A transcriptome-wide association study among 97,898 women to identify candidate susceptibility genes for epithelial ovarian cancer risk

Yingchang Lu, Alicia Beeghly-Fadiel, Lang Wu, Xingyi Guo, Bingshan Li, Joellen M. Schildkraut, Hae Kyung Im, Yian A. Chen, Jennifer B. Permuth, Brett M. Reid, Jamie K. Teer, Kirsten B. Moysich, Irene L. Andrulis, Hoda Anton-Culver, Banu K. Arun, Elisa V. Bandera, Rosa B. Barkardottir, Daniel R. Barnes, Javier Benitez, Line Bjorge & 124 others James Brenton, Ralf Butzow, Trinidad Caldes, Maria A. Caligo, Ian Campbell, Jenny Chang-Claude, Kathleen B.M. Claes, Fergus J. Couch, Daniel W. Cramer, Mary B. Daly, Anna DeFazio, Joe Dennis, Orland Diez, Susan M. Domchek, Thilo D rk, Douglas F. Easton, Diana M. Eccles, Peter A. Fasching, Ren e.T. Fortner, George Fountzilas, Eitan Friedman, Patricia A. Ganz, Judy Garber, Graham G. Giles, Andrew K. Godwin, David E. Goldgar, Marc T. Goodman, Mark H. Greene, Jacek Gronwald, Ute Hamann, Florian Heitz, Michelle A.T. Hildebrandt, Claus K. Høgdall, Antoinette Hollestelle, Peter J. Hulick, David G. Huntsman, Evgeny N. Imyanitov, Claudine Isaacs, Anna Jakubowska, Paul James, Beth Y. Karlan, Linda E. Kelemen, Lambertus A. Kiemeney, Susanne K. Kjaer, Ava Kwong, Nhu D. Le, Goska Leslie, Fabienne Lesueur, Douglas A. Levine, Amalia Mattiello, Taymaa May, Lesley McGuffog, Iain A. McNeish, Melissa A. Merritt, Francesmary Modugno, Marco Montagna, Susan L. Neuhausen, Heli Nevanlinna, Finn C. Nielsen, Liene Nikitina-Zake, Robert L. Nussbaum, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Sara H. Olson, H. kan Olsson, Ana Osorio, Sue K. Park, Michael T. Parsons, Petra H.M. Peeters, Tanja Pejovic, Paolo Peterlongo, Catherine M. Phelan, Miquel Angel Pujana, Susan J. Ramus, Gad Rennert, Harvey Risch, Gustavo C. Rodriguez, Cristina Rodríguez-Antona, Isabelle Romieu, Matti A. Rookus, Mary Anne Rossing, Iwona K. Rzepecka, Dale P. Sandler, Rita K. Schmutzler, Veronica W. Setiawan, Priyanka Sharma, Weiva Sieh, Jacques Simard, Christian F. Singer, Honglin Song, Melissa C. Southey, Amanda B. Spurdle, Rebecca Sutphen, Anthony J. Swerdlow, Manuel R. Teixeira, Soo H. Teo, Mads Thomassen, Marc Tischkowitz, Amanda E. Toland, Antonia Trichopoulou, Nadine Tung, Shelley S. Tworoger, Elizabeth J. Van Rensburg, Adriaan Vanderstichele, Ana Vega, Digna Velez Edwards, Penelope M. Webb, Jeffrey N. Weitzel, Nicolas Wentzensen, Emily White, Alicja Wolk, Anna H. Wu, Drakoulis Yannoukakos, Kristin K. Zorn, Simon A. Gayther, Antonis C. Antoniou, Andrew Berchuck, Ellen L. Goode, Georgia Chenevix-Trench, Thomas A. Sellers, Paul D.P. Pharoah, Wei Zheng, Jirong Long

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 106, we identified 35 genes, including FZD4 at 11q14.2 (Z ¼ 5.08, P ¼ 3.83 107, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 103). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.

Original languageEnglish
Pages (from-to)5419-5430
Number of pages12
JournalCancer Research
Volume78
Issue number18
DOIs
Publication statusPublished - 15 Sep 2018

Cite this

Lu, Yingchang ; Beeghly-Fadiel, Alicia ; Wu, Lang ; Guo, Xingyi ; Li, Bingshan ; Schildkraut, Joellen M. ; Im, Hae Kyung ; Chen, Yian A. ; Permuth, Jennifer B. ; Reid, Brett M. ; Teer, Jamie K. ; Moysich, Kirsten B. ; Andrulis, Irene L. ; Anton-Culver, Hoda ; Arun, Banu K. ; Bandera, Elisa V. ; Barkardottir, Rosa B. ; Barnes, Daniel R. ; Benitez, Javier ; Bjorge, Line ; Brenton, James ; Butzow, Ralf ; Caldes, Trinidad ; Caligo, Maria A. ; Campbell, Ian ; Chang-Claude, Jenny ; Claes, Kathleen B.M. ; Couch, Fergus J. ; Cramer, Daniel W. ; Daly, Mary B. ; DeFazio, Anna ; Dennis, Joe ; Diez, Orland ; Domchek, Susan M. ; D rk, Thilo ; Easton, Douglas F. ; Eccles, Diana M. ; Fasching, Peter A. ; Fortner, Ren e.T. ; Fountzilas, George ; Friedman, Eitan ; Ganz, Patricia A. ; Garber, Judy ; Giles, Graham G. ; Godwin, Andrew K. ; Goldgar, David E. ; Goodman, Marc T. ; Greene, Mark H. ; Gronwald, Jacek ; Hamann, Ute ; Heitz, Florian ; Hildebrandt, Michelle A.T. ; Høgdall, Claus K. ; Hollestelle, Antoinette ; Hulick, Peter J. ; Huntsman, David G. ; Imyanitov, Evgeny N. ; Isaacs, Claudine ; Jakubowska, Anna ; James, Paul ; Karlan, Beth Y. ; Kelemen, Linda E. ; Kiemeney, Lambertus A. ; Kjaer, Susanne K. ; Kwong, Ava ; Le, Nhu D. ; Leslie, Goska ; Lesueur, Fabienne ; Levine, Douglas A. ; Mattiello, Amalia ; May, Taymaa ; McGuffog, Lesley ; McNeish, Iain A. ; Merritt, Melissa A. ; Modugno, Francesmary ; Montagna, Marco ; Neuhausen, Susan L. ; Nevanlinna, Heli ; Nielsen, Finn C. ; Nikitina-Zake, Liene ; Nussbaum, Robert L. ; Offit, Kenneth ; Olah, Edith ; Olopade, Olufunmilayo I. ; Olson, Sara H. ; Olsson, H. kan ; Osorio, Ana ; Park, Sue K. ; Parsons, Michael T. ; Peeters, Petra H.M. ; Pejovic, Tanja ; Peterlongo, Paolo ; Phelan, Catherine M. ; Pujana, Miquel Angel ; Ramus, Susan J. ; Rennert, Gad ; Risch, Harvey ; Rodriguez, Gustavo C. ; Rodríguez-Antona, Cristina ; Romieu, Isabelle ; Rookus, Matti A. ; Rossing, Mary Anne ; Rzepecka, Iwona K. ; Sandler, Dale P. ; Schmutzler, Rita K. ; Setiawan, Veronica W. ; Sharma, Priyanka ; Sieh, Weiva ; Simard, Jacques ; Singer, Christian F. ; Song, Honglin ; Southey, Melissa C. ; Spurdle, Amanda B. ; Sutphen, Rebecca ; Swerdlow, Anthony J. ; Teixeira, Manuel R. ; Teo, Soo H. ; Thomassen, Mads ; Tischkowitz, Marc ; Toland, Amanda E. ; Trichopoulou, Antonia ; Tung, Nadine ; Tworoger, Shelley S. ; Van Rensburg, Elizabeth J. ; Vanderstichele, Adriaan ; Vega, Ana ; Edwards, Digna Velez ; Webb, Penelope M. ; Weitzel, Jeffrey N. ; Wentzensen, Nicolas ; White, Emily ; Wolk, Alicja ; Wu, Anna H. ; Yannoukakos, Drakoulis ; Zorn, Kristin K. ; Gayther, Simon A. ; Antoniou, Antonis C. ; Berchuck, Andrew ; Goode, Ellen L. ; Chenevix-Trench, Georgia ; Sellers, Thomas A. ; Pharoah, Paul D.P. ; Zheng, Wei ; Long, Jirong. / A transcriptome-wide association study among 97,898 women to identify candidate susceptibility genes for epithelial ovarian cancer risk. In: Cancer Research. 2018 ; Vol. 78, No. 18. pp. 5419-5430.
@article{64c7b78d871643d7b3b82ea119a9ce2a,
title = "A transcriptome-wide association study among 97,898 women to identify candidate susceptibility genes for epithelial ovarian cancer risk",
abstract = "Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 106, we identified 35 genes, including FZD4 at 11q14.2 (Z ¼ 5.08, P ¼ 3.83 107, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 103). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.",
author = "Yingchang Lu and Alicia Beeghly-Fadiel and Lang Wu and Xingyi Guo and Bingshan Li and Schildkraut, {Joellen M.} and Im, {Hae Kyung} and Chen, {Yian A.} and Permuth, {Jennifer B.} and Reid, {Brett M.} and Teer, {Jamie K.} and Moysich, {Kirsten B.} and Andrulis, {Irene L.} and Hoda Anton-Culver and Arun, {Banu K.} and Bandera, {Elisa V.} and Barkardottir, {Rosa B.} and Barnes, {Daniel R.} and Javier Benitez and Line Bjorge and James Brenton and Ralf Butzow and Trinidad Caldes and Caligo, {Maria A.} and Ian Campbell and Jenny Chang-Claude and Claes, {Kathleen B.M.} and Couch, {Fergus J.} and Cramer, {Daniel W.} and Daly, {Mary B.} and Anna DeFazio and Joe Dennis and Orland Diez and Domchek, {Susan M.} and {D rk}, Thilo and Easton, {Douglas F.} and Eccles, {Diana M.} and Fasching, {Peter A.} and Fortner, {Ren e.T.} and George Fountzilas and Eitan Friedman and Ganz, {Patricia A.} and Judy Garber and Giles, {Graham G.} and Godwin, {Andrew K.} and Goldgar, {David E.} and Goodman, {Marc T.} and Greene, {Mark H.} and Jacek Gronwald and Ute Hamann and Florian Heitz and Hildebrandt, {Michelle A.T.} and H{\o}gdall, {Claus K.} and Antoinette Hollestelle and Hulick, {Peter J.} and Huntsman, {David G.} and Imyanitov, {Evgeny N.} and Claudine Isaacs and Anna Jakubowska and Paul James and Karlan, {Beth Y.} and Kelemen, {Linda E.} and Kiemeney, {Lambertus A.} and Kjaer, {Susanne K.} and Ava Kwong and Le, {Nhu D.} and Goska Leslie and Fabienne Lesueur and Levine, {Douglas A.} and Amalia Mattiello and Taymaa May and Lesley McGuffog and McNeish, {Iain A.} and Merritt, {Melissa A.} and Francesmary Modugno and Marco Montagna and Neuhausen, {Susan L.} and Heli Nevanlinna and Nielsen, {Finn C.} and Liene Nikitina-Zake and Nussbaum, {Robert L.} and Kenneth Offit and Edith Olah and Olopade, {Olufunmilayo I.} and Olson, {Sara H.} and Olsson, {H. kan} and Ana Osorio and Park, {Sue K.} and Parsons, {Michael T.} and Peeters, {Petra H.M.} and Tanja Pejovic and Paolo Peterlongo and Phelan, {Catherine M.} and Pujana, {Miquel Angel} and Ramus, {Susan J.} and Gad Rennert and Harvey Risch and Rodriguez, {Gustavo C.} and Cristina Rodr{\'i}guez-Antona and Isabelle Romieu and Rookus, {Matti A.} and Rossing, {Mary Anne} and Rzepecka, {Iwona K.} and Sandler, {Dale P.} and Schmutzler, {Rita K.} and Setiawan, {Veronica W.} and Priyanka Sharma and Weiva Sieh and Jacques Simard and Singer, {Christian F.} and Honglin Song and Southey, {Melissa C.} and Spurdle, {Amanda B.} and Rebecca Sutphen and Swerdlow, {Anthony J.} and Teixeira, {Manuel R.} and Teo, {Soo H.} and Mads Thomassen and Marc Tischkowitz and Toland, {Amanda E.} and Antonia Trichopoulou and Nadine Tung and Tworoger, {Shelley S.} and {Van Rensburg}, {Elizabeth J.} and Adriaan Vanderstichele and Ana Vega and Edwards, {Digna Velez} and Webb, {Penelope M.} and Weitzel, {Jeffrey N.} and Nicolas Wentzensen and Emily White and Alicja Wolk and Wu, {Anna H.} and Drakoulis Yannoukakos and Zorn, {Kristin K.} and Gayther, {Simon A.} and Antoniou, {Antonis C.} and Andrew Berchuck and Goode, {Ellen L.} and Georgia Chenevix-Trench and Sellers, {Thomas A.} and Pharoah, {Paul D.P.} and Wei Zheng and Jirong Long",
year = "2018",
month = "9",
day = "15",
doi = "10.1158/0008-5472.CAN-18-0951",
language = "English",
volume = "78",
pages = "5419--5430",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research",
number = "18",

}

Lu, Y, Beeghly-Fadiel, A, Wu, L, Guo, X, Li, B, Schildkraut, JM, Im, HK, Chen, YA, Permuth, JB, Reid, BM, Teer, JK, Moysich, KB, Andrulis, IL, Anton-Culver, H, Arun, BK, Bandera, EV, Barkardottir, RB, Barnes, DR, Benitez, J, Bjorge, L, Brenton, J, Butzow, R, Caldes, T, Caligo, MA, Campbell, I, Chang-Claude, J, Claes, KBM, Couch, FJ, Cramer, DW, Daly, MB, DeFazio, A, Dennis, J, Diez, O, Domchek, SM, D rk, T, Easton, DF, Eccles, DM, Fasching, PA, Fortner, RET, Fountzilas, G, Friedman, E, Ganz, PA, Garber, J, Giles, GG, Godwin, AK, Goldgar, DE, Goodman, MT, Greene, MH, Gronwald, J, Hamann, U, Heitz, F, Hildebrandt, MAT, Høgdall, CK, Hollestelle, A, Hulick, PJ, Huntsman, DG, Imyanitov, EN, Isaacs, C, Jakubowska, A, James, P, Karlan, BY, Kelemen, LE, Kiemeney, LA, Kjaer, SK, Kwong, A, Le, ND, Leslie, G, Lesueur, F, Levine, DA, Mattiello, A, May, T, McGuffog, L, McNeish, IA, Merritt, MA, Modugno, F, Montagna, M, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, Nikitina-Zake, L, Nussbaum, RL, Offit, K, Olah, E, Olopade, OI, Olson, SH, Olsson, HK, Osorio, A, Park, SK, Parsons, MT, Peeters, PHM, Pejovic, T, Peterlongo, P, Phelan, CM, Pujana, MA, Ramus, SJ, Rennert, G, Risch, H, Rodriguez, GC, Rodríguez-Antona, C, Romieu, I, Rookus, MA, Rossing, MA, Rzepecka, IK, Sandler, DP, Schmutzler, RK, Setiawan, VW, Sharma, P, Sieh, W, Simard, J, Singer, CF, Song, H, Southey, MC, Spurdle, AB, Sutphen, R, Swerdlow, AJ, Teixeira, MR, Teo, SH, Thomassen, M, Tischkowitz, M, Toland, AE, Trichopoulou, A, Tung, N, Tworoger, SS, Van Rensburg, EJ, Vanderstichele, A, Vega, A, Edwards, DV, Webb, PM, Weitzel, JN, Wentzensen, N, White, E, Wolk, A, Wu, AH, Yannoukakos, D, Zorn, KK, Gayther, SA, Antoniou, AC, Berchuck, A, Goode, EL, Chenevix-Trench, G, Sellers, TA, Pharoah, PDP, Zheng, W & Long, J 2018, 'A transcriptome-wide association study among 97,898 women to identify candidate susceptibility genes for epithelial ovarian cancer risk' Cancer Research, vol. 78, no. 18, pp. 5419-5430. https://doi.org/10.1158/0008-5472.CAN-18-0951

A transcriptome-wide association study among 97,898 women to identify candidate susceptibility genes for epithelial ovarian cancer risk. / Lu, Yingchang; Beeghly-Fadiel, Alicia; Wu, Lang; Guo, Xingyi; Li, Bingshan; Schildkraut, Joellen M.; Im, Hae Kyung; Chen, Yian A.; Permuth, Jennifer B.; Reid, Brett M.; Teer, Jamie K.; Moysich, Kirsten B.; Andrulis, Irene L.; Anton-Culver, Hoda; Arun, Banu K.; Bandera, Elisa V.; Barkardottir, Rosa B.; Barnes, Daniel R.; Benitez, Javier; Bjorge, Line; Brenton, James; Butzow, Ralf; Caldes, Trinidad; Caligo, Maria A.; Campbell, Ian; Chang-Claude, Jenny; Claes, Kathleen B.M.; Couch, Fergus J.; Cramer, Daniel W.; Daly, Mary B.; DeFazio, Anna; Dennis, Joe; Diez, Orland; Domchek, Susan M.; D rk, Thilo; Easton, Douglas F.; Eccles, Diana M.; Fasching, Peter A.; Fortner, Ren e.T.; Fountzilas, George; Friedman, Eitan; Ganz, Patricia A.; Garber, Judy; Giles, Graham G.; Godwin, Andrew K.; Goldgar, David E.; Goodman, Marc T.; Greene, Mark H.; Gronwald, Jacek; Hamann, Ute; Heitz, Florian; Hildebrandt, Michelle A.T.; Høgdall, Claus K.; Hollestelle, Antoinette; Hulick, Peter J.; Huntsman, David G.; Imyanitov, Evgeny N.; Isaacs, Claudine; Jakubowska, Anna; James, Paul; Karlan, Beth Y.; Kelemen, Linda E.; Kiemeney, Lambertus A.; Kjaer, Susanne K.; Kwong, Ava; Le, Nhu D.; Leslie, Goska; Lesueur, Fabienne; Levine, Douglas A.; Mattiello, Amalia; May, Taymaa; McGuffog, Lesley; McNeish, Iain A.; Merritt, Melissa A.; Modugno, Francesmary; Montagna, Marco; Neuhausen, Susan L.; Nevanlinna, Heli; Nielsen, Finn C.; Nikitina-Zake, Liene; Nussbaum, Robert L.; Offit, Kenneth; Olah, Edith; Olopade, Olufunmilayo I.; Olson, Sara H.; Olsson, H. kan; Osorio, Ana; Park, Sue K.; Parsons, Michael T.; Peeters, Petra H.M.; Pejovic, Tanja; Peterlongo, Paolo; Phelan, Catherine M.; Pujana, Miquel Angel; Ramus, Susan J.; Rennert, Gad; Risch, Harvey; Rodriguez, Gustavo C.; Rodríguez-Antona, Cristina; Romieu, Isabelle; Rookus, Matti A.; Rossing, Mary Anne; Rzepecka, Iwona K.; Sandler, Dale P.; Schmutzler, Rita K.; Setiawan, Veronica W.; Sharma, Priyanka; Sieh, Weiva; Simard, Jacques; Singer, Christian F.; Song, Honglin; Southey, Melissa C.; Spurdle, Amanda B.; Sutphen, Rebecca; Swerdlow, Anthony J.; Teixeira, Manuel R.; Teo, Soo H.; Thomassen, Mads; Tischkowitz, Marc; Toland, Amanda E.; Trichopoulou, Antonia; Tung, Nadine; Tworoger, Shelley S.; Van Rensburg, Elizabeth J.; Vanderstichele, Adriaan; Vega, Ana; Edwards, Digna Velez; Webb, Penelope M.; Weitzel, Jeffrey N.; Wentzensen, Nicolas; White, Emily; Wolk, Alicja; Wu, Anna H.; Yannoukakos, Drakoulis; Zorn, Kristin K.; Gayther, Simon A.; Antoniou, Antonis C.; Berchuck, Andrew; Goode, Ellen L.; Chenevix-Trench, Georgia; Sellers, Thomas A.; Pharoah, Paul D.P.; Zheng, Wei; Long, Jirong.

In: Cancer Research, Vol. 78, No. 18, 15.09.2018, p. 5419-5430.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - A transcriptome-wide association study among 97,898 women to identify candidate susceptibility genes for epithelial ovarian cancer risk

AU - Lu, Yingchang

AU - Beeghly-Fadiel, Alicia

AU - Wu, Lang

AU - Guo, Xingyi

AU - Li, Bingshan

AU - Schildkraut, Joellen M.

AU - Im, Hae Kyung

AU - Chen, Yian A.

AU - Permuth, Jennifer B.

AU - Reid, Brett M.

AU - Teer, Jamie K.

AU - Moysich, Kirsten B.

AU - Andrulis, Irene L.

AU - Anton-Culver, Hoda

AU - Arun, Banu K.

AU - Bandera, Elisa V.

AU - Barkardottir, Rosa B.

AU - Barnes, Daniel R.

AU - Benitez, Javier

AU - Bjorge, Line

AU - Brenton, James

AU - Butzow, Ralf

AU - Caldes, Trinidad

AU - Caligo, Maria A.

AU - Campbell, Ian

AU - Chang-Claude, Jenny

AU - Claes, Kathleen B.M.

AU - Couch, Fergus J.

AU - Cramer, Daniel W.

AU - Daly, Mary B.

AU - DeFazio, Anna

AU - Dennis, Joe

AU - Diez, Orland

AU - Domchek, Susan M.

AU - D rk, Thilo

AU - Easton, Douglas F.

AU - Eccles, Diana M.

AU - Fasching, Peter A.

AU - Fortner, Ren e.T.

AU - Fountzilas, George

AU - Friedman, Eitan

AU - Ganz, Patricia A.

AU - Garber, Judy

AU - Giles, Graham G.

AU - Godwin, Andrew K.

AU - Goldgar, David E.

AU - Goodman, Marc T.

AU - Greene, Mark H.

AU - Gronwald, Jacek

AU - Hamann, Ute

AU - Heitz, Florian

AU - Hildebrandt, Michelle A.T.

AU - Høgdall, Claus K.

AU - Hollestelle, Antoinette

AU - Hulick, Peter J.

AU - Huntsman, David G.

AU - Imyanitov, Evgeny N.

AU - Isaacs, Claudine

AU - Jakubowska, Anna

AU - James, Paul

AU - Karlan, Beth Y.

AU - Kelemen, Linda E.

AU - Kiemeney, Lambertus A.

AU - Kjaer, Susanne K.

AU - Kwong, Ava

AU - Le, Nhu D.

AU - Leslie, Goska

AU - Lesueur, Fabienne

AU - Levine, Douglas A.

AU - Mattiello, Amalia

AU - May, Taymaa

AU - McGuffog, Lesley

AU - McNeish, Iain A.

AU - Merritt, Melissa A.

AU - Modugno, Francesmary

AU - Montagna, Marco

AU - Neuhausen, Susan L.

AU - Nevanlinna, Heli

AU - Nielsen, Finn C.

AU - Nikitina-Zake, Liene

AU - Nussbaum, Robert L.

AU - Offit, Kenneth

AU - Olah, Edith

AU - Olopade, Olufunmilayo I.

AU - Olson, Sara H.

AU - Olsson, H. kan

AU - Osorio, Ana

AU - Park, Sue K.

AU - Parsons, Michael T.

AU - Peeters, Petra H.M.

AU - Pejovic, Tanja

AU - Peterlongo, Paolo

AU - Phelan, Catherine M.

AU - Pujana, Miquel Angel

AU - Ramus, Susan J.

AU - Rennert, Gad

AU - Risch, Harvey

AU - Rodriguez, Gustavo C.

AU - Rodríguez-Antona, Cristina

AU - Romieu, Isabelle

AU - Rookus, Matti A.

AU - Rossing, Mary Anne

AU - Rzepecka, Iwona K.

AU - Sandler, Dale P.

AU - Schmutzler, Rita K.

AU - Setiawan, Veronica W.

AU - Sharma, Priyanka

AU - Sieh, Weiva

AU - Simard, Jacques

AU - Singer, Christian F.

AU - Song, Honglin

AU - Southey, Melissa C.

AU - Spurdle, Amanda B.

AU - Sutphen, Rebecca

AU - Swerdlow, Anthony J.

AU - Teixeira, Manuel R.

AU - Teo, Soo H.

AU - Thomassen, Mads

AU - Tischkowitz, Marc

AU - Toland, Amanda E.

AU - Trichopoulou, Antonia

AU - Tung, Nadine

AU - Tworoger, Shelley S.

AU - Van Rensburg, Elizabeth J.

AU - Vanderstichele, Adriaan

AU - Vega, Ana

AU - Edwards, Digna Velez

AU - Webb, Penelope M.

AU - Weitzel, Jeffrey N.

AU - Wentzensen, Nicolas

AU - White, Emily

AU - Wolk, Alicja

AU - Wu, Anna H.

AU - Yannoukakos, Drakoulis

AU - Zorn, Kristin K.

AU - Gayther, Simon A.

AU - Antoniou, Antonis C.

AU - Berchuck, Andrew

AU - Goode, Ellen L.

AU - Chenevix-Trench, Georgia

AU - Sellers, Thomas A.

AU - Pharoah, Paul D.P.

AU - Zheng, Wei

AU - Long, Jirong

PY - 2018/9/15

Y1 - 2018/9/15

N2 - Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 106, we identified 35 genes, including FZD4 at 11q14.2 (Z ¼ 5.08, P ¼ 3.83 107, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 103). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.

AB - Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 106, we identified 35 genes, including FZD4 at 11q14.2 (Z ¼ 5.08, P ¼ 3.83 107, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 103). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.

UR - http://www.scopus.com/inward/record.url?scp=85053297183&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-18-0951

DO - 10.1158/0008-5472.CAN-18-0951

M3 - Article

VL - 78

SP - 5419

EP - 5430

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 18

ER -