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.
authors.affiliation: Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California 94158, USA.|Institute for Human Genetics, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hoffmann
authors.affiliation: Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California 94158, USA.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Passarelli
authors.affiliation: Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California 94158, USA.
authors.forename: Rebecca E
authors.identifier: 0000-0003-0316-8303
authors.initials: RE
authors.lastname: Graff
authors.affiliation: Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California 94158, USA.
authors.forename: Nima C
authors.initials: NC
authors.lastname: Emami
authors.affiliation: Division of Research, Kaiser Permanente, Northern California, Oakland, California 94612, USA.
authors.forename: Lori C
authors.initials: LC
authors.lastname: Sakoda
authors.affiliation: Division of Research, Kaiser Permanente, Northern California, Oakland, California 94612, USA.
authors.forename: Eric
authors.identifier: 0000-0002-5829-8191
authors.initials: E
authors.lastname: Jorgenson
authors.affiliation: Division of Research, Kaiser Permanente, Northern California, Oakland, California 94612, USA.
authors.forename: Laurel A
authors.initials: LA
authors.lastname: Habel
authors.affiliation: Division of Research, Kaiser Permanente, Northern California, Oakland, California 94612, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Shan
authors.affiliation: Division of Research, Kaiser Permanente, Northern California, Oakland, California 94612, USA.
authors.forename: Dilrini K
authors.initials: DK
authors.lastname: Ranatunga
authors.affiliation: Division of Research, Kaiser Permanente, Northern California, Oakland, California 94612, USA.
authors.forename: Charles P
authors.initials: CP
authors.lastname: Quesenberry
authors.affiliation: Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California 91101, USA.
authors.forename: Chun R
authors.initials: CR
authors.lastname: Chao
authors.affiliation: Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California 91101, USA.
authors.forename: Nirupa R
authors.initials: NR
authors.lastname: Ghai
authors.affiliation: Department of Urology, Kaiser Oakland Medical Center, Northern California, Oakland, California 94612, USA.
authors.forename: David
authors.initials: D
authors.lastname: Aaronson
authors.affiliation: Department of Urology, Kaiser Oakland Medical Center, Northern California, Oakland, California 94612, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Presti
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden.
authors.forename: Tobias
authors.initials: T
authors.lastname: Nordström
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20814, USA.
authors.forename: Zhaoming
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20814, USA.
authors.forename: Sonja I
authors.initials: SI
authors.lastname: Berndt
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20814, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Mosley
authors.affiliation: Icahn Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029 USA.|Departments of Laboratory Medicine, Surgery, and Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.|Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 7LD, UK.|Department of Translational Medicine, Lund University, Malmö 205 02, Sweden.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Klein
authors.affiliation: Icahn Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029 USA.|Departments of Laboratory Medicine, Surgery, and Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.|Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 7LD, UK.|Department of Translational Medicine, Lund University, Malmö 205 02, Sweden.
authors.forename: Mridu
authors.initials: M
authors.lastname: Middha
authors.affiliation: Departments of Laboratory Medicine, Surgery, and Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.|Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 7LD, UK.|Department of Translational Medicine, Lund University, Malmö 205 02, Sweden.
authors.forename: Hans
authors.initials: H
authors.lastname: Lilja
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö 205 02, Sweden.
authors.forename: Olle
authors.initials: O
authors.lastname: Melander
authors.affiliation: Institute for Human Genetics, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Mark N
authors.initials: MN
authors.lastname: Kvale
authors.affiliation: Institute for Human Genetics, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Pui-Yan
authors.initials: PY
authors.lastname: Kwok
authors.affiliation: Division of Research, Kaiser Permanente, Northern California, Oakland, California 94612, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Schaefer
authors.affiliation: Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California 94158, USA.|Institute for Human Genetics, University of California San Francisco, San Francisco, California 94143, USA.|Division of Research, Kaiser Permanente, Northern California, Oakland, California 94612, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Risch
authors.affiliation: Division of Research, Kaiser Permanente, Northern California, Oakland, California 94612, USA.|Department of Urology, University of California San Francisco, San Francisco, California 94158, USA.
authors.forename: Stephen K
authors.identifier: 0000-0002-5599-8387
authors.initials: SK
authors.lastname: Van Den Eeden
authors.affiliation: Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California 94158, USA.|Institute for Human Genetics, University of California San Francisco, San Francisco, California 94143, USA.|Department of Urology, University of California San Francisco, San Francisco, California 94158, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Witte
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D044466:Asian People; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D044383:Black People; D015870:Gene Expression; D005787:Gene Frequency; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D017430:Prostate-Specific Antigen / Q000235:genetics* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D044465:White People
chemical_list: D014408:Biomarkers, Tumor; D017430:Prostate-Specific Antigen