeneca outside the submitted work. M.M. Nothen reports grants from Deutsche Forschungsgemeinschaft during the conduct of the study; personal fees from Life&Brain GmbH outside the submitted work. H. Manner reports grants from Erbe Elektromedizin, Germany outside the submitted work. D.C. Whiteman reports grants from the National Health and Medical Research Council of Australia during the conduct of the study. S. MacGregor reports grants from the Australian National Health and Medical Research Council during the conduct of the study. T.L. Vaughan reports grants from the Fred Hutch Cancer Center during the conduct of the study. No disclosures were reported by the other authors. Funding Information: J.Y. Dai and X. Wang were supported by the NCI grant R01 CA222833. M.F. Buas was supported by NCI grant R03CA223731. Computation is in part supported by NIH grant S10OD028685 to Fred Hutch Cancer Research Center. A full list of acknowledgments for consortia data used for this study is provided in the Supplementary Data. Publisher Copyright: © 2022 American Association for Cancer Research.

PY - 2022/9/2

Y1 - 2022/9/2

N2 - BACKGROUND: Over 20 susceptibility single-nucleotide polymorphisms (SNP) have been identified for esophageal adenocarcinoma (EAC) and its precursor, Barrett esophagus (BE), explaining a small portion of heritability. METHODS: Using genetic data from 4,323 BE and 4,116 EAC patients aggregated by international consortia including the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON), we conducted a comprehensive transcriptome-wide association study (TWAS) for BE/EAC, leveraging Genotype Tissue Expression (GTEx) gene-expression data from six tissue types of plausible relevance to EAC etiology: mucosa and muscularis from the esophagus, gastroesophageal (GE) junction, stomach, whole blood, and visceral adipose. Two analytical approaches were taken: standard TWAS using the predicted gene expression from local expression quantitative trait loci (eQTL), and set-based SKAT association using selected eQTLs that predict the gene expression. RESULTS: Although the standard approach did not identify significant signals, the eQTL set-based approach identified eight novel associations, three of which were validated in independent external data (eQTL SNP sets for EXOC3, ZNF641, and HSP90AA1). CONCLUSIONS: This study identified novel genetic susceptibility loci for EAC and BE using an eQTL set-based genetic association approach. IMPACT: This study expanded the pool of genetic susceptibility loci for EAC and BE, suggesting the potential of the eQTL set-based genetic association approach as an alternative method for TWAS analysis.

AB - BACKGROUND: Over 20 susceptibility single-nucleotide polymorphisms (SNP) have been identified for esophageal adenocarcinoma (EAC) and its precursor, Barrett esophagus (BE), explaining a small portion of heritability. METHODS: Using genetic data from 4,323 BE and 4,116 EAC patients aggregated by international consortia including the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON), we conducted a comprehensive transcriptome-wide association study (TWAS) for BE/EAC, leveraging Genotype Tissue Expression (GTEx) gene-expression data from six tissue types of plausible relevance to EAC etiology: mucosa and muscularis from the esophagus, gastroesophageal (GE) junction, stomach, whole blood, and visceral adipose. Two analytical approaches were taken: standard TWAS using the predicted gene expression from local expression quantitative trait loci (eQTL), and set-based SKAT association using selected eQTLs that predict the gene expression. RESULTS: Although the standard approach did not identify significant signals, the eQTL set-based approach identified eight novel associations, three of which were validated in independent external data (eQTL SNP sets for EXOC3, ZNF641, and HSP90AA1). CONCLUSIONS: This study identified novel genetic susceptibility loci for EAC and BE using an eQTL set-based genetic association approach. IMPACT: This study expanded the pool of genetic susceptibility loci for EAC and BE, suggesting the potential of the eQTL set-based genetic association approach as an alternative method for TWAS analysis.

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U2 - 10.1158/1055-9965.EPI-22-0096

DO - 10.1158/1055-9965.EPI-22-0096

M3 - Article

C2 - 35709760

AN - SCOPUS:85137136814

SN - 1055-9965

VL - 31

SP - 1735

EP - 1745

JO - Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology

JF - Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology

IS - 9

ER -

Wang X, Gharahkhani P, Levine DM, Fitzgerald RC, Gockel I, Corley DA et al. eQTL Set-Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2022 Sept 2;31(9):1735-1745. doi: 10.1158/1055-9965.EPI-22-0096

eQTL Set-Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma

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