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Genome-Wide Association Study of Prostate-Specific Antigen Levels

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Genome-Wide Association Study of Prostate-Specific Antigen Levels ARTICLE Received 29 Jul 2016 | Accepted 12 Dec 2016 | Published 31 Jan 2017 DOI: 10.1038/ncomms14248 OPEN Genome-wide association study of prostate- specific antigen levels identifies novel loci independent of prostate cancer Thomas J. Hoffmann1,2,*, Michael N. Passarelli1,*, Rebecca E. Graff1, Nima C. Emami1, Lori C. Sakoda3, Eric Jorgenson3, Laurel A. Habel3, Jun Shan3, Dilrini K. Ranatunga3, Charles P. Quesenberry3, Chun R. Chao4, Nirupa R. Ghai4, David Aaronson5, Joseph Presti5, Tobias Nordstro¨m6, Zhaoming Wang7, Sonja I. Berndt7, Stephen J. Chanock7, Jonathan D. Mosley8, Robert J. Klein9,10,11,12, Mridu Middha9,10,11,12, Hans Lilja10,11,12, Olle Melander13, Mark N. Kvale2, Pui-Yan Kwok2, Catherine Schaefer3, Neil Risch1,2,3, Stephen K. Van Den Eeden3,14 & John S. Witte1,2,14 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 (Po5 Â 10 À 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. 1 Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California 94158, USA. 2 Institute for Human Genetics, University of California San Francisco, San Francisco, California 94143, USA. 3 Division of Research, Kaiser Permanente, Northern California, Oakland, California 94612, USA. 4 Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California 91101, USA. 5 Department of Urology, Kaiser Oakland Medical Center, Northern California, Oakland, California 94612, USA. 6 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden. 7 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. 8 Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA. 9 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. 10 Departments of Laboratory Medicine, Surgery, and Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. 11 Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 7LD, UK. 12 Department of Translational Medicine, Lund University, Malmo¨ 205 02, Sweden. 13 Department of Clinical Sciences, Lund University, Malmo¨ 205 02, Sweden. 14 Department of Urology, University of California San Francisco, San Francisco, California 94158, USA. * These authors contributed equally to this work. Correspondence and requests for materials should be addressed to S.K.V.D.E. (email: [email protected]) or to J.S.W. (email: [email protected]). NATURE COMMUNICATIONS | 8:14248 | DOI: 10.1038/ncomms14248 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms14248 rostate specific antigen (PSA) is a blood-based biomarker (1) true disease-related increases in PSA levels; (2) the use of used for the detection and surveillance of prostate cancer PSA levels to restrict controls in case-control studies of PCa; P(PCa)1. PCa can cause disruption of the prostate’s cellular and/or 3) non-cancer related PSA levels that prompt additional architecture, which in turn can result in PSA leaking biopsy screening (Supplementary Fig. 1). One study reported14 into circulating blood. However, PSA levels can also be affected that correcting PSA levels using four PSA-associated variants by benign prostatic hyperplasia (BPH), local inflammation reclassifies 3.0% of individuals as needing biopsies and 3.0% as or infection, prostate volume, age2, and germline genetics. In not needing biopsies. It did not, however, assess whether cases this regard, PSA is an organ—but not cancer—specific biomarker. and controls were reclassified in the desired direction or look at PSA screening for PCa has been used for over 20 years, but its clinical outcomes. use has declined recently because of concerns about over- To discover more variants directly associated with PSA levels, diagnosis and over-treatment3,4. While PSA levels at mid-life may here we undertake a large genome-wide association study modestly predict long-term PCa risk5, and high PSA levels are (GWAS) of PSA. Our study includes a total of 45,931 men: correlated with more aggressive and lethal forms of disease6–8, 40,328 men from a large Kaiser Permanente (KP) cohort25,26 and low PSA levels do not rule out PCa, and high PSA levels have 5,603 independent controls. We first search genome-wide for a low predictive value for PCa9. In the Prostate, Lung, Colorectal, variants associated with PSA levels among KP non-Hispanic Ovarian (PLCO) Cancer Screening Trial, which had substantial white non-cases (i.e., individuals who had not been diagnosed crossover, there was no appreciable reduction in mortality with PCa, N ¼ 28,503). Then we test our findings for replication directly related to PSA screening10. Another randomized in the remaining 17,428 men, comprised of 11,825 additional trial, however, showed that PSA screening may reduce men in the KP cohort (non-cases of other race or ethnicity PCa mortality11. Between 20 and 60% of PSA-screened PCas groups, and PCa cases using their PSA levels at least two years are estimated to be over-diagnoses, and non-aggressive before cancer diagnosis) and 5,603 external replication non-cases. PSA-detected PCas are often treated with therapy that may We further investigate which variants were exclusively associated involve substantial side effects12,13. with PSA levels and not with PCa in the KP cohort. Finally, The value of PSA screening may be higher among individuals we assess how much variation in PSA levels is explained by defined by particular characteristics, such as family history of the replicated variants and how much can be explained by the PCa, ethnicity, age, and genetic factors. PSA is a glycoprotein remaining SNPs on the array. enzyme encoded by kallikrein-3 (KLK3) on chromosome 19, but evidence from genetic association studies suggests that PSA levels are a complex polygenic trait, influenced by several different Results genes. Determining the genetic basis of PSA levels unrelated to GWAS of PSA levels. Details of the discovery and replication cancer may help increase both the sensitivity and specificity of samples are presented in Table 1. The discovery GWAS included screening for PCa by adjusting PSA levels for constitutive 28,503 non-Hispanic white men from KP who had not been germline genetics. Doing so could improve PSA screening diagnosed with PCa at the time of the electronic health record performance. Clinicians could more accurately decide who should (EHR) data extraction in 2012. The 17,428 replication samples have a prostate biopsy, thereby reducing unnecessary procedures included KP non-cases of Latino, East Asian, and African and their associated morbidities, as well as decreasing over- American backgrounds, KP non-Hispanic white PCa cases diagnosis14,15. (using PSA measures from at least two years prior to diagnosis), Twin studies estimate that 40–45% of the variation in and three independent studies of non-Hispanic white non-cases. PSA levels can be explained by inherited factors16,17. However, Median PSA levels were similar across the discovery and repli- the single-nucleotide polymorphisms (SNPs) that have been cation populations, except for the KP PCa cases, who had higher identified thus far14,18–24 only explain a limited percentage of the PSA levels. variation in PSA levels (4.2% in 4,620 subjects from Iceland, Our approach to discovery and replication is outlined in Fig. 1. and 11.8% in 454 subjects from the UK)14. In addition, several of The primary criterion for inclusion of SNPs in the main tables of the loci that harbor SNPs associated with PSA levels also harbor this manuscript was that the meta-analysis of discovery and SNPs associated with PCa, making it complicated to disentangle replication cohorts met the conventional genome-wide signifi- genetic effects on PSA levels versus PCa. PSA level associations cance threshold of Po5 Â 10 À 8. To be considered for the meta- with PCa risk variants may reflect a number of factors, including: analysis, SNPs also had to have Po5 Â 10 À 7 in the discovery Table 1 | Sample size, age and PSA levels of subjects included in discovery GWAS and replication studies. Study population N Mean age* (s.d.) Median PSA* (MAD) Discovery KP non-Hispanic White non-cases 28,503 68.8 (10.2) 1.5 (1.2) Replication KP Latino non-cases 2,716 65.6 (11.2) 1.4 (1.2) KP East Asian non-cases 2,518 66.0 (10.5) 1.5 (1.2) KP African American non-cases 1,585 66.1 (9.3) 1.4 (1.2) KP non-Hispanic White Cases 5,006 60.8 (7.6) 2.7 (2.2) Vanderbilt White non-cases 1,411 59.7 (11.4) 0.8 (3.5) PEGASUS White non-cases 2,833 63.3 (5.1) 1.1 (0.89) Malmo¨ White non-cases 1,359 61.4 (6.3) 1.0 (0.70) GWAS, genome-wide association study; KP, Kaiser Permanente; MAD, median absolute deviation; PSA, prostate-specific antigen.
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