Journal article
Fine mapping of a region of chromosome 11q13 reveals multiple independent loci associated with risk of prostate cancer
Human molecular genetics, Vol.20(14), pp.2869-78
07/15/2011
DOI: 10.1093/hmg/ddr189
PMCID: PMC3118760
PMID: 21531787
Abstract
Genome-wide association studies have identified prostate cancer susceptibility alleles on chromosome 11q13. As part of the Cancer Genetic Markers of Susceptibility (CGEMS) Initiative, the region flanking the most significant marker, rs10896449, was fine mapped in 10 272 cases and 9123 controls of European origin (10 studies) using 120 common single nucleotide polymorphisms (SNPs) selected by a two-staged tagging strategy using HapMap SNPs. Single-locus analysis identified 18 SNPs below genome-wide significance (P< 10(-8)) with rs10896449 the most significant (P= 7.94 × 10(-19)). Multi-locus models that included significant SNPs sequentially identified a second association at rs12793759 [odds ratio (OR) = 1.14, P= 4.76 × 10(-5), adjusted P= 0.004] that is independent of rs10896449 and remained significant after adjustment for multiple testing within the region. rs10896438, a proxy of previously reported rs12418451 (r(2)= 0.96), independent of both rs10896449 and rs12793759 was detected (OR = 1.07, P= 5.92 × 10(-3), adjusted P= 0.054). Our observation of a recombination hotspot that separates rs10896438 from rs10896449 and rs12793759, and low linkage disequilibrium (rs10896449-rs12793759, r(2)= 0.17; rs10896449-rs10896438, r(2)= 0.10; rs12793759-rs10896438, r(2)= 0.12) corroborate our finding of three independent signals. By analysis of tagged SNPs across ∼123 kb using next generation sequencing of 63 controls of European origin, 1000 Genome and HapMap data, we observed multiple surrogates for the three independent signals marked by rs10896449 (n= 31), rs10896438 (n= 24) and rs12793759 (n= 8). Our results indicate that a complex architecture underlying the common variants contributing to prostate cancer risk at 11q13. We estimate that at least 63 common variants should be considered in future studies designed to investigate the biological basis of the multiple association signals.
Details
- Title: Subtitle
- Fine mapping of a region of chromosome 11q13 reveals multiple independent loci associated with risk of prostate cancer
- Creators
- Charles C ChungJulia CiampaMeredith Yeager - Clinical Genetics Branch, Division of Cancer Epidemiology & GeneticsKevin B Jacobs - Clinical Genetics Branch, Division of Cancer Epidemiology & GeneticsSonja I Berndt - Clinical Genetics Branch, Division of Cancer Epidemiology & GeneticsRichard B HayesJesus Gonzalez-BosquetPeter Kraft - Department of EpidemiologySholom Wacholder - Clinical Genetics Branch, Division of Cancer Epidemiology & GeneticsNick Orr - Clinical Genetics Branch, Division of Cancer Epidemiology & GeneticsKai YuAmy Hutchinson - Clinical Genetics Branch, Division of Cancer Epidemiology & GeneticsJoseph BolandQuan ChenHeather Spencer Feigelson - institute for health researchMichael J ThunW Ryan DiverDemetrius Albanes - Division of Cancer Epidemiology and GeneticsJarmo Virtamo - Department of Chronic Disease PreventionStephanie WeinsteinFredrick R SchumacherGeraldine Cancel-Tassin - Centre de Recherche pour les Pathologies ProstatiquesOlivier Cussenot - Commissariat à l'énergie atomique et aux énergies alternativesAntoine Valeri - Service d'urologieGerald L AndrioleE David CrawfordChristopher A HaimanBrian E HendersonLaurence KolonelLoic Le Marchand - University of Hawai‘i [Mānoa]Afshan Siddiq - Department of Genomics of Common DiseaseElio Riboli - Department of Epidemiology and Public HealthTim J Key - Radcliffe InfirmaryRudolf Kaaks - Division of Cancer EpidemiologyWilliam B IsaacsSarah D IsaacsHenrik Grönberg - Department of Medical Epidemiology and BiostatisticsFredrik WiklundJianfeng XuLars J VattenKristian HveemInger NjolstadDaniela S GerhardMargaret TuckerRobert N HooverJoseph F FraumeniDavid J Hunter - DURHAMGilles Thomas - Equipe 6Nilanjan Chatterjee - Clinical Genetics Branch, Division of Cancer Epidemiology & GeneticsStephen J Chanock - Pediatric Oncology Branch
- Contributors
- Marie-Pierre Scanella (Editor)
- Resource Type
- Journal article
- Publication Details
- Human molecular genetics, Vol.20(14), pp.2869-78
- Publisher
- Oxford University Press (OUP)
- DOI
- 10.1093/hmg/ddr189
- PMID
- 21531787
- PMCID
- PMC3118760
- ISSN
- 0964-6906
- eISSN
- 1460-2083
- Language
- English
- Date published
- 07/15/2011
- Academic Unit
- Obstetrics and Gynecology
- Record Identifier
- 9983931737202771
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