Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Peer reviewe

Germline variation at 8q24 and prostate cancer risk in men of European ancestry

Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10−15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62–4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification

Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel

Background Polygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women. Methods We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel. Results In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28). Conclusions Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women

The Vehicle, Spring 1982

Vol. 23, No. 2 Table of Contents WelcomeDeb Hoelscherpage 4 Why We Talked All NightCathy Georgepage 5 MorningKathleen Alakspage 5 Adventures With BreakfastSusan Mehlpage 6 Her Golden YearsKathleen Alakspage 7 Policy RiderIsabel M. Parrottpage 10 As a Man Pets his CatBrian Nordinpage 11 Mr. Simmel\u27s BirthdayScott Fishelpage 12 When Last I Saw GrandpaElise Dinquelpage 14 CommunionKathleen Alakspage 15 Within the CrowdsElise Dinquelpage 16 PenniesScott Fishelpage 17 The AlleyScott Fishelpage 18 MindsightCathy Georgepage 19 Image MakerLori A. Beanepage 20 UntitledD.L. Lewispage 21 Class NotesJanean Longpage 26 Math ProblemSusan Mehlpage 27 Poolside SpectatorBrian Nordinpage 28 The ShellBarb Unkrautpage 28 My Old BedroomD.A.page 30 My Brother\u27s StoryJohn Stockmanpage 31 DecisionSherry Martinpage 33 GreaseKathleen Alakspage 34 Blizzard\u27s WorldSusan Burbpage 36 The DustingMichelle Mitchellpage 37 The SupperLenore Howardpage 38 Soup HaikuJohn Stockmanpage 40 I Want to ArgueCathy Georgepage 41 Flute: A Bohemian Love SongGary Ervinpage 42 MomentSherry Martinpage 43 ReflectionDeb Hoelscherpage 43 Art CoverKeila Tooley PhotographKim Hutchcraftpage 3 PhotographKim Hutchcraftpage 13 PhotographKim Hutchcraftpage 35 DrawingChristine Gorkapage 29 DrawingJanet Buenzpage 44https://thekeep.eiu.edu/vehicle/1041/thumbnail.jp

The Vehicle, Spring 1982

Vol. 23, No. 2 Table of Contents WelcomeDeb Hoelscherpage 4 Why We Talked All NightCathy Georgepage 5 MorningKathleen Alakspage 5 Adventures With BreakfastSusan Mehlpage 6 Her Golden YearsKathleen Alakspage 7 Policy RiderIsabel M. Parrottpage 10 As a Man Pets his CatBrian Nordinpage 11 Mr. Simmel\u27s BirthdayScott Fishelpage 12 When Last I Saw GrandpaElise Dinquelpage 14 CommunionKathleen Alakspage 15 Within the CrowdsElise Dinquelpage 16 PenniesScott Fishelpage 17 The AlleyScott Fishelpage 18 MindsightCathy Georgepage 19 Image MakerLori A. Beanepage 20 UntitledD.L. Lewispage 21 Class NotesJanean Longpage 26 Math ProblemSusan Mehlpage 27 Poolside SpectatorBrian Nordinpage 28 The ShellBarb Unkrautpage 28 My Old BedroomD.A.page 30 My Brother\u27s StoryJohn Stockmanpage 31 DecisionSherry Martinpage 33 GreaseKathleen Alakspage 34 Blizzard\u27s WorldSusan Burbpage 36 The DustingMichelle Mitchellpage 37 The SupperLenore Howardpage 38 Soup HaikuJohn Stockmanpage 40 I Want to ArgueCathy Georgepage 41 Flute: A Bohemian Love SongGary Ervinpage 42 MomentSherry Martinpage 43 ReflectionDeb Hoelscherpage 43 Art CoverKeila Tooley PhotographKim Hutchcraftpage 3 PhotographKim Hutchcraftpage 13 PhotographKim Hutchcraftpage 35 DrawingChristine Gorkapage 29 DrawingJanet Buenzpage 44https://thekeep.eiu.edu/vehicle/1041/thumbnail.jp

Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel

BackgroundPolygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women.MethodsWe generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel.ResultsIn the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28).ConclusionsExtant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women

Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants

The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups

Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel.

Peer reviewed: TrueFunder: Statistics NetherlandsFunder: Lower Saxonian Cancer SocietyFunder: Lise Boserup FundFunder: Heidelberger Zentrum für Personalisierte Onkologie Deutsches Krebsforschungszentrum In Der Helmholtz-Gemeinschaft; FundRef: http://dx.doi.org/10.13039/100018027Funder: Komen FoundationFunder: Claudia von Schilling Foundation for Breast Cancer ResearchFunder: Ligue Contre le Cancer; FundRef: http://dx.doi.org/10.13039/501100004099Funder: Sigrid Juselius FoundationFunder: Kuopion Yliopistollinen Sairaala; FundRef: http://dx.doi.org/10.13039/501100004092Funder: Sheffield Experimental Cancer Medicine CentreFunder: Stockholm läns landsting; FundRef: http://dx.doi.org/10.13039/501100011727Funder: Department of Health and Human Services (USA)Funder: Stichting Tegen Kanker; FundRef: http://dx.doi.org/10.13039/501100005026Funder: David F. and Margaret T. Grohne Family Foundation; FundRef: http://dx.doi.org/10.13039/100009769Funder: Sundhed og Sygdom, Det Frie Forskningsråd; FundRef: http://dx.doi.org/10.13039/100008392Funder: Stavros Niarchos FoundationFunder: Institute of the Ruhr University BochumFunder: Institute of Cancer Research; FundRef: http://dx.doi.org/10.13039/501100000027Funder: Fondation du cancer du sein du Québec; FundRef: http://dx.doi.org/10.13039/100016328Funder: Institut National de la Santé et de la Recherche Médicale; FundRef: http://dx.doi.org/10.13039/501100001677Funder: Institute for Prevention and Occupational MedicineFunder: K.G. Jebsen Centre for Breast Cancer ResearchFunder: Research Centre for Genetic Engineering and BiotechnologyFunder: Robert and Kate Niehaus Clinical Cancer Genetics InitiativeFunder: Rudolf Bartling FoundationFunder: Karolinska Institutet; FundRef: http://dx.doi.org/10.13039/501100004047Funder: Robert Bosch Stiftung; FundRef: http://dx.doi.org/10.13039/501100001646Funder: Intramural Research Funds of the National Cancer Institute (USA)Funder: Intramural Research Program of the Division of Cancer Epidemiology and GeneticsFunder: Centre International de Recherche sur le Cancer; FundRef: http://dx.doi.org/10.13039/100008700Funder: Queensland Cancer FundFunder: Red Temática de Investigación Cooperativa en CáncerFunder: Intramural Research Program of the National Institutes of HealthFunder: National Health Service (UK)Funder: Ministerie van Volksgezondheid, Welzijn en Sport; FundRef: http://dx.doi.org/10.13039/501100002999Funder: Märit and Hans Rausings Initiative Against Breast CancerFunder: Associazione Italiana per la Ricerca sul Cancro; FundRef: http://dx.doi.org/10.13039/501100005010Funder: Fundación Científica Asociación Española Contra el Cáncer; FundRef: http://dx.doi.org/10.13039/501100002704Funder: Agence Nationale de la Recherche; FundRef: http://dx.doi.org/10.13039/501100001665Funder: Dutch Prevention Funds,Funder: Agence Nationale de Sécurité Sanitaire de l'Alimentation, de l'Environnement et du TravailFunder: American Cancer Society; FundRef: http://dx.doi.org/10.13039/100000048Funder: Dutch Zorg OnderzoekFunder: Alexander von Humboldt-Stiftung; FundRef: http://dx.doi.org/10.13039/100005156Funder: Ministerio de Economia y Competitividad (Spain)Funder: Against Breast Cancer; FundRef: http://dx.doi.org/10.13039/100013129Funder: Mutuelle Générale de l’Education NationaleFunder: Dietmar-Hopp Foundation,Funder: Division of Cancer Prevention, National Cancer Institute; FundRef: http://dx.doi.org/10.13039/100007316Funder: World Cancer Research Fund; FundRef: http://dx.doi.org/10.13039/501100000321Funder: Genome QuébecFunder: National Cancer Research NetworkFunder: Berta Kamprad Foundation FBKSFunder: Biomedical Research Centre at Guy’s and St ThomasFunder: Genome Canada; FundRef: http://dx.doi.org/10.13039/100008762Funder: Friends of Hannover Medical SchoolFunder: Breast Cancer Research Foundation; FundRef: http://dx.doi.org/10.13039/100001006Funder: Breast Cancer NowFunder: UK National Institute for Health Research Biomedical Research CentreFunder: University of Crete; FundRef: http://dx.doi.org/10.13039/501100004429Funder: National Breast Cancer Foundation (Finland)Funder: European Regional Development Fund; FundRef: http://dx.doi.org/10.13039/501100008530Funder: National Breast Cancer Foundation (Australia)Funder: Directorate-General XII, Science, Research, and Development; FundRef: http://dx.doi.org/10.13039/501100012517Funder: Baden Württemberg Ministry of Science, Research and ArtsFunder: VicHealth; FundRef: http://dx.doi.org/10.13039/501100001231Funder: Victorian Breast Cancer Research Consortium.Funder: Finnish Cancer FoundationFunder: Fomento de la Investigación Clínica IndependienteFunder: the Cancer Biology Research Center (CBRC), Djerassi Oncology CenterFunder: Tel Aviv University Center for AI and Data ScienceFunder: University of OuluFunder: National Breast Cancer Foundation (JS)Funder: Safra Center for BioinformaticsFunder: Fondation de France, Institut National du CancerFunder: University of Utah; FundRef: http://dx.doi.org/10.13039/100007747Funder: National Cancer Center Research and Development Fund (Japan)Funder: Oak Foundation; FundRef: http://dx.doi.org/10.13039/100001275Funder: New South Wales Cancer CouncilFunder: North Carolina University Cancer Research FundFunder: Kreftforeningen; FundRef: http://dx.doi.org/10.13039/100008730Funder: Northern California Breast Cancer Family RegistryFunder: Institut Gustave RoussyFunder: Huntsman Cancer Institute, University of Utah; FundRef: http://dx.doi.org/10.13039/100010638Funder: Ovarian Cancer Research Fund; FundRef: http://dx.doi.org/10.13039/100001282Funder: NIHR Oxford Biomedical Research Centre; FundRef: http://dx.doi.org/10.13039/501100013373Funder: Hellenic Health Foundation; FundRef: http://dx.doi.org/10.13039/501100018706Funder: Oulun Yliopistollinen Sairaala; FundRef: http://dx.doi.org/10.13039/501100018949Funder: Helmholtz SocietyFunder: Herlev and Gentofte HospitalFunder: PSRSIIRI-701Funder: Helsinki University Hospital Research FundFunder: Cancer Council Victoria; FundRef: http://dx.doi.org/10.13039/501100000951Funder: National Research Council (Italy)Funder: Cancer Council Tasmania; FundRef: http://dx.doi.org/10.13039/501100001169Funder: Cancer Council Western Australia; FundRef: http://dx.doi.org/10.13039/501100001170Funder: Hamburger Krebsgesellschaft; FundRef: http://dx.doi.org/10.13039/100018515Funder: Gustav V Jubilee foundationFunder: National Program of Cancer RegistriesFunder: Cancer Council South Australia; FundRef: http://dx.doi.org/10.13039/501100000950Funder: Cancer Council NSW; FundRef: http://dx.doi.org/10.13039/501100001102Funder: Guy's & St. Thomas' NHS Foundation TrustFunder: Cancer Institute NSW; FundRef: http://dx.doi.org/10.13039/501100001171Funder: Cancer Foundation of Western AustraliaFunder: Netherlands Cancer Registry (NKR),Funder: Cancer Fund of North SavoBACKGROUND: Polygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women. METHODS: We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel. RESULTS: In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28). CONCLUSIONS: Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women

Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants.

The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups

Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling