A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk.

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 × 10-6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10-7, 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 × 10-3). 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.Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419-30. ©2018 AACR.

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

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