Genome-wide association study of prostate-specific antigen levels identifies novel loci independent of prostate cancer

Thomas J. Hoffmann; Michael N. Passarelli; Rebecca E. Graff; Nima C. Emami; Lori C. Sakoda; Eric Jorgenson; Laurel A. Habel; Jun Shan; Dilrini K. Ranatunga; Charles P. Quesenberry; Chun R. Chao; Nirupa R. Ghai; David Aaronson; Joseph Presti; Tobias Nordström; Zhaoming Wang; Sonja I. Berndt; Stephen J. Chanock; Jonathan D. Mosley; Robert J. Klein; Mridu Middha; Hans Lilja; Olle Melander; Mark N. Kvale; Pui Yan Kwok; Catherine Schaefer; Neil Risch; Stephen K. Van Den Eeden; John S. Witte

doi:10.1038/ncomms14248

Genome-wide association study of prostate-specific antigen levels identifies novel loci independent of prostate cancer

Thomas J. Hoffmann, Michael N. Passarelli, Rebecca E. Graff, Nima C. Emami, Lori C. Sakoda, Eric Jorgenson, Laurel A. Habel, Jun Shan, Dilrini K. Ranatunga, Charles P. Quesenberry, Chun R. Chao, Nirupa R. Ghai, David Aaronson, Joseph Presti, Tobias Nordström, Zhaoming Wang, Sonja I. Berndt, Stephen J. Chanock, Jonathan D. Mosley, Robert J. KleinMridu Middha, Hans Lilja, Olle Melander, Mark N. Kvale, Pui Yan Kwok, Catherine Schaefer, Neil Risch, Stephen K. Van Den Eeden, John S. Witte

School of Medicine

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

30 Scopus citations

Abstract

Prostate-specific antigen (PSA) levels have been used for detection and surveillance of prostate cancer (PCa). However, factors other than PCa - such as genetics - can impact PSA. Here we present findings from a genome-wide association study (GWAS) of PSA in 28,503 Kaiser Permanente whites and 17,428 men from replication cohorts. We detect 40 genome-wide significant (P<5 × 10^-8) single-nucleotide polymorphisms (SNPs): 19 novel, 15 previously identified for PSA (14 of which were also PCa-associated), and 6 previously identified for PCa only. Further analysis incorporating PCa cases suggests that at least half of the 40 SNPs are PSA-associated independent of PCa. The 40 SNPs explain 9.5% of PSA variation in non-Hispanic whites, and the remaining GWAS SNPs explain an additional 31.7%; this percentage is higher in younger men, supporting the genetic basis of PSA levels. These findings provide important information about genetic markers for PSA that may improve PCa screening, thereby reducing over-diagnosis and over-treatment.

Original language	English (US)
Article number	14248
Journal	Nature communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms14248
State	Published - Jan 31 2017

ASJC Scopus subject areas

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Physics and Astronomy(all)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)

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Hoffmann, T. J., Passarelli, M. N., Graff, R. E., Emami, N. C., Sakoda, L. C., Jorgenson, E., Habel, L. A., Shan, J., Ranatunga, D. K., Quesenberry, C. P., Chao, C. R., Ghai, N. R., Aaronson, D., Presti, J., Nordström, T., Wang, Z., Berndt, S. I., Chanock, S. J., Mosley, J. D., ... Witte, J. S. (2017). Genome-wide association study of prostate-specific antigen levels identifies novel loci independent of prostate cancer. Nature communications, 8, [14248]. https://doi.org/10.1038/ncomms14248

Hoffmann, TJ, Passarelli, MN, Graff, RE, Emami, NC, Sakoda, LC, Jorgenson, E, Habel, LA, Shan, J, Ranatunga, DK, Quesenberry, CP, Chao, CR, Ghai, NR, Aaronson, D, Presti, J, Nordström, T, Wang, Z, Berndt, SI, Chanock, SJ, Mosley, JD, Klein, RJ, Middha, M, Lilja, H, Melander, O, Kvale, MN, Kwok, PY, Schaefer, C, Risch, N, Van Den Eeden, SK & Witte, JS 2017, 'Genome-wide association study of prostate-specific antigen levels identifies novel loci independent of prostate cancer', Nature communications, vol. 8, 14248. https://doi.org/10.1038/ncomms14248

@article{c201935fb6f24df3936529537c3a9a45,

title = "Genome-wide association study of prostate-specific antigen levels identifies novel loci independent of prostate cancer",

abstract = "Prostate-specific antigen (PSA) levels have been used for detection and surveillance of prostate cancer (PCa). However, factors other than PCa - such as genetics - can impact PSA. Here we present findings from a genome-wide association study (GWAS) of PSA in 28,503 Kaiser Permanente whites and 17,428 men from replication cohorts. We detect 40 genome-wide significant (P<5 × 10-8) single-nucleotide polymorphisms (SNPs): 19 novel, 15 previously identified for PSA (14 of which were also PCa-associated), and 6 previously identified for PCa only. Further analysis incorporating PCa cases suggests that at least half of the 40 SNPs are PSA-associated independent of PCa. The 40 SNPs explain 9.5% of PSA variation in non-Hispanic whites, and the remaining GWAS SNPs explain an additional 31.7%; this percentage is higher in younger men, supporting the genetic basis of PSA levels. These findings provide important information about genetic markers for PSA that may improve PCa screening, thereby reducing over-diagnosis and over-treatment.",

author = "Hoffmann, {Thomas J.} and Passarelli, {Michael N.} and Graff, {Rebecca E.} and Emami, {Nima C.} and Sakoda, {Lori C.} and Eric Jorgenson and Habel, {Laurel A.} and Jun Shan and Ranatunga, {Dilrini K.} and Quesenberry, {Charles P.} and Chao, {Chun R.} and Ghai, {Nirupa R.} and David Aaronson and Joseph Presti and Tobias Nordstr{\"o}m and Zhaoming Wang and Berndt, {Sonja I.} and Chanock, {Stephen J.} and Mosley, {Jonathan D.} and Klein, {Robert J.} and Mridu Middha and Hans Lilja and Olle Melander and Kvale, {Mark N.} and Kwok, {Pui Yan} and Catherine Schaefer and Neil Risch and {Van Den Eeden}, {Stephen K.} and Witte, {John S.}",

note = "Funding Information: This work was supported by NIH grants CA127298, CA088164 and CA112355 (J.S.W., M.N.P. and R.E.G.), the UCSF Goldberg-Benioff Program in Cancer Translational Biology (J.S.W.), and a career development award from the Vanderbilt Faculty Research Scholars Fund (J.D.M.). Support for participant enrollment, survey completion, and biospecimen collection for the RPGEH was provided by the Robert Wood Johnson Foundation, the Wayne and Gladys Valley Foundation, the Ellison Medical Foundation, and Kaiser Permanente national and regional community benefit programs. Genotyping of the GERA cohort was funded by a grant from the National Institute on Aging, the National Institute of Mental Health, and the NIH Common Fund (RC2 AG036607 to C.A.S. and N.J.R.). PEGASUS was supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH. BioVU is supported by institutional funding and by the Vanderbilt CTSA grant UL1TR000445 (NCATS/NIH), RC2GM092618 (NIGMS/OD) and U01HG004603 (NHGRI/NIGMS).The analysis of the Malmo Diet and Cancer cohort was supported by the NIH R01 CA175491. Publisher Copyright: {\textcopyright} The Author(s) 2017.",

year = "2017",

month = jan,

day = "31",

doi = "10.1038/ncomms14248",

language = "English (US)",

volume = "8",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Genome-wide association study of prostate-specific antigen levels identifies novel loci independent of prostate cancer

AU - Hoffmann, Thomas J.

AU - Passarelli, Michael N.

AU - Graff, Rebecca E.

AU - Emami, Nima C.

AU - Sakoda, Lori C.

AU - Jorgenson, Eric

AU - Habel, Laurel A.

AU - Shan, Jun

AU - Ranatunga, Dilrini K.

AU - Quesenberry, Charles P.

AU - Chao, Chun R.

AU - Ghai, Nirupa R.

AU - Aaronson, David

AU - Presti, Joseph

AU - Nordström, Tobias

AU - Wang, Zhaoming

AU - Berndt, Sonja I.

AU - Chanock, Stephen J.

AU - Mosley, Jonathan D.

AU - Klein, Robert J.

AU - Middha, Mridu

AU - Lilja, Hans

AU - Melander, Olle

AU - Kvale, Mark N.

AU - Kwok, Pui Yan

AU - Schaefer, Catherine

AU - Risch, Neil

AU - Van Den Eeden, Stephen K.

AU - Witte, John S.

N1 - Funding Information: This work was supported by NIH grants CA127298, CA088164 and CA112355 (J.S.W., M.N.P. and R.E.G.), the UCSF Goldberg-Benioff Program in Cancer Translational Biology (J.S.W.), and a career development award from the Vanderbilt Faculty Research Scholars Fund (J.D.M.). Support for participant enrollment, survey completion, and biospecimen collection for the RPGEH was provided by the Robert Wood Johnson Foundation, the Wayne and Gladys Valley Foundation, the Ellison Medical Foundation, and Kaiser Permanente national and regional community benefit programs. Genotyping of the GERA cohort was funded by a grant from the National Institute on Aging, the National Institute of Mental Health, and the NIH Common Fund (RC2 AG036607 to C.A.S. and N.J.R.). PEGASUS was supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH. BioVU is supported by institutional funding and by the Vanderbilt CTSA grant UL1TR000445 (NCATS/NIH), RC2GM092618 (NIGMS/OD) and U01HG004603 (NHGRI/NIGMS).The analysis of the Malmo Diet and Cancer cohort was supported by the NIH R01 CA175491. Publisher Copyright: © The Author(s) 2017.

PY - 2017/1/31

Y1 - 2017/1/31

N2 - Prostate-specific antigen (PSA) levels have been used for detection and surveillance of prostate cancer (PCa). However, factors other than PCa - such as genetics - can impact PSA. Here we present findings from a genome-wide association study (GWAS) of PSA in 28,503 Kaiser Permanente whites and 17,428 men from replication cohorts. We detect 40 genome-wide significant (P<5 × 10-8) single-nucleotide polymorphisms (SNPs): 19 novel, 15 previously identified for PSA (14 of which were also PCa-associated), and 6 previously identified for PCa only. Further analysis incorporating PCa cases suggests that at least half of the 40 SNPs are PSA-associated independent of PCa. The 40 SNPs explain 9.5% of PSA variation in non-Hispanic whites, and the remaining GWAS SNPs explain an additional 31.7%; this percentage is higher in younger men, supporting the genetic basis of PSA levels. These findings provide important information about genetic markers for PSA that may improve PCa screening, thereby reducing over-diagnosis and over-treatment.

AB - Prostate-specific antigen (PSA) levels have been used for detection and surveillance of prostate cancer (PCa). However, factors other than PCa - such as genetics - can impact PSA. Here we present findings from a genome-wide association study (GWAS) of PSA in 28,503 Kaiser Permanente whites and 17,428 men from replication cohorts. We detect 40 genome-wide significant (P<5 × 10-8) single-nucleotide polymorphisms (SNPs): 19 novel, 15 previously identified for PSA (14 of which were also PCa-associated), and 6 previously identified for PCa only. Further analysis incorporating PCa cases suggests that at least half of the 40 SNPs are PSA-associated independent of PCa. The 40 SNPs explain 9.5% of PSA variation in non-Hispanic whites, and the remaining GWAS SNPs explain an additional 31.7%; this percentage is higher in younger men, supporting the genetic basis of PSA levels. These findings provide important information about genetic markers for PSA that may improve PCa screening, thereby reducing over-diagnosis and over-treatment.

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UR - http://www.scopus.com/inward/citedby.url?scp=85011317435&partnerID=8YFLogxK

U2 - 10.1038/ncomms14248

DO - 10.1038/ncomms14248

M3 - Article

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AN - SCOPUS:85011317435

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

M1 - 14248

ER -

Genome-wide association study of prostate-specific antigen levels identifies novel loci independent of prostate cancer

Abstract

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