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 - Dörk, Thilo

AU - Easton, Douglas F

AU - Eccles, Diana M

AU - Fasching, Peter A

AU - Fortner, Renée 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 - Høgdall, Claus K

AU - Kjaer, Susanne K

AU - Nielsen, Finn C

AU - et al.

N1 - ©2018 American Association for Cancer Research.

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 × 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.

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 × 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.

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

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

M3 - Journal article

C2 - 30054336

VL - 78

SP - 5419

EP - 5430

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 18

ER -