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

  • Yi Lu (a1), Xiaoqing Chen (a1), Jonathan Beesley (a1), Sharon E. Johnatty (a1), Anna deFazio (a2) (a3), Australian Ovarian Cancer Study (AOCS) Study Group, Sandrina Lambrechts (a4), Diether Lambrechts (a5) (a6), Evelyn Despierre (a4), Ignace Vergotes (a4), Jenny Chang-Claude (a7), Rebecca Hein (a7), Stefan Nickels (a7), Shan Wang-Gohrke (a8), Thilo Dörk (a9), Matthias Dürst (a10), Natalia Antonenkova (a11), Natalia Bogdanova (a11) (a12), Marc T. Goodman (a13), Galina Lurie (a13), Lynne R. Wilkens (a13), Michael E. Carney (a14), Ralf Butzow (a15), Heli Nevanlinna (a15), Tuomas Heikkinen (a15), Arto Leminen (a15), Lambertus A. Kiemeney (a16) (a17) (a18), Leon F.A.G. Massuger (a19), Anne M. van Altena (a19), Katja K. Aben (a17) (a18), Susanne Krüger Kjaer (a20), Estrid Høgdall (a20), Allan Jensen (a21), Angela Brooks-Wilson (a22) (a23), Nhu Le (a24), Linda Cook (a25), Madalene Earp (a23), Linda Kelemen (a26), Douglas Easton (a27), Paul Pharoah (a27), Honglin Song (a27), Jonathan Tyrer (a27), Susan Ramus (a28), Usha Menon (a29), Alexandra Gentry-Maharaj (a29), Simon A. Gayther (a28), Elisa V. Bandera (a30) (a31), Sara H. Olson (a31), Irene Orlow (a31), Lorna Rodriguez-Rodriguez (a30), Stuart Macgregor (a1) and Georgia Chenevix-Trench (a1)...


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.


Corresponding author

address for correspondence: Stuart Macgregor, Queensland Institute of Medical Research, Locked Bag 2000, Herston, Queensland 4029, Australia. E-mail:


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