A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk
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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; Dörk, Thilo; Easton, Douglas F; Eccles, Diana M; Fasching, Peter A; Fortner, Renée 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, Håkan; 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 RES, Vol. 78, No. 18, 15.09.2018, p. 5419-5430.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 - 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, Håkan
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
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.
KW - Journal Article
U2 - 10.1158/0008-5472.CAN-18-0951
DO - 10.1158/0008-5472.CAN-18-0951
M3 - SCORING: Journal article
C2 - 30054336
VL - 78
SP - 5419
EP - 5430
JO - CANCER RES
JF - CANCER RES
SN - 0008-5472
IS - 18
ER -