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Twin Res Hum Genet. 2012 Oct;15(5):615-623. doi: 10.1017/thg.2012.38. Epub 2012 Jul 13.

Genome-wide association study for ovarian cancer susceptibility using pooled DNA.

Author information

1
Queensland Institute of Medical Research, Brisbane, Australia.
2
Department of Obstetrics and Gynaecology, University of Sydney, Sydney, Australia.
3
Westmead Institute for Cancer Research, Westmead Hospital, Sydney, Australia.
4
Division of Gynaecological Oncology, Department of Obstetrics and Gynaecology, University Hospital Leuven, University of Leuven, Leuven, Belgium.
5
Vesalius Research Center, VIB, Leuven, Belgium.
6
Vesalius Research Center, University of Leuven, Belgium.
7
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
8
Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany.
9
Hannover Medical School, Gynaecology Research Unit, Hannover, Germany.
10
Friedrich Schiller University, Dept. of Gynaecology, Jena, Germany.
11
Byelorussian Institute for Oncology and Medical Radiology Aleksandrov N.N., Minsk, Belarus.
12
Hannover Medical School, Clinics of Radiation Oncology, Hannover, Germany.
13
Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, United States.
14
Department of Obstetrics and Gynecology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, United States.
15
Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland.
16
Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
17
Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
18
Comprehensive Cancer Center, The Netherlands Location Nijmegen, Nijmegen, the Netherlands.
19
Department of Gynaecology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
20
Dept. of Viruses, Hormones and Cancer, Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark.
21
Dept. of Gynecology, Juliane Marie Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
22
Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada.
23
Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
24
Cancer Control Research, BC Cancer Agency, Vancouver, BC, Canada.
25
Division of Epidemiology and Biostatistics, University of New Mexico, Albuquerque, New Mexico, USA.
26
Alberta Health Services-Cancer Care, Calgary, AB, Canada.
27
Departments of Oncology and Public Health and Primary Care, University of Cambridge, UK.
28
Department of Preventive Medicine, Keck School of Medicine, University of Southern California.
29
Gynaecological Oncology Unit, UCL EGA Institute for Women's Health, University College London, UK.
30
The Cancer Institute of New Jersey, New Brunswick, NJ, USA.
31
Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
#
Contributed equally

Abstract

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.

PMID:
22794196
PMCID:
PMC3785301
DOI:
10.1017/thg.2012.38
[Indexed for MEDLINE]
Free PMC Article

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