| Literature DB >> 30054336 |
Yingchang Lu1, Alicia Beeghly-Fadiel1, Lang Wu1, Xingyi Guo1, Bingshan Li2, Joellen M Schildkraut3, Hae Kyung Im4, Yian A Chen5, Jennifer B Permuth6, Brett M Reid6, Jamie K Teer5, Kirsten B Moysich7, Irene L Andrulis8,9, Hoda Anton-Culver10, Banu K Arun11, Elisa V Bandera12, Rosa B Barkardottir13,14, Daniel R Barnes15, Javier Benitez16,17, Line Bjorge18,19, James Brenton20, Ralf Butzow21, Trinidad Caldes22, Maria A Caligo23, Ian Campbell24,25,26, Jenny Chang-Claude27,28, Kathleen B M Claes29, Fergus J Couch30, Daniel W Cramer31,32, Mary B Daly33, Anna deFazio34,35, Joe Dennis15, Orland Diez36, Susan M Domchek37, Thilo Dörk38, Douglas F Easton15,39, Diana M Eccles40, Peter A Fasching41,42, Renée T Fortner27, George Fountzilas43, Eitan Friedman44,45, Patricia A Ganz46, Judy Garber47, Graham G Giles48,49,50, Andrew K Godwin51, David E Goldgar52, Marc T Goodman53,54, Mark H Greene55, Jacek Gronwald56, Ute Hamann57, Florian Heitz58,59, Michelle A T Hildebrandt60, Claus K Høgdall61, Antoinette Hollestelle62, Peter J Hulick63,64, David G Huntsman65,66,67, Evgeny N Imyanitov68, Claudine Isaacs69, Anna Jakubowska56, Paul James25,70, Beth Y Karlan71, Linda E Kelemen72, Lambertus A Kiemeney73, Susanne K Kjaer74,75, Ava Kwong76,77,78, Nhu D Le79, Goska Leslie15, Fabienne Lesueur80,81,82,83, Douglas A Levine84,85, Amalia Mattiello86, Taymaa May87, Lesley McGuffog15, Iain A McNeish88, Melissa A Merritt89,90, Francesmary Modugno91,92,93, Marco Montagna94, Susan L Neuhausen95, Heli Nevanlinna96, Finn C Nielsen97, Liene Nikitina-Zake98, Robert L Nussbaum99, Kenneth Offit100,101, Edith Olah102, Olufunmilayo I Olopade103, Sara H Olson104, Håkan Olsson105, Ana Osorio16,106, Sue K Park107,108,109, Michael T Parsons110, Petra H M Peeters111, Tanja Pejovic112,113, Paolo Peterlongo114, Catherine M Phelan6, Miquel Angel Pujana115, Susan J Ramus116,117, Gad Rennert118, Harvey Risch119, Gustavo C Rodriguez120, Cristina Rodríguez-Antona121, Isabelle Romieu122, Matti A Rookus123, Mary Anne Rossing124,125, Iwona K Rzepecka126, Dale P Sandler127, Rita K Schmutzler128,129, Veronica W Setiawan130, Priyanka Sharma131, Weiva Sieh132, Jacques Simard133, Christian F Singer134, Honglin Song39, Melissa C Southey26, Amanda B Spurdle110, Rebecca Sutphen135, Anthony J Swerdlow136,137, Manuel R Teixeira138,139, Soo H Teo140,141, Mads Thomassen142, Marc Tischkowitz143,144, Amanda E Toland145, Antonia Trichopoulou146,147, Nadine Tung148, Shelley S Tworoger6,149, Elizabeth J van Rensburg150, Adriaan Vanderstichele151, Ana Vega152, Digna Velez Edwards153, Penelope M Webb154, Jeffrey N Weitzel155, Nicolas Wentzensen156, Emily White157,125, Alicja Wolk158, Anna H Wu130, Drakoulis Yannoukakos159, Kristin K Zorn160, Simon A Gayther130,161,162, Antonis C Antoniou15, Andrew Berchuck163, Ellen L Goode164, Georgia Chenevix-Trench110, Thomas A Sellers6, Paul D P Pharoah15,39, Wei Zheng1, Jirong Long165.
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 × 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. ©2018 American Association for Cancer Research.Entities:
Mesh：
Year: 2018 PMID： 30054336 PMCID： PMC6139053 DOI： 10.1158/0008-5472.CAN-18-0951
Source DB: PubMed Journal: Cancer Res ISSN： 0008-5472 Impact factor: 13.312