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dc.contributor.authorAmin Al Olama, Seyed Alien
dc.contributor.authorSchumacher, Freden
dc.date.accessioned2018-02-12T15:42:03Z
dc.date.available2018-02-12T15:42:03Z
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/273150
dc.description.abstractCurrently genome-wide association studies (GWAS) and fine-mapping efforts have identified over 100 prostate cancer (PrCa) susceptibility loci, yet over two thirds of the PrCa familial relative risk (FRR) remains unexplained. Therefore, we used a custom high-density array comprised of ~533K SNPs, where ~50% provided a GWAS backbone and the remainder included top association signals from several cancer-specific meta-analyses. We combined newly genotyped data from 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data for 32,255 PrCa cases and 33,202 controls of European ancestry. After excluding previously reported loci, our combined meta-analysis of 79,194 PrCa cases and 61,112 controls identified 62 novel susceptibility loci associated (P<5.0x10-8) with overall PrCa, and a locus significantly associated with early-onset PrCa (age at diagnosis ≤ 55 years). Among our novel findings, we identified significant associations with four missense variants including rs1800057 (OR=1.16; P=8.2x10-9; G>C [Pro1054Arg]) in ATM and rs2066827 (OR=1.06; P=2.3x10-9; T>G [Val109Gly]) in CDKN1B. The combination of our novel 62 PrCa loci with previously known loci captures 28.4% of the PrCa FRR. Using a polygenic risk score based on previous and newly identified PrCa loci, we estimate elevated PrCa risks for men in the top 90-99%-ile (RR=2.69; 95%CI: 2.55-2.82) and 1%-ile (RR=5.71; 95%CI: 5.04-6.48) risk stratum compared to the population average. These findings demonstrate the utility of high-density arrays, genotyping new sample series, and collaborative efforts for novel discovery. These results will moderately improve risk prediction, enhance fine-mapping efforts, and provide insight into the underlying biology of PrCa susceptibility.
dc.publisherSpringer Nature
dc.relation.isreplacedby1810/277937
dc.relation.isreplacedbyhttps://www.repository.cam.ac.uk/handle/1810/277937
dc.titleProstate cancer meta-analysis of more than 140,000 men identifies 63 novel prostate cancer susceptibility locien
dc.typeArticle
prism.publicationNameNature Geneticsen
dc.identifier.doi10.17863/CAM.18848
dcterms.dateAccepted2017-11-21en
rioxxterms.versionAM*
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2017-11-21en
dc.contributor.orcidAmin Al Olama, Seyed Ali [0000-0002-7178-3431]
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idNational Institutes of Health (NIH) (via University of Southern California) (1 U19 CA148537-01)
rioxxterms.freetoread.startdate2018-12-11


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