Ερευνητικό υλικό ΕΚΠΑ

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

Αγγλικά

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 x 10(-6), we identified 35 genes, including FZD4 at 11q14.2 (Z =
5.08, P = 3.83 x 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 x 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.
(C) 2018 AACR.

2018

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

Current Cancer Research

AMER ASSOC CANCER RESEARCH

78

18

5419-5430

https://doi.org/10.1158/0008-5472.CAN-18-0951

10.1158/0008-5472.CAN-18-0951

https://pergamos.lib.uoa.gr/uoa/dl/object/3181463