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

Authors: Lu, Y.; Beeghly-Fadiel, A.; Wu, L.; Guo, X.; Li, B.; Schildkraut, J. M.; Im, H. K.; Chen, Y. A.; Permuth, J. B.; Reid, B. M.; Teer, J. K.; Moysich, K. B.; Andrulis, I. L.; Anton-Culver, H.; Arun, B. K.; Bandera, E. V.; Barkardottir, R. B.; Barnes, D. R.; Benitez, J.; Bjorge, L.; Brenton, J.; Butzow, R.; Caldes, T.; Caligo, M. A.; Campbell, I.; Chang-Claude, J.; Claes, K. B. M.; Couch, F. J.; Cramer, D. W.; Daly, M. B.; deFazio, A.; Dennis, J.; Diez, O.; Domchek, S. M.; Dörk, T.; Easton, D. F.; Eccles, D. M.; Fasching, P. A.; Fortner, R. T.; Fountzilas, G.; Friedman, E.; Ganz, P. A.; Garber, J.; Giles, G. G.; Godwin, A. K.; Goldgar, D. E.; Goodman, M. T.; Greene, M. H.; Gronwald, J.; Hamann, U.; Heitz, F.; Hildebrandt, M. A. T.; Høgdall, C. K.; Hollestelle, A.; Hulick, P. J.; Huntsman, D. G.; Imyanitov, E. N.; Isaacs, C.; Jakubowska, A.; James, P.; Karlan, B. Y.; Kelemen, L. E.; Kiemeney, L. A.; Kjaer, S. K.; Kwong, A.; Le, N. D.; Leslie, G.; Lesueur, F.; Levine, D. A.; Mattiello, A.; May, T.; McGuffog, L.; McNeish, I. A.; Merritt, M. A.; Modugno, F.; Montagna, M.; Neuhausen, S. L.; Nevanlinna, H.; Nielsen, F. C.; Nikitina-Zake, L.; Nussbaum, R. L.; Offit, K.; Olah, E.; Olopade, O. I.; Olson, S. H.; Olsson, H. K.; Osorio, A.; Park, S. K.; Parsons, M. T.; Peeters, P. H. M.; Pejovic, T.; Peterlongo, P.; Phelan, C. M.; Pujana, M. A.; Ramus, S. J.; Rennert, G.; Risch, H.; Rodriguez, G. C.; Rodríguez-Antona, C.; Romieu, I.; Rookus, M. A.; Rossing, M. A.; Rzepecka, I. K.; Sandler, D. P.; Schmutzler, R. K.; Setiawan, V. W.; Sharma, P.; Sieh, W.; Simard, J.; Singer, C. F.; Song, H.; Southey, M. C.; Spurdle, A. B.; Sutphen, R.; Swerdlow, A. J.; Teixeira, M. R.; Teo, S. H.; Thomassen, M.; Tischkowitz, M.; Toland, A. E.; Trichopoulou, A.; Tung, N.; Tworoger, S. S.; van Rensburg, E. J.; Vanderstichele, A.; Vega, A.; Velez Edwards, D.; Webb, P. M.; Weitzel, J. N.; Wentzensen, N.; White, E.; Wolk, A.; Wu, A. H.; Yannoukakos, D.; Zorn, K. K.; Gayther, S. A.; Antoniou, A. C.; Berchuck, A.; Goode, E. L.; Chenevix-Trench, G.; Sellers, T. A.; Pharoah, P. D. P.; Zheng, W.; Long, J.
Article 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 1⁄4 5.08, P 1⁄4 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. © 2018 American Association for Cancer Research.
Journal Title: Cancer Research
Volume: 78
Issue: 18
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2018-09-15
Start Page: 5419
End Page: 5430
Language: English
DOI: 10.1158/0008-5472.can-18-0951
PROVIDER: scopus
PMCID: PMC6139053
PUBMED: 30054336
Notes: Article -- Export Date: 1 October 2018 -- Source: Scopus
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MSK Authors
  1. Kenneth Offit
    485 Offit
  2. Sara H Olson
    205 Olson
  3. Douglas A Levine
    351 Levine