Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation
Open accessAbstract
Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.
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Genetic ancestry may be causally related to some genetic traits and diseases, unlike the social construct of race.
“Fairness and diversity have especially important considerations in such applications given that genetic ancestry may be causally related to some genetic traits and diseases (178, 183-186), as opposed to the social construct of race (173).”
From Artificial Intelligence in Oncology: Current Landscape, Challenges, and Future Directions (2024) · cites this paper as [185]
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- Authors
- Gusev, A., Shi, H., Kichaev, G., Pomerantz, M., Li, F., Long, H. W., Ingles, S. A., Kittles, R. A., Strom, S. S., Rybicki, B. A., Nemesure, B., Isaacs, W. B., Zheng, W., Pettaway, C. A., Yeboah, E. D., Tettey, Y., Biritwum, R. B., Adjei, A. A., Tay, E., Truelove, A., Niwa, S., Chokkalingam, A. P., John, E. M., Murphy, A. B., Signorello, L. B., Carpten, J., Leske, M. C., Wu, S.-Y., Hennis, A. J. M., Neslund-Dudas, C., Hsing, A. W., Chu, L., Goodman, P. J., Klein, E. A., Witte, J. S., Casey, G., Kaggwa, S., Cook, M. B., Stram, D. O., Blot, W. J., Eeles, R. A., Easton, D., Kote-Jarai, Z., Al Olama, A. A., Benlloch, S., Muir, K., Giles, G. G., Southey, M. C., Fitzgerald, L. M., Gronberg, H., Wiklund, F., Aly, M., Henderson, B. E., Schleutker, J., Wahlfors, T., Tammela, T. L. J., Nordestgaard, B. G., Key, T. J., Travis, R. C., Neal, D. E., Donovan, J. L., Hamdy, F. C., Pharoah, P., Pashayan, N., Khaw, K.-T., Stanford, J. L., Thibodeau, S. N., McDonnell, S. K., Schaid, D. J., Maier, C., Vogel, W., Luedeke, M., Herkommer, K., Kibel, A. S., Cybulski, C., Wokolorczyk, D., Kluzniak, W., Cannon-Albright, L., Teerlink, C., Brenner, H., Dieffenbach, A. K., Arndt, V., Park, J. Y., Sellers, T. A., Lin, H.-Y., Slavov, C., Kaneva, R., Mitev, V., Batra, J., Spurdle, A., Clements, J. A., Teixeira, M. R., Pandha, H., Michael, A., Paulo, P., Maia, S., Kierzek, A., The PRACTICAL consortium, Cook, M., Guy, M., Govindasami, K., Leongamornlert, D., Sawyer, E. J., Wilkinson, R., Saunders, E. J., Tymrakiewicz, M., Dadaev, T., Morgan, A., Fisher, C., Hazel, S., Livni, N., Lophatananon, A., Pedersen, J., Hopper, J. L., Adolfson, J., Stattin, P., Johansson, J.-E., Cavalli-Bjoerkman, C., Karlsson, A., Broms, M., Auvinen, A., Kujala, P., Maeaettaenen, L., Murtola, T., Taari, K., Weischer, M., Nielsen, S. F., Klarskov, P., Roder, A., Iversen, P., Wallinder, H., Gustafsson, S., Cox, A., Brown, P., George, A., Marsden, G., Lane, A., Davis, M., Zheng, W., Signorello, L. B., Blot, W. J., Tillmans, L., Riska, S., Wang, L., Rinckleb, A., Lubiski, J., Stegmaier, C., Pow-Sang, J., Park, H., Radlein, S., Rincon, M., Haley, J., Zachariah, B., Kachakova, D., Popov, E., Mitkova, A., Vlahova, A., Dikov, T., Christova, S., Heathcote, P., Wood, G., Malone, G., Saunders, P., Eckert, A., Yeadon, T., Kerr, K., Collins, A., Turner, M., Srinivasan, S., Kedda, M.-A., Alexander, K., Omara, T., Wu, H., Henrique, R., Pinto, P., Santos, J., Barros-Silva, J., Conti, D. V., Albanes, D., Berg, C., Berndt, S. I., Campa, D., Crawford, E. D., Diver, W. R., Gapstur, S. M., Gaziano, J. M., Giovannucci, E., Hoover, R., Hunter, D. J., Johansson, M., Kraft, P., Le Marchand, L., Lindström, S., Navarro, C., Overvad, K., Riboli, E., Siddiq, A., Stevens, V. L., Trichopoulos, D., Vineis, P., Yeager, M., Trynka, G., Raychaudhuri, S., Schumacher, F. R., Price, A. L., Freedman, M. L., Haiman, C. A., & Pasaniuc, B.
- Affiliations
- Broad Institute (US)
- University of California, Los Angeles (US)
- Harvard University (US)
- Dana-Farber Cancer Institute (US)
- University of Southern California (US)
- University of Arizona (US)
- The University of Texas MD Anderson Cancer Center (US)
- Henry Ford Health (US)
- Stony Brook University (US)
- Johns Hopkins University (US)
- University of Ghana (GH)
- Westat (United States) (US)
- University of California, Berkeley (US)
- Cancer Prevention Institute of California (US)
- Northwestern University (US)
- Translational Genomics Research Institute (US)
- University of the West Indies (BB)
- Fred Hutch Cancer Center (US)
- Cleveland Clinic (US)
- University of California, San Francisco (US)
- Makerere University (UG)
- National Cancer Institute (US)
- National Health Service (GB)
- University of Cambridge (GB)
- University of Manchester (GB)
- The University of Melbourne (AU)
- Cancer Council Victoria (AU)
- Karolinska Institutet (SE)
- Danderyds sjukhus (SE)
- University of Turku (FI)
- Fimlab (Finland) (FI)
- Tampere University Hospital (FI)
- University of Copenhagen (DK)
- University of Oxford (GB)
- University of Bristol (GB)
- Aarhus University (DK)
- University of Washington (US)
- Mayo Clinic (US)
- University Hospital Ulm (DE)
- TUM Klinikum (DE)
- Brigham and Women's Hospital (US)
- International Hereditary Cancer Center (PL)
- University of Utah (US)
- German Cancer Research Center (DE)
- Moffitt Cancer Center (US)
- Alexandrovska Hospital (BG)
- Medical University of Sofia (BG)
- Queensland University of Technology (AU)
- QIMR Berghofer Medical Research Institute (AU)
- Universidade do Porto (PT)
- University of Surrey (GB)
- Instituto Português de Oncologia Francisco Gentil (PT)
- Institute of Cancer Research (GB)
- TissuPath (AU)
- Tampere University (FI)
- University of Helsinki (FI)
- Herlev Hospital (DK)
- Copenhagen University Hospital (DK)
- Imperial College London (GB)
- University of Sheffield (GB)
- Krebsregister Saarland (DE)
- National Institutes of Health (US)
- University of Colorado Denver (US)
- American Cancer Society (US)
- Centre international de recherche sur le cancer (FR)
- Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (ES)
- Italian institute for Genomic Medicine (IT)
- Corresponding author
- Gusev, Alexander
- ORCID
- Gusev, Alexander
- Shi, Huwenbo
- Kichaev, Gleb
- Pomerantz, Mark
- Li, Fugen
- Long, Henry W.
- Ingles, Sue A.
- Kittles, Rick A.
- Rybicki, Benjamin A.
- Nemesure, Barbara
- Isaacs, William B.
- Pettaway, Curtis A.
- Yeboah, Edward D.
- Tettey, Yao
- Biritwum, Richard B.
- Adjei, Andrew A.
- Chokkalingam, Anand P.
- John, Esther M.
- Murphy, Adam B.
- Carpten, John
- Neslund-Dudas, Christine
- Hsing, Ann W.
- Goodman, Phyllis J.
- Klein, Eric A.
- Witte, John S.
- Casey, Graham
- Cook, Michael B.
- Stram, Daniel O.
- Eeles, Rosalind A.
- Easton, Douglas
- Muir, Kenneth
- Giles, Graham G.
- Southey, Melissa C.
- Fitzgerald, Liesel M.
- Wiklund, Fredrik
- Aly, Markus
- Schleutker, Johanna
- Wahlfors, Tiina
- Tammela, Teuvo L. J.
- Nordestgaard, Børge G.
- Key, Tim J.
- Travis, Ruth C.
- Neal, David E.
- Donovan, Jenny L.
- Hamdy, Freddie C.
- Pharoah, Paul
- Pashayan, Nora
- Khaw, Kay-Tee
- Stanford, Janet L.
- Thibodeau, Stephen N.
- McDonnell, Shannon K.
- Schaid, Daniel J.
- Vogel, Walther
- Herkommer, Kathleen
- Kibel, Adam S.
- Cybulski, Cezary
- Teerlink, Craig
- Brenner, Hermann
- Arndt, Volker
- Park, Jong Y.
- Sellers, Thomas A.
- Lin, Hui-Yi
- Slavov, Chavdar
- Kaneva, Radka
- Mitev, Vanio
- Batra, Jyotsna
- Spurdle, Amanda
- Clements, Judith A.
- Teixeira, Manuel R.
- Pandha, Hardev
- Michael, Agnieszka
- Paulo, Paula
- Maia, Sofia
- Kierzek, Andrzej
- Leongamornlert, Daniel
- Saunders, Edward J.
- Dadaev, Tokhir
- Fisher, Cyril
- Lophatananon, Artitaya
- Hopper, John L.
- Auvinen, Anssi
- Murtola, Teemu
- Taari, Kimmo
- Weischer, Maren
- Nielsen, Sune F.
- Cox, Angela
- Marsden, Gemma
- Tillmans, Lori
- Wang, Liang
- Radlein, Selina
- Rincon, Maria
- Kachakova, Darina
- Popov, Elenko
- Collins, Angus
- Srinivasan, Srilakshmi
- Alexander, Kimberly
- Wu, Huihai
- Henrique, Rui
- Pinto, Pedro
- Santos, Joana
- Conti, David V.
- Albanes, Demetrius
- Berg, Christine
- Berndt, Sonja I.
- Campa, Daniele
- Crawford, E. David
- Diver, W. Ryan
- Gapstur, Susan M.
- Giovannucci, Edward
- Hoover, Robert
- Hunter, David J.
- Johansson, Mattias
- Kraft, Peter
- Lindström, Sara
- Navarro, Carmen
- Overvad, Kim
- Siddiq, Afshan
- Stevens, Victoria L.
- Vineis, Paolo
- Yeager, Meredith
- Trynka, Gosia
- Raychaudhuri, Soumya
- Price, Alkes L.
- Freedman, Matthew L.
- Haiman, Christopher A.
- Venue
- Nature Communications
- Published
- 2016-04-07
- Volume
- 7
- Issue
- 1
- Pages
- 10979-10979
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4829663
- OpenAlex
- W2325429517
- Cited by
- 51
- References
- 40
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 6 · 2021: 6 · 2020: 12 · 2019: 7 · 2018: 8 · 2017: 6 · 2016: 2
- FWCI
- 6.19
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion, cc-by)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- Tampere University Institutional Repository (Tampere University) (publishedVersion, cc-by)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- Warwick Research Archive Portal (University of Warwick) (acceptedVersion)
- QUT ePrints (Queensland University of Technology) (submittedVersion, cc-by-nc)
- Surrey Research Insight Open Access (The University of Surrey) (submittedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- eCite Digital Repository (University of Tasmania) (submittedVersion, cc-by)
- DiVA at Umeå University (Umeå University) (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Figshare (submittedVersion)
- Työväentutkimus Vuosikirja (submittedVersion, other-oa)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Bristol Research (University of Bristol) (submittedVersion, cc-by)
- Spiral (Imperial College London) (submittedVersion, cc-by)
- Tampere University Institutional Repository (Tampere University) (submittedVersion, cc-by)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Faculty of Health; Institute of Health and Biomedical Innovation
- Apollo (cc-by)
- Funders
- Prostate Cancer Foundation
- World Health Organization
- Wellcome Trust (UK10K, 102215, 076113)
- Francis Crick Institute (10124, 10119)
- Cancer Research UK (C1281/A12014, 10119, C5047/A7357, C5047/A15007’, (C8197/A10865), C1287‐A10118, 12014, C5047/A3354, 10710, C12292/A11174, 19170, ‘C5047/A10692, 15007, C522/A8649, C5047/A8384, 10118, 14136, (C8197/A10123), 10124, 16491, 17528, C490/A10124, C16913-A6135, C1287-A10710, G0500966/75466, 13065)
- National Institute for Health and Care Research (NF-SI-0509-10242, NF-SI-0512-10114, NF-SI-0513-10121)
- European Commission (223175)
- National Institutes of Health (5r01ar063759-07, CA194393)
- Medical Research Council (MR/N003284/1, MC_PC_15018)
- National Institute of Mental Health (R01MH101244)
- National Cancer Institute (R01CA128978, R01CA092447, R01CA128813, U01CA188392, P30 CA 68485, CA63464, R01CA056678, R01CA082664, U19CA148065, R01CA072818, U01CA194393, U01CA063464, UM1CA182883, UG1CA189974, CA098758, R37CA054281, U19CA148537, R01 CA188392, R01CA054281, R01CA063464, CA 54281, R01CA092579, U01CA098758, U19CA148112, R01 CA 72818, (CA128978, U10CA037429, R01CA193910, P30CA016672, P30CA068485, P30CA060553, P30CA042014, U01CA164973, R35CA197449)
- National Institute of General Medical Sciences (R01GM105857, F32GM106584, R01GM107427)
- National Institute of Allergy and Infectious Diseases (U19AI111224)
- National Institute of Environmental Health Sciences (R01ES011126)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01-AR063759)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- prostate cancer, heritability, single nucleotide polymorphisms, tissue-specific gene regulation, cell-type-specific epigenetics, H3K27 acetylation, DNase I hypersensitive sites, LNCaP cells, European ancestry, African American ancestry, cancer risk loci
- MeSH terms
- Acetylation, Atlases as Topic, Black or African American, Histones, Humans, Male, Prostatic Neoplasms, Linkage Disequilibrium, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Inheritance Patterns, Epigenesis, Genetic, White People, Cell Line, Tumor, Genome-Wide Association Study, Genetic Loci
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