A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer

Julius Gudmundsson; Patrick Sulem; Daniel F. Gudbjartsson; Gisli Masson; Bjarni A. Agnarsson; Kristrun R. Benediktsdottir; Asgeir Sigurdsson; Olafur Th Magnusson; Sigurjon A. Gudjonsson; Droplaug N. Magnusdottir; Hrefna Johannsdottir; Hafdis Th Helgadottir; Simon N. Stacey; Adalbjorg Jonasdottir; Stefania B. Olafsdottir; Gudmar Thorleifsson; Jon G. Jonasson; Laufey Tryggvadottir; Sebastian Navarrete; Fernando Fuertes; Brian T. Helfand; Qiaoyan Hu; Irma E. Csiki; Ioan N. Mates; Viorel Jinga; Katja K.H. Aben; Inge M. Van Oort; Sita H. Vermeulen; Jenny L. Donovan; Freddy C. Hamdy; Chi Fai Ng; Peter K.F. Chiu; Kin Mang Lau; Maggie C.Y. Ng; Jeffrey R. Gulcher; Augustine Kong; William J. Catalona; Jose I. Mayordomo; Gudmundur V. Einarsson; Rosa B. Barkardottir; Eiríkur Jónsson; Dana Mates; David E. Neal; Lambertus A. Kiemeney; Unnur Thorsteinsdottir; Thorunn Rafnar; Kari Stefansson

doi:10.1038/ng.2437

A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer

Julius Gudmundsson^*, Patrick Sulem, Daniel F. Gudbjartsson, Gisli Masson, Bjarni A. Agnarsson, Kristrun R. Benediktsdottir, Asgeir Sigurdsson, Olafur Th Magnusson, Sigurjon A. Gudjonsson, Droplaug N. Magnusdottir, Hrefna Johannsdottir, Hafdis Th Helgadottir, Simon N. Stacey, Adalbjorg Jonasdottir, Stefania B. Olafsdottir, Gudmar Thorleifsson, Jon G. Jonasson, Laufey Tryggvadottir, Sebastian Navarrete, Fernando FuertesBrian T. Helfand, Qiaoyan Hu, Irma E. Csiki, Ioan N. Mates, Viorel Jinga, Katja K.H. Aben, Inge M. Van Oort, Sita H. Vermeulen, Jenny L. Donovan, Freddy C. Hamdy, Chi Fai Ng, Peter K.F. Chiu, Kin Mang Lau, Maggie C.Y. Ng, Jeffrey R. Gulcher, Augustine Kong, William J. Catalona, Jose I. Mayordomo, Gudmundur V. Einarsson, Rosa B. Barkardottir, Eiríkur Jónsson, Dana Mates, David E. Neal, Lambertus A. Kiemeney, Unnur Thorsteinsdottir, Thorunn Rafnar, Kari Stefansson

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

142 Citations (Scopus)

Abstract

In Western countries, prostate cancer is the most prevalent cancer of men and one of the leading causes of cancer-related death in men. Several genome-wide association studies have yielded numerous common variants conferring risk of prostate cancer. Here, we analyzed 32.5 million variants discovered by whole-genome sequencing 1,795 Icelanders. We identified a new low-frequency variant at 8q24 associated with prostate cancer in European populations, rs188140481[A] (odds ratio (OR) = 2.90; P combined = 6.2 × 10-34), with an average risk allele frequency in controls of 0.54%. This variant is only very weakly correlated (r 2 ≤ 0.06) with previously reported risk variants at 8q24, and its association remains significant after adjustment for all known risk-associated variants. Carriers of rs188140481[A] were diagnosed with prostate cancer 1.26 years younger than non-carriers (P = 0.0059). We also report results for a previously described HOXB13 variant (rs138213197[T]), confirming it as a prostate cancer risk variant in populations from across Europe.

Original language	English
Pages (from-to)	1326-1329
Number of pages	4
Journal	Nature Genetics
Volume	44
Issue number	12
DOIs	https://doi.org/10.1038/ng.2437
Publication status	Published - Dec 2012

Bibliographical note

Funding Information:
We thank the individuals who participated in the study and whose contribution made this work possible. This project was funded in part by contract number 202059 (PROMARK) from the Seventh Framework Programme of the European Union and, in part, by the Urological Research Foundation (U01 CA089600, P50 CA90386 and P30 CA60553). The UK ProtecT study is ongoing and is funded by the Health Technology Assessment Programme (projects 96/20/06 and 96/20/99). The ProtecT trial is supported by the Department of Health, England; Cancer Research UK grant C522/A8649; Medical Research Council of England grant G0500966_ID-75466; the National Cancer Research Institute (NCRI), UK; and the Southwest National Health Service Research and Development. The biorepository from ProtecT is supported by the NCRI (ProMPT) study and Cambridge and Oxford British Medical Research Council grants from the National Institute for Health Research.

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10.1038/ng.2437

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Gudmundsson, J., Sulem, P., Gudbjartsson, D. F., Masson, G., Agnarsson, B. A., Benediktsdottir, K. R., Sigurdsson, A., Magnusson, O. T., Gudjonsson, S. A., Magnusdottir, D. N., Johannsdottir, H., Helgadottir, H. T., Stacey, S. N., Jonasdottir, A., Olafsdottir, S. B., Thorleifsson, G., Jonasson, J. G., Tryggvadottir, L., Navarrete, S., ... Stefansson, K. (2012). A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer. Nature Genetics, 44(12), 1326-1329. https://doi.org/10.1038/ng.2437

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title = "A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer",

abstract = "In Western countries, prostate cancer is the most prevalent cancer of men and one of the leading causes of cancer-related death in men. Several genome-wide association studies have yielded numerous common variants conferring risk of prostate cancer. Here, we analyzed 32.5 million variants discovered by whole-genome sequencing 1,795 Icelanders. We identified a new low-frequency variant at 8q24 associated with prostate cancer in European populations, rs188140481[A] (odds ratio (OR) = 2.90; P combined = 6.2 × 10-34), with an average risk allele frequency in controls of 0.54%. This variant is only very weakly correlated (r 2 ≤ 0.06) with previously reported risk variants at 8q24, and its association remains significant after adjustment for all known risk-associated variants. Carriers of rs188140481[A] were diagnosed with prostate cancer 1.26 years younger than non-carriers (P = 0.0059). We also report results for a previously described HOXB13 variant (rs138213197[T]), confirming it as a prostate cancer risk variant in populations from across Europe.",

author = "Julius Gudmundsson and Patrick Sulem and Gudbjartsson, {Daniel F.} and Gisli Masson and Agnarsson, {Bjarni A.} and Benediktsdottir, {Kristrun R.} and Asgeir Sigurdsson and Magnusson, {Olafur Th} and Gudjonsson, {Sigurjon A.} and Magnusdottir, {Droplaug N.} and Hrefna Johannsdottir and Helgadottir, {Hafdis Th} and Stacey, {Simon N.} and Adalbjorg Jonasdottir and Olafsdottir, {Stefania B.} and Gudmar Thorleifsson and Jonasson, {Jon G.} and Laufey Tryggvadottir and Sebastian Navarrete and Fernando Fuertes and Helfand, {Brian T.} and Qiaoyan Hu and Csiki, {Irma E.} and Mates, {Ioan N.} and Viorel Jinga and Aben, {Katja K.H.} and {Van Oort}, {Inge M.} and Vermeulen, {Sita H.} and Donovan, {Jenny L.} and Hamdy, {Freddy C.} and Ng, {Chi Fai} and Chiu, {Peter K.F.} and Lau, {Kin Mang} and Ng, {Maggie C.Y.} and Gulcher, {Jeffrey R.} and Augustine Kong and Catalona, {William J.} and Mayordomo, {Jose I.} and Einarsson, {Gudmundur V.} and Barkardottir, {Rosa B.} and Eir{\'i}kur J{\'o}nsson and Dana Mates and Neal, {David E.} and Kiemeney, {Lambertus A.} and Unnur Thorsteinsdottir and Thorunn Rafnar and Kari Stefansson",

note = "Funding Information: We thank the individuals who participated in the study and whose contribution made this work possible. This project was funded in part by contract number 202059 (PROMARK) from the Seventh Framework Programme of the European Union and, in part, by the Urological Research Foundation (U01 CA089600, P50 CA90386 and P30 CA60553). The UK ProtecT study is ongoing and is funded by the Health Technology Assessment Programme (projects 96/20/06 and 96/20/99). The ProtecT trial is supported by the Department of Health, England; Cancer Research UK grant C522/A8649; Medical Research Council of England grant G0500966_ID-75466; the National Cancer Research Institute (NCRI), UK; and the Southwest National Health Service Research and Development. The biorepository from ProtecT is supported by the NCRI (ProMPT) study and Cambridge and Oxford British Medical Research Council grants from the National Institute for Health Research.",

year = "2012",

month = dec,

doi = "10.1038/ng.2437",

language = "English",

volume = "44",

pages = "1326--1329",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "12",

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Gudmundsson, J, Sulem, P, Gudbjartsson, DF, Masson, G, Agnarsson, BA, Benediktsdottir, KR, Sigurdsson, A, Magnusson, OT, Gudjonsson, SA, Magnusdottir, DN, Johannsdottir, H, Helgadottir, HT, Stacey, SN, Jonasdottir, A, Olafsdottir, SB, Thorleifsson, G, Jonasson, JG, Tryggvadottir, L, Navarrete, S, Fuertes, F, Helfand, BT, Hu, Q, Csiki, IE, Mates, IN, Jinga, V, Aben, KKH, Van Oort, IM, Vermeulen, SH, Donovan, JL, Hamdy, FC, Ng, CF, Chiu, PKF, Lau, KM, Ng, MCY, Gulcher, JR, Kong, A, Catalona, WJ, Mayordomo, JI, Einarsson, GV, Barkardottir, RB, Jónsson, E, Mates, D, Neal, DE, Kiemeney, LA, Thorsteinsdottir, U, Rafnar, T & Stefansson, K 2012, 'A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer', Nature Genetics, vol. 44, no. 12, pp. 1326-1329. https://doi.org/10.1038/ng.2437

TY - JOUR

T1 - A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer

AU - Gudmundsson, Julius

AU - Sulem, Patrick

AU - Gudbjartsson, Daniel F.

AU - Masson, Gisli

AU - Agnarsson, Bjarni A.

AU - Benediktsdottir, Kristrun R.

AU - Sigurdsson, Asgeir

AU - Magnusson, Olafur Th

AU - Gudjonsson, Sigurjon A.

AU - Magnusdottir, Droplaug N.

AU - Johannsdottir, Hrefna

AU - Helgadottir, Hafdis Th

AU - Stacey, Simon N.

AU - Jonasdottir, Adalbjorg

AU - Olafsdottir, Stefania B.

AU - Thorleifsson, Gudmar

AU - Jonasson, Jon G.

AU - Tryggvadottir, Laufey

AU - Navarrete, Sebastian

AU - Fuertes, Fernando

AU - Helfand, Brian T.

AU - Hu, Qiaoyan

AU - Csiki, Irma E.

AU - Mates, Ioan N.

AU - Jinga, Viorel

AU - Aben, Katja K.H.

AU - Van Oort, Inge M.

AU - Vermeulen, Sita H.

AU - Donovan, Jenny L.

AU - Hamdy, Freddy C.

AU - Ng, Chi Fai

AU - Chiu, Peter K.F.

AU - Lau, Kin Mang

AU - Ng, Maggie C.Y.

AU - Gulcher, Jeffrey R.

AU - Kong, Augustine

AU - Catalona, William J.

AU - Mayordomo, Jose I.

AU - Einarsson, Gudmundur V.

AU - Barkardottir, Rosa B.

AU - Jónsson, Eiríkur

AU - Mates, Dana

AU - Neal, David E.

AU - Kiemeney, Lambertus A.

AU - Thorsteinsdottir, Unnur

AU - Rafnar, Thorunn

AU - Stefansson, Kari

N1 - Funding Information: We thank the individuals who participated in the study and whose contribution made this work possible. This project was funded in part by contract number 202059 (PROMARK) from the Seventh Framework Programme of the European Union and, in part, by the Urological Research Foundation (U01 CA089600, P50 CA90386 and P30 CA60553). The UK ProtecT study is ongoing and is funded by the Health Technology Assessment Programme (projects 96/20/06 and 96/20/99). The ProtecT trial is supported by the Department of Health, England; Cancer Research UK grant C522/A8649; Medical Research Council of England grant G0500966_ID-75466; the National Cancer Research Institute (NCRI), UK; and the Southwest National Health Service Research and Development. The biorepository from ProtecT is supported by the NCRI (ProMPT) study and Cambridge and Oxford British Medical Research Council grants from the National Institute for Health Research.

PY - 2012/12

Y1 - 2012/12

N2 - In Western countries, prostate cancer is the most prevalent cancer of men and one of the leading causes of cancer-related death in men. Several genome-wide association studies have yielded numerous common variants conferring risk of prostate cancer. Here, we analyzed 32.5 million variants discovered by whole-genome sequencing 1,795 Icelanders. We identified a new low-frequency variant at 8q24 associated with prostate cancer in European populations, rs188140481[A] (odds ratio (OR) = 2.90; P combined = 6.2 × 10-34), with an average risk allele frequency in controls of 0.54%. This variant is only very weakly correlated (r 2 ≤ 0.06) with previously reported risk variants at 8q24, and its association remains significant after adjustment for all known risk-associated variants. Carriers of rs188140481[A] were diagnosed with prostate cancer 1.26 years younger than non-carriers (P = 0.0059). We also report results for a previously described HOXB13 variant (rs138213197[T]), confirming it as a prostate cancer risk variant in populations from across Europe.

AB - In Western countries, prostate cancer is the most prevalent cancer of men and one of the leading causes of cancer-related death in men. Several genome-wide association studies have yielded numerous common variants conferring risk of prostate cancer. Here, we analyzed 32.5 million variants discovered by whole-genome sequencing 1,795 Icelanders. We identified a new low-frequency variant at 8q24 associated with prostate cancer in European populations, rs188140481[A] (odds ratio (OR) = 2.90; P combined = 6.2 × 10-34), with an average risk allele frequency in controls of 0.54%. This variant is only very weakly correlated (r 2 ≤ 0.06) with previously reported risk variants at 8q24, and its association remains significant after adjustment for all known risk-associated variants. Carriers of rs188140481[A] were diagnosed with prostate cancer 1.26 years younger than non-carriers (P = 0.0059). We also report results for a previously described HOXB13 variant (rs138213197[T]), confirming it as a prostate cancer risk variant in populations from across Europe.

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VL - 44

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EP - 1329

JO - Nature Genetics

JF - Nature Genetics

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ER -

A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer

Abstract

Bibliographical note

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