Twin Research and Human Genetics

Articles

Genome-Wide Association Study for Ovarian Cancer Susceptibility Using Pooled DNA

Yi Lua1, Xiaoqing Chena1, Jonathan Beesleya1, Sharon E. Johnattya1, Anna deFazioa2a3, Australian Ovarian Cancer Study (AOCS) Study Group, Sandrina Lambrechtsa4, Diether Lambrechtsa5a6, Evelyn Despierrea4, Ignace Vergotesa4, Jenny Chang-Claudea7, Rebecca Heina7, Stefan Nickelsa7, Shan Wang-Gohrkea8, Thilo Dörka9, Matthias Dürsta10, Natalia Antonenkovaa11, Natalia Bogdanovaa11a12, Marc T. Goodmana13, Galina Luriea13, Lynne R. Wilkensa13, Michael E. Carneya14, Ralf Butzowa15, Heli Nevanlinnaa15, Tuomas Heikkinena15, Arto Leminena15, Lambertus A. Kiemeneya16a17a18, Leon F.A.G. Massugera19, Anne M. van Altenaa19, Katja K. Abena17a18, Susanne Krüger Kjaera20, Estrid Høgdalla20, Allan Jensena21, Angela Brooks-Wilsona22a23, Nhu Lea24, Linda Cooka25, Madalene Earpa23, Linda Kelemena26, Douglas Eastona27, Paul Pharoaha27, Honglin Songa27, Jonathan Tyrera27, Susan Ramusa28, Usha Menona29, Alexandra Gentry-Maharaja29, Simon A. Gaythera28, Elisa V. Banderaa30a31, Sara H. Olsona31, Irene Orlowa31, Lorna Rodriguez-Rodrigueza30, Stuart Macgregora1 c1* and Georgia Chenevix-Trencha1*

a1 Queensland Institute of Medical Research, Brisbane, Australia

a2 Department of Obstetrics and Gynaecology, University of Sydney, Sydney, Australia

a3 Westmead Institute for Cancer Research, Westmead Hospital, Sydney, Australia

a4 Division of Gynaecological Oncology, Department of Obstetrics and Gynaecology, University Hospital Leuven, University of Leuven, Leuven, Belgium

a5 Vesalius Research Center, VIB, Leuven, Belgium

a6 Vesalius Research Center, University of Leuven, Belgium

a7 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

a8 Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany

a9 Gynaecology Research Unit, Hannover Medical School, Hannover, Germany

a10 Department of Gynaecology, Friedrich Schiller University, Jena, Germany

a11 Byelorussian Institute for Oncology and Medical Radiology, Aleksandrov NN, Minsk, Belarus

a12 Clinics of Radiation Oncology, Hannover Medical School, Hannover, Germany

a13 Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA

a14 Department of Obstetrics and Gynecology, John A Burns School of Medicine, University of Hawaii, Honolulu, HI, USA

a15 Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland

a16 Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

a17 Department of Epidemiology, Biostatistics and HTA, Nijmegen Medical Centre, Radboud University, Nijmegen, The Netherlands

a18 Comprehensive Cancer Center, Nijmegen, The Netherlands

a19 Department of Gynaecology, Nijmegen Medical Centre, Radboud University, Nijmegen, The Netherlands

a20 Department of Viruses, Hormones and Cancer, Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark

a21 Department of Gynecology, Juliane Marie Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

a22 Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada

a23 Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada

a24 Cancer Control Research, BC Cancer Agency, Vancouver, British Columbia, Canada

a25 Division of Epidemiology and Biostatistics, University of New Mexico, Albuquerque, NM, USA

a26 Alberta Health Services — Cancer Care, Calgary, Alberta, Canada

a27 Departments of Oncology and Public Health and Primary Care, University of Cambridge, Cambridge, UK

a28 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

a29 Gynaecological Oncology Unit, UCL EGA Institute for Women's Health, University College London, London, UK

a30 The Cancer Institute of New Jersey, New Brunswick, NJ, USA

a31 Memorial Sloan-Kettering Cancer Center, New York, NY, USA

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.

(Received March 06 2012)

(Accepted April 19 2012)

Keywords:

  • GWAS;
  • DNA Pooling;
  • Ovarian cancer risk;
  • Nanodrop spectroscopy

Correspondence:

c1 address for correspondence: Stuart Macgregor, Queensland Institute of Medical Research, Locked Bag 2000, Herston, Queensland 4029, Australia. E-mail: stuart.macgregor@qimr.edu.au

Footnotes

* These two authors contributed equally.

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