Genome-wide association study for ovarian cancer susceptibility using pooled DNA.
Recent Genome-Wide Association Studies (GWAS) have identified four low-penetrance ovarian cancer susceptibility loci. We hypothesized that further moderate- or low-penetrance variants exist among the subset of single-nucleotide polymorphisms (SNPs) not well tagged by the genotyping arrays used in the previous studies, which would account for some of the remaining risk. We therefore conducted a time- and cost-effective stage 1 GWAS on 342 invasive serous cases and 643 controls genotyped on pooled DNA using the high-density Illumina 1M-Duo array. We followed up 20 of the most significantly associated SNPs, which are not well tagged by the lower density arrays used by the published GWAS, and genotyping them on individual DNA. Most of the top 20 SNPs were clearly validated by individually genotyping the samples used in the pools. However, none of the 20 SNPs replicated when tested for association in a much larger stage 2 set of 4,651 cases and 6,966 controls from the Ovarian Cancer Association Consortium. Given that most of the top 20 SNPs from pooling were validated in the same samples by individual genotyping, the lack of replication is likely to be due to the relatively small sample size in our stage 1 GWAS rather than due to problems with the pooling approach. We conclude that there are unlikely to be any moderate or large effects on ovarian cancer risk untagged by less dense arrays. However, our study lacked power to make clear statements on the existence of hitherto untagged small-effect variants.
Queensland Institute of Medical Research, Brisbane, Australia.
Yi
Y
Lu
Queensland Institute of Medical Research, Brisbane, Australia.
Xiaoqing
X
Chen
Queensland Institute of Medical Research, Brisbane, Australia.
Jonathan
J
Beesley
Queensland Institute of Medical Research, Brisbane, Australia.
Sharon E
SE
Johnatty
Department of Obstetrics and Gynaecology, University of Sydney, Sydney, Australia.|Westmead Institute for Cancer Research, Westmead Hospital, Sydney, Australia.
Anna
A
deFazio
Division of Gynaecological Oncology, Department of Obstetrics and Gynaecology, University Hospital Leuven, University of Leuven, Leuven, Belgium.
Sandrina
S
Lambrechts
Vesalius Research Center, VIB, Leuven, Belgium.|Vesalius Research Center, University of Leuven, Belgium.
Diether
D
Lambrechts
Division of Gynaecological Oncology, Department of Obstetrics and Gynaecology, University Hospital Leuven, University of Leuven, Leuven, Belgium.
Evelyn
E
Despierre
Division of Gynaecological Oncology, Department of Obstetrics and Gynaecology, University Hospital Leuven, University of Leuven, Leuven, Belgium.
Ignace
I
Vergotes
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Jenny
J
Chang-Claude
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Rebecca
R
Hein
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Stefan
S
Nickels
Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany.
Shan
S
Wang-Gohrke
Hannover Medical School, Gynaecology Research Unit, Hannover, Germany.
Thilo
T
Dörk
Friedrich Schiller University, Dept. of Gynaecology, Jena, Germany.
Matthias
M
Dürst
Byelorussian Institute for Oncology and Medical Radiology Aleksandrov N.N., Minsk, Belarus.
Natalia
N
Antonenkova
Byelorussian Institute for Oncology and Medical Radiology Aleksandrov N.N., Minsk, Belarus.|Hannover Medical School, Clinics of Radiation Oncology, Hannover, Germany.
Natalia
N
Bogdanova
Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, United States.
Marc T
MT
Goodman
Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, United States.
Galina
G
Lurie
Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, United States.
Lynne R
LR
Wilkens
Department of Obstetrics and Gynecology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, United States.
Michael E
ME
Carney
Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland.
Ralf
R
Butzow
Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland.
Heli
H
Nevanlinna
Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland.
Tuomas
T
Heikkinen
Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland.
Arto
A
Leminen
Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.|Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.|Comprehensive Cancer Center, The Netherlands Location Nijmegen, Nijmegen, the Netherlands.
Lambertus A
LA
Kiemeney
Department of Gynaecology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
Leon F A G
LFAG
Massuger
Department of Gynaecology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
Anne M
AM
van Altena
Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.|Comprehensive Cancer Center, The Netherlands Location Nijmegen, Nijmegen, the Netherlands.
Katja K
KK
Aben
Dept. of Viruses, Hormones and Cancer, Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark.
Susanne Krüger
SK
Kjaer
Dept. of Viruses, Hormones and Cancer, Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark.
Estrid
E
Høgdall
Dept. of Gynecology, Juliane Marie Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Allan
A
Jensen
Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada.|Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
Angela
A
Brooks-Wilson
Cancer Control Research, BC Cancer Agency, Vancouver, BC, Canada.
Nhu
N
Le
Division of Epidemiology and Biostatistics, University of New Mexico, Albuquerque, New Mexico, USA.
Linda
L
Cook
Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
Madalene
M
Earp
Alberta Health Services-Cancer Care, Calgary, AB, Canada.
Linda
L
Kelemen
Departments of Oncology and Public Health and Primary Care, University of Cambridge, UK.
Douglas
D
Easton
Departments of Oncology and Public Health and Primary Care, University of Cambridge, UK.
Paul
P
Pharoah
Departments of Oncology and Public Health and Primary Care, University of Cambridge, UK.
Honglin
H
Song
Departments of Oncology and Public Health and Primary Care, University of Cambridge, UK.
Jonathan
J
Tyrer
Department of Preventive Medicine, Keck School of Medicine, University of Southern California.
Susan
S
Ramus
Gynaecological Oncology Unit, UCL EGA Institute for Women's Health, University College London, UK.
Usha
U
Menon
Gynaecological Oncology Unit, UCL EGA Institute for Women's Health, University College London, UK.
Alexandra
A
Gentry-Maharaj
Department of Preventive Medicine, Keck School of Medicine, University of Southern California.
Simon A
SA
Gayther
The Cancer Institute of New Jersey, New Brunswick, NJ, USA.|Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Elisa V
EV
Bandera
Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Sara H
SH
Olson
Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Irene
I
Orlow
The Cancer Institute of New Jersey, New Brunswick, NJ, USA.
Lorna
L
Rodriguez-Rodriguez
Queensland Institute of Medical Research, Brisbane, Australia.
Stuart
S
Macgregor
Queensland Institute of Medical Research, Brisbane, Australia.
Georgia
G
Chenevix-Trench
D000368:Aged; D001315:Australia; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results; D018401:Sample Size