Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes
Abstract
We performed a genome-wide association scan to search for sequence variants conferring risk of prostate cancer using 1,501 Icelandic men with prostate cancer and 11,290 controls. Follow-up studies involving three additional case-control groups replicated an association of two variants on chromosome 17 with the disease. These two variants, 33 Mb apart, fall within a region previously implicated by family-based linkage studies on prostate cancer. The risks conferred by these variants are moderate individually (allele odds ratio of about 1.20), but because they are common, their joint population attributable risk is substantial. One of the variants is in TCF2 (HNF1beta), a gene known to be mutated in individuals with maturity-onset diabetes of the young type 5. Results from eight case-control groups, including one West African and one Chinese, demonstrate that this variant confers protection against type 2 diabetes.
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These findings inform prioritization of therapeutic targets, providing clues to potential on-target side effects and opportunities for drug repurposing.
“These findings inform the prioritization of therapeutic targets, providing clues to potential on-target side effects and opportunities for drug repurposing87–89.”
From A brief history of human disease genetics (2020) · cites this paper as [87]
Other pleiotropic relationships connect diseases and traits in surprising ways, highlighting shared polygenic effects and cell-type specificity and delivering insights into shared biology and overlapping mechanisms.
“Others connect diseases and traits in surprising ways, highlighting shared polygenic, pleiotropic effects and cell-type specificity, and delivering insights into shared biology and overlapping mechanisms86,87.”
From A brief history of human disease genetics (2020) · cites this paper as [87]
Cites
Statistical Aspects of the Analysis of Data From Retrospective Studies of Disease
(1959) · JNCI: Journal of the National Cancer Institute · doi:10.1093/jnci/22.4.719 · Cited by 14,689 · see citing works
Genomic Control for Association Studies
Devlin, B., & Roeder, K. (1999) · Biometrics · doi:10.1111/j.0006-341x.1999.00997.x · Cited by 3,162 · see citing works
Linkage strategies for genetically complex traits. I. Multilocus models.
RISCH, N. J. (1990) · PubMed · Cited by 1,315 · see citing works
Genome-wide association study of prostate cancer identifies a second risk locus at 8q24
Yeager, M., Orr, N., Hayes, R. B., Jacobs, K. B., Kraft, P., Wacholder, S., Minichiello, M. J., Fearnhead, P., Yu, K. F., Chatterjee, N., et al. (2007) · Nature Genetics · doi:10.1038/ng2022 · Cited by 1,122 · see citing works
Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24
Guðmundsson, J., Sulem, P., Manolescu, A. R., Amundadottir, L. T., Gudbjartsson, D. F., Helgason, A., Rafnar, Þ., Bergþorsson, J. Þ., Agnarsson, B. A., Baker, A., et al. (2007) · Nature Genetics · doi:10.1038/ng1999 · Cited by 856 · see citing works
Self-citationA common variant associated with prostate cancer in European and African populations
Amundadottir, L. T., Sulem, P., Gudmundsson, J., Helgason, A., Baker, A., Agnarsson, B. A., Sigurdsson, A., Benediktsdottir, K. R., Cazier, J.-B., Sainz, J., et al. (2006) · Nature Genetics · doi:10.1038/ng1808 · Cited by 787 · see citing works
Self-citationMultiple regions within 8q24 independently affect risk for prostate cancer
Haiman, C. A., Patterson, N., Freedman, M. L., Myers, S. R., Pike, M. C., Waliszewska, A., Neubauer, J., Tandon, A., Schirmer, C., McDonald, G. J., et al. (2007) · Nature Genetics · doi:10.1038/ng2015 · Cited by 663 · see citing works
Falk, C. T., & Rubinstein, P. G. (1987) · Annals of Human Genetics · doi:10.1111/j.1469-1809.1987.tb00875.x · Cited by 618 · see citing works
The gene encoding phosphodiesterase 4D confers risk of ischemic stroke
Grétarsdóttir, S., Þorleifsson, G., Reynisdottir, S. T., Manolescu, A. R., Jonsdottir, S., Jónsdóttir, Þ., Gudmundsdottir, T., Bjarnadottir, S. M., Einarsson, O. B., Gudjonsdottir, H. M., et al. (2003) · Nature Genetics · doi:10.1038/ng1245 · Cited by 563 · see citing works
Self-citationA meta-analysis of diabetes mellitus and the risk of prostate cancer
Kasper, J. S., & Giovannucci, E. (2006) · Cancer Epidemiology, Biomarkers & Prevention · doi:10.1158/1055-9965.epi-06-0410 · Cited by 491 · see citing works
Mutations in hepatocyte nuclear factor-1β and their related phenotypes
Edghill, E. L., Bingham, C., Ellard, S., & Hattersley, A. T. (2005) · Journal of Medical Genetics · doi:10.1136/jmg.2005.032854 · Cited by 345 · see citing works
Bellanné‐Chantelot, C., Clauin, S., Chauveau, D., Collin, P., DAUMONT, M., Douillard, C., Dubois‐Laforgue, D., Dusselier, L., Gautier, J., Jadoul, M. Y., et al. (2005) · Diabetes · doi:10.2337/diabetes.54.11.3126 · Cited by 274 · see citing works
Using Linkage Genome Scans to Improve Power of Association in Genome Scans
Roeder, K., Bacanu, S., Wasserman, L., & Devlin, B. (2006) · The American Journal of Human Genetics · doi:10.1086/500026 · Cited by 207 · see citing works
Winckler, W., Weedon, M. N., Graham, R., McCarroll, S. A., Purcell, S., Almgren, P., Tuomilehto, J., Gaudet, D., Boström, K. B., Walker, M., et al. (2007) · Diabetes · doi:10.2337/db06-0202 · Cited by 201 · see citing works
Xu, J., Dimitrov, L. M., Chang, B., et al. (2005) · The American Journal of Human Genetics · doi:10.1086/432377 · Cited by 146 · see citing works
Protection of privacy by third-party encryption in genetic research in Iceland
Gulcher, J. R., Kristjánsson, K., Guðbjartsson, H., & Stefánsson, K. (2000) · European Journal of Human Genetics · doi:10.1038/sj.ejhg.5200530 · Cited by 138 · see citing works
Self-citationLange, E. M., Gillanders, E. M., Davis, C., et al. (2003) · The Prostate · doi:10.1002/pros.10307 · Cited by 92 · see citing works
A novel endonuclease IV post-PCR genotyping system
Kutyavin, I. V., Milesi, D., Belousov, Y. S., Podyminogin, M. A., Vorobiev, A. A., Gorn, V. V., Lukhtanov, E. A., Vermeulen, N. M. J., & Mahoney, W. C. (2006) · Nucleic Acids Research · doi:10.1093/nar/gkl679 · Cited by 85 · see citing works
Genetic Variation in the HSD17B1 Gene and Risk of Prostate Cancer
Kraft, P., Pharoah, P. D. P., Chanock, S. J., Albanes, D., Kolonel, L. N., Hayes, R. B., Altshuler, D., Andriole, G. L., Berg, C. D., Boeing, H., et al. (2005) · PLoS Genetics · doi:10.1371/journal.pgen.0010068 · Cited by 68 · see citing works
Self-citationHill-Harfe, K. L., Kaplan, L., Stalker, H. J., Zori, R. T., Pop, R., Scherer, G., & Wallace, M. R. (2005) · The American Journal of Human Genetics · doi:10.1086/429254 · Cited by 43 · see citing works
Lange, E. M., Robbins, C. M., Gillanders, E. M., et al. (2006) · Human Genetics · doi:10.1007/s00439-006-0274-2 · Cited by 33 · see citing works
Zuhlke, K. A., Madeoy, J. J., Beebe‐Dimmer, J., et al. (2004) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-04-0554 · Cited by 29 · see citing works
Prohibitin mutations are uncommon in prostate cancer families linked to chromosome 17q
White, K. A., Lange, E. M., Ray, A. M., et al. (2006) · Prostate Cancer and Prostatic Diseases · doi:10.1038/sj.pcan.4500878 · Cited by 12 · see citing works
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McCarthy, M. I., Abecasis, G. R., Cardon, L. R., Goldstein, D. B., Little, J., Ioannidis, J. P. A., & Hirschhorn, J. N. (2008) · Nature Reviews Genetics · doi:10.1038/nrg2344 · Cited by 2,891 · see citing works
Wellcome Trust Case Control Consortium, Zeggini, E., Scott, L. J., Saxena, R., Voight, B. F., Marchini, J. L., Hu, T., de Bakker, P. I., Abecasis, G. R., Almgren, P., et al. (2008) · Nature Genetics · doi:10.1038/ng.120 · Cited by 1,864 · see citing works
Self-citationGenetic Mapping in Human Disease
Altshuler, D., Daly, M. J., & Lander, E. S. (2008) · Science · doi:10.1126/science.1156409 · Cited by 1,452 · see citing works
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Wellcome Trust Case Control Consortium, & The Australo-Anglo-American Spondylitis Consortium (TASC) (2007) · Nature Genetics · doi:10.1038/ng.2007.17 · Cited by 1,374 · see citing works
Human genetic variation and its contribution to complex traits
Frazer, K. A., Murray, S. S., Schork, N. J., & Topol, E. J. (2009) · Nature Reviews Genetics · doi:10.1038/nrg2554 · Cited by 1,073 · see citing works
Genomics, type 2 diabetes, and obesity
McCarthy, M. I. (2010) · New England Journal of Medicine · doi:10.1056/nejmra0906948 · Cited by 938 · see citing works
Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci
Study, T. P., Schumacher, F. R., (APCB), A. P. C. B., Study, T. I., Canary PASS Investigators, Breast and Prostate Cancer Cohort Consortium (BPC3), The PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium, (CAPS), C. O. T. P. I. S., Prostate Cancer Genome-wide Association Study of Uncommon Susceptibility Loci (PEGASUS), The Genetic Associations and Mechanisms in Oncology (GAME-ON)/Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE) Consortium, et al. (2018) · Nature Genetics · doi:10.1038/s41588-018-0142-8 · Cited by 902 · see citing works
A HapMap harvest of insights into the genetics of common disease
Manolio, T. A., Brooks, L. D., & Collins, F. S. (2008) · Journal of Clinical Investigation · doi:10.1172/jci34772 · Cited by 889 · see citing works
Little, J., Higgins, J. P. T., Ioannidis, J. P. A., Moher, D., Gagnon, F., von Elm, E., Khoury, M. J., Cohen, B., Davey-Smith, G., Grimshaw, J., et al. (2009) · PLoS Medicine · doi:10.1371/journal.pmed.1000022 · Cited by 811 · see citing works
Ramachandran, A., Wan Ma, R. C., & Snehalatha, C. (2010) · The Lancet · doi:10.1016/s0140-6736(09)60937-5 · Cited by 782 · see citing works
A brief history of human disease genetics
Claussnitzer, M., Cho, J. H., Collins, R., Cox, N. J., Dermitzakis, E. T., Hurles, M. E., Kathiresan, S., Kenny, E. E., Lindgren, C. M., MacArthur, D. G., et al. (2020) · Nature · doi:10.1038/s41586-019-1879-7 · Cited by 697 · see citing works
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Murphy, R., Ellard, S., & Hattersley, A. T. (2008) · Nature Clinical Practice Endocrinology & Metabolism · doi:10.1038/ncpendmet0778 · Cited by 502 · see citing works
Rung, J., Cauchi, S., Albrechtsen, A., Shen, L., Rocheleau, G., Cavalcanti-Proença, C., Bacot, F., Balkau, B., Belisle, A., Borch-Johnsen, K., et al. (2009) · Nature Genetics · doi:10.1038/ng.443 · Cited by 479 · see citing works
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Self-citationPerry, J. R. B., Weedon, M. N., Langenberg, C., Jackson, A. U., Lyssenko, V., Sparsø, T., Thorleifsson, G., Grallert, H., Ferrucci, L., Maggio, M., et al. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddp522 · Cited by 217 · see citing works
Self-citationWaters, K. M., Stram, D. O., Hassanein, M. T., Le Marchand, L., Wilkens, L. R., Maskarinec, G., Monroe, K. R., Kolonel, L. N., Altshuler, D., Henderson, B. E., et al. (2010) · PLoS Genetics · doi:10.1371/journal.pgen.1001078 · Cited by 191 · see citing works
Ahlqvist, E., Ahluwalia, T. S., & Groop, L. (2011) · Clinical Chemistry · doi:10.1373/clinchem.2010.157016 · Cited by 166 · see citing works
Tang, W.-Y., Morey, L. M., Cheung, Y. Y., Birch, L., Prins, G. S., & Ho, S.-M. (2012) · Endocrinology · doi:10.1210/en.2011-1308 · Cited by 164 · see citing works
Statistical methods to detect pleiotropy in human complex traits
Hackinger, S., & Zeggini, E. (2017) · Open Biology · doi:10.1098/rsob.170125 · Cited by 143 · see citing works
Waters, K. M., Le Marchand, L., Kolonel, L. N., Monroe, K. R., Stram, D. O., Henderson, B. E., & Haiman, C. A. (2009) · Cancer Epidemiology, Biomarkers & Prevention · doi:10.1158/1055-9965.epi-08-1142 · Cited by 116 · see citing works
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Sebastiani, P., Timofeev, N., Dworkis, D. A., Perls, T. T., & Steinberg, M. H. (2009) · American Journal of Hematology · doi:10.1002/ajh.21440 · Cited by 67 · see citing works
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Dandona, P., Dhindsa, S., Chandel, A., & Chaudhuri, A. (2009) · Postgraduate Medicine · doi:10.3810/pgm.2009.05.2001 · Cited by 47 · see citing works
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Klein, R. J., Xu, X., Mukherjee, S., Willis, J., & Hayes, J. (2010) · Cell · doi:10.1016/j.cell.2010.07.026 · Cited by 41 · see citing works
Genetic variants in<i>MTNR1B</i>affecting insulin secretion
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Billings, L. K., Jablonski, K. A., Warner, A. S., Cheng, Y.-C., McAteer, J. B., Tipton, L., Shuldiner, A. R., Ehrmann, D. A., Manning, A. K., Dabelea, D., et al. (2017) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2016-3429 · Cited by 20 · see citing works
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- Authors
- Gudmundsson, J., Sulem, P., Steinthorsdottir, V., Bergthorsson, J. T., Thorleifsson, G., Manolescu, A., Rafnar, T., Gudbjartsson, D., Agnarsson, B. A., Baker, A., Sigurdsson, A., Benediktsdottir, K. R., Jakobsdottir, M., Blondal, T., Stacey, S. N., Helgason, A., Gunnarsdottir, S., Olafsdottir, A., Kristinsson, K. T., Birgisdottir, B., Ghosh, S., Thorlacius, S., Magnusdottir, D., Stefansdottir, G., Kristjansson, K., Bagger, Y., Wilensky, R. L., Reilly, M. P., Morris, A. D., Kimber, C. H., Adeyemo, A., Chen, Y., Zhou, J., So, W.-Y., Tong, P. C. Y., Ng, M. C. Y., Hansen, T., Andersen, G., Borch-Johnsen, K., Jorgensen, T., Tres, A., Fuertes, F., Ruiz-Echarri, M., Asin, L., Saez, B., van Boven, E., Klaver, S., Swinkels, D. W., Aben, K. K., Graif, T., Cashy, J., Suarez, B. K., van Vierssen Trip, O., Frigge, M. L., Ober, C., Hofker, M. H., Wijmenga, C., Christiansen, C., Rader, D. J., Palmer, C. N. A., Rotimi, C., Chan, J. C. N., Pedersen, O., Sigurdsson, G., Benediktsson, R., Jonsson, E., Einarsson, G. V., Mayordomo, J. I., Catalona, W. J., Kiemeney, L. A., Barkardottir, R. B., Gulcher, J. R., Thorsteinsdottir, U., Kong, A., & Stefansson, K.
- Affiliations
- deCODE Genetics (Iceland) (IS)
- National University Hospital of Iceland (IS)
- Center for Clinical & Basic Research (DK)
- University of Pennsylvania (US)
- Ninewells Hospital (GB)
- Howard University (US)
- Chinese University of Hong Kong (HK)
- Steno Diabetes Center Copenhagen (DK)
- Universidad de Zaragoza (ES)
- Radboud University Nijmegen (NL)
- Northwestern University (US)
- Washington University in St. Louis (US)
- University of Chicago (US)
- University Medical Center Groningen (NL)
- Aarhus University (DK)
- ORCID
- Sulem, Patrick
- Manolescu, Andrei
- Gudbjartsson, Daniel
- Agnarsson, Bjarni A
- Baker, Adam
- Stacey, Simon N
- Helgason, Agnar
- Reilly, Muredach P
- Morris, Andrew D
- Adeyemo, Adebowale
- Zhou, Jie
- So, Wing-Yee
- Ng, Maggie C Y
- Hansen, Torben
- Andersen, Gitte
- Swinkels, Dorine W
- Aben, Katja K
- Frigge, Michael L
- Ober, Carole
- Wijmenga, Cisca
- Christiansen, Claus
- Rader, Daniel J
- Rotimi, Charles
- Chan, Juliana C N
- Pedersen, Oluf
- Benediktsson, Rafn
- Mayordomo, Jose I
- Kiemeney, Lambertus A
- Barkardottir, Rosa B
- Kong, Augustine
- Venue
- Nature Genetics
- Published
- 2007-07-01
- Volume
- 39
- Issue
- 8
- Pages
- 977-983
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2171682260
- Cited by
- 723
- References
- 23
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 7 · 2023: 16 · 2022: 8 · 2021: 11 · 2020: 19 · 2019: 8 · 2018: 16 · 2017: 21 · 2016: 23 · 2015: 35 · 2014: 40 · 2013: 48 · 2012: 71
- FWCI
- 57.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (submittedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Hirsla (Landspítali University Hospital) (submittedVersion)
- Funders
- Wellcome Trust
- Radboud Universiteit
- National Institutes of Health (5r01dk072128-04)
- Fogarty International Center (T37TW000041, 3T37TW00041-03S2)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK072128)
- National Center for Research Resources (RR03048)
- 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
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Diagnosis and Treatment
- Keywords
- prostate cancer, chromosome 17, HNF1B, type 2 diabetes, genetic susceptibility, single nucleotide polymorphisms, population attributable risk
- MeSH terms
- Chromosomes, Human, Pair 17, Diabetes Mellitus, Type 2, Haplotypes, Humans, Male, Prostatic Neoplasms, Case-Control Studies, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Hepatocyte Nuclear Factor 1-beta
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