Nonadditive Effects of Common Genetic Variants Have a Negligent Contribution to Cancer Heritability

Common genetic variation associated with complex traits identified by genome-wide association studies (GWAS) only partially explains the total heritability estimated by family studies (1, 2). Some of this “missing heritability” could be explained by nonadditive genetic effects. Interactions of alleles at a single locus (dominance effects) contribute to rare monogenic human traits, but prior studies have found limited evidence of their influence on most complex traits (1, 2). However, dominance genetic effects are known to play a role in numerous cancers through the influence of rare high-penetrance variants on hereditary cancer syndromes (3). Despite this, the dominance effects of common genetic variation on cancer heritability are not well understood, as most previous cancer GWAS only modeled additive SNP effects. There is evidence that some common variants have dominance effects, such as an intronic variant in HERC2 that shows associations with melanoma risk (2, 4). A previous analysis of common variant dominance effects in the UK Biobank (UKB) cohort tested multiple phenotypes including a few cancer types (2). Of the cancers that were assessed for dominance genetic effects, the majority were based on self-report with only breast, skin, and other digestive organ cancers defined using International Classification of Diseases codes from cancer registry records. We used genome-wide association data from the UKB cohort and individual case–control studies downloaded from the database of Genotypes and Phenotypes (dbGaP) to estimate additive and dominance genetic contributions to breast, colorectal, lung, melanoma, nonmelanoma skin, ovarian, and prostate cancer. These seven cancers were selected because of adequate sample size availability and evidence of a nonnegligible SNP heritability based on previous studies (5, 6).

We downloaded previously generated, individual-level genotype data for breast, colorectal, lung, ovarian, melanoma, nonmelanoma skin, and prostate cancers from dbGaP and UKB (Table 1). For the UKB, cases were defined using International Classification of Diseases 9/10 codes retrieved from the national cancer registry, and controls were defined as those with no record of a cancer diagnosis and no self-report of cancer. We applied standard sample quality control filters to each dataset, including sample call rate and sex discrepancies. We restricted analyses to individuals with principal component analysis–derived European ancestry for all datasets. Related individuals were excluded from analyses by pruning an individual from related pairs (coefficient of relatedness > 0.05 based on the genetic relatedness matrices).

We filtered variants for SNP call rate (<95%), deviation from Hardy–Weinberg equilibrium (P value < 1 × 10⁻⁶), and low minor allele frequency (<1%). Data from comparable genotyping arrays were used in each population (Table 1). After applying our filters, >364,000 autosomal SNPs were available for each analysis, providing good coverage of common genetic variation in the genome. We then used the genome-based restricted maximum likelihood (GREML) for the dominance variance method implemented in GCTA to estimate additive and dominance effects on each cancer (1, 7). All UKB analyses were adjusted for the genotyping array and the top five genetic principal components (PC). All dbGaP analyses were adjusted for the dbGaP study and the top five genetic PCs. Observed scale estimates were converted to the liability scale using the methods described by Lee et al. (8) and cancer prevalence estimates of 9.4%, 2.9%, 3.2%, 1.2%, 1.9%, 1.6%, and 10.5% for breast, colorectal, lung, melanoma, nonmelanoma skin, ovarian, and prostate cancer, respectively (9). Data processing and quality control were conducted in R v4.2.3 and PLINK 2.0. Statistical analyses were conducted in GCTA v1.94.1, using the same GCTA commands for all GREML models (7).

Analyses were conducted using publicly available GWAS data as cited. Individual-level data can be accessed via dbGaP (accession numbers phs001265.v1.p1, phs001903.v1.p1, phs001273.v4.p2, phs001882.v1.p1, and phs001391.v1.p1). UKB data were downloaded from the UK Biobank Resource on June 26, 2022 (application 70925).

Final sample sizes for dominance GREML analyses by cancer site and data source are listed in Table 1. Estimates of narrow-sense (additive) heritability $(hSNP2)$ ranged from 0.11 to 0.34 on the liability scale, with the highest estimate for prostate cancer and the lowest for lung cancer (Table 2). Estimates of dominance effects $(δSNP2)$ ranged from 0 to 0.04. Estimates of $hSNP2$ and $δSNP2$ were similar in dbGaP and UKB analyses for all cancers except lung $hSNP2$⁠, which was 0.23 in UKB and 0.11 in dbGaP.

We did not observe meaningful dominance effect contributions to heritability for any of the cancers studied. In contrast, appreciable additive effect contributions to cancer heritability were observed for all cancers. The relative magnitudes of our $hSNP2$ estimates across cancers are generally consistent with previous estimates of $hSNP2$ based on GWAS summary statistics (5, 6). Overall, cancer-specific estimates of additive SNP heritability were consistent across datasets apart from lung cancer in which $hSNP2$ estimates on the liability scale were markedly different (UKB: 0.23, dbGaP: 0.11). These discrepancies may be partially explained by large differences in the lung cancer sample case–control ratios (UKB: 13.1% cases, dbGaP: 55.7% cases), prevalence of smoking in the population (UKB: 59.2% of controls reported ever smoking, dbGaP: 66.3% of controls reported ever smoking across dbGaP studies), and sex ratios (UKB: 52.7% female, dbGaP: 37.7% female). Results suggest that dominance effects of common genetic variants play minimal roles in cancer traits, thus supporting the validity of assuming an additive inheritance model in cancer GWAS. Findings are consistent with previous studies of common variant dominance effects on phenotypic variation in other human complex traits (1, 2). Some estimates of dominance effects were nonzero in some instances but not statistically significant and not observed across both dbGaP and UKB datasets. Study limitations include small sample sizes for some cancers (e.g., lung, melanoma) and an inability to compare $hSNP2$ estimates across study populations for some cancer types (e.g., melanoma, nonmelanoma, and ovarian). These analyses were restricted to individuals of European genetic ancestry as GREML estimates are highly sensitive to population stratification, and we did not have access to genotype data with sufficient sample size to conduct analyses in other populations. Heritability is population-specific, and caution is warranted for generalizing the results of our analyses to other cancer types or populations not included here. Further analyses in other cancer types and populations will be needed to examine the contributions of common variant nonadditive effects to cancer heritability more comprehensively.

A. Hammermeister Suger reports grants from the NCI, NIH, during the conduct of the study. P. Kraft reports grants from the NIH during the conduct of the study. S. Lindström reports grants from the NIH during the conduct of the study. No disclosures were reported by the other authors.

A. Hammermeister Suger: Formal analysis, methodology, writing–original draft, writing–review and editing. T.A. Harrison: Data curation, formal analysis, writing–original draft, writing–review and editing. B. Henning: Data curation, formal analysis, methodology, writing–review and editing. C. Turman: Conceptualization, resources, supervision, methodology, writing–review and editing. P. Kraft: Conceptualization, resources, data curation, supervision, methodology, writing–original draft, writing–review and editing. S. Lindström: Conceptualization, resources, supervision, methodology, writing–original draft.

Financial support: This research was supported by CA194393. A. Hammermeister Suger was supported by grant number T32CA09168 from the National Cancer Institute (NCI), NIH. The study’s contents are solely the responsibility of the authors and do not necessarily represent the official views of the NCI, NIH. UK Biobank: We are grateful to the UK Biobank participants who have generously agreed to provide a broad range of information for health-related research. This research was conducted using the UK Biobank Resource under Application Number 70925. dbGaP Breast: OncoArray genotyping and phenotype data harmonization for the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) breast-cancer case–control samples was supported by X01 HG007491 and U19 CA148065 and by Cancer Research UK (C1287/A16563). Genotyping was conducted by the Center for Inherited Disease Research (CIDR), Centre for Cancer Genetic Epidemiology, University of Cambridge, and NCI. The following studies contributed germline DNA from breast cancer cases and controls: the Two Sister Study (2SISTER), Breast Oncology Galicia Network (BREOGAN), Copenhagen General Population Study (CGPS), Cancer Prevention Study 2 (CPSII), The European Prospective Investigation into Cancer and Nutrition (EPIC), Melbourne Collaborative Cohort Study (MCCS), Multiethnic Cohort (MEC), Nashville Breast Health Study (NBHS), Nurses Health Study (NHS), Nurses Health Study 2 (NHS2), Polish Breast Cancer Study (PBCS), Prostate Lung Colorectal and Ovarian Cancer Screening Trial (PLCO), Studies of Epidemiology and Risk Factors in Cancer Heredity (SEARCH), The Sister Study (SISTER), Swedish Mammographic Cohort (SMC), Women of African Ancestry Breast Cancer Study (WAABCS), and Women’s Health Initiative (WHI). dbGaP Colorectal: Colorectal Transdisciplinary Study (CORECT): NCI (U19CA148107, R01CA81488, P30CA014089, R01CA197350, P01CA196569, and R01CA201407) and NIEHS (T32 ES013678). The content of this work does not necessarily reflect the views or policies of NCI or any of the collaborating centers in the CORECT Consortium, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the CORECT Consortium. Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO): NCI (U01 CA137088, R01 CA059045, and U01 CA164930). We thank all those at the GECCO Coordinating Center for helping bring together the data and the people who made this project possible. Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study: US Public Health Service contracts (N01-CN-45165, N01-RC-45035, N01-RC-37004, and HHSN261201000006C) from NCI. Center for Inherited Disease Research (CIDR) genotyping for the Oncoarray was conducted under contract 268201200008I (to K. Doheny), through 101HG007491-01 (C.I. Amos). The OncoArray GWAS was performed by CIDR (X01-HG008596 and X-01-HG007585). CIDR is fully funded through a federal contract from NIH to The Johns Hopkins University, HHSN268201200008I. ColoCare: NIH [R01CA189184, U01CA206110, and 2P30CA015704-40 (Gilliland)], the Matthias Lackas Foundation, the German Consortium for Translational Cancer Research, and the EU TRANSCAN initiative. We thank the many investigators and staff who made this research possible in ColoCare Seattle and ColoCare Heidelberg. ColoCare was initiated and developed at the Fred Hutchinson Cancer Research Center by Drs. Ulrich and Grady. The Colon Cancer Family Registry (CCFR): NCI (U01 CA167551) and U01/U24 NCI cooperative agreements with the following CCFR centers: Australasian (CA074778 and CA097735), USC Consortium (CA074799), Mayo Clinic (CA074800), Ontario (OFCCR; CA074783), Hawaii (CA074806), and Seattle (SFCCR; CA074794; and R01CA076366 to PAN). Support for case ascertainment was provided in part from the Surveillance, Epidemiology, and End Results (SEER) Program and the following U.S. state cancer registries: AZ, CO, MN, NC, and NH, and by the Victoria Cancer Registry (Australia) and Ontario Cancer Registry (Canada). Additional funding for the OFCCR/ARCTIC was through award GL201-043 from the Ontario Research Fund (to BWZ), award 112746 from the Canadian Institutes of Health Research (to TJH), through a Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society (to SG), and through generous support from the Ontario Ministry of Research and Innovation. The SCCFR Illumina HumanCytoSNP array was supported through NCI (R01 CA076366 to PAN). The CCFR Set-1 (Illumina 1M/1M-Duo) and Set-2 (IlluminaOmni1-Quad) scans were supported by NIH (U01 CA122839, R01CA143247 to GC). The CCFR Set-3 (Affymetrix Axiom CORECT Set array) was supported by NIH (U19CA148107, R01CA81488 to SBG). The CCFR Set-4 (Illumina OncoArray 600 K SNP array) was supported by NIH (U19CA148107 to SBG) and by CIDR (HHSN268201200008I). The Colon CFR graciously thanks the generous contributions of their study participants, dedication of study staff, and the financial support from the U.S. National Cancer Institute, without which this important registry would not exist. The content of this manuscript does not necessarily reflect the views or policies of the NIH or any of the collaborating centers in the CCFR, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government, any cancer registry, or the CCFR. ESTHER/VERDI: The BadenWurttemberg Ministry of Science, Research and Arts and the German Cancer Aid. GALicia Estudio Oncologico de coloN (GALEON): FIS Intrasalud (PI13/01136). Department of Surgery of University Hospital of Santiago (CHUS), Sara Miranda Ponte, Carmen M. Redondo, and staff of the Department of Pathology and Biobank of CHUS, Instituto de Investigacion Sanitaria de Santiago (IDIS), Instituto de Investigacion Sanitaria Galicia Sur (IISGS), SERGAS, Vigo, Spain, and Programa Grupos Emergentes, Cancer Genetics Unit, CHUVI Vigo Hospital, Instituto de Salud Carlos III, Spain. Hispanic Colorectal Cancer GWAS: NIH (R01CA155101, U01HG004726, R01CA140561, T32 ES013678, U19 CA148107, and P30 CA014089). We are indebted to the individuals who participated in this study. Without their assistance, we could not have conducted any of our research. PopGen Biobank (KIEL)—German National Genome Research Network (NGFN) through the POPGEN Biobank: BmBF 01GR0468 The GEM Platform (BmBF 01GS0426), the National Genotyping Platform, and the NGFN network for environmental disorders. Melbourne Collaborative Cohort Study (MCCS): VicHealth, Cancer Council Victoria, and Australian NHMRC (509348, 209057, 251553, and 504711). Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database. Multiethnic Cohort Study (MEC): NIH (R37CA054281, P01CA033619, and R01CA063464, R01CA132839, U01 HG004726, R37CA054281, P01CA033619, and R01CA063464). Molecular Epidemiology of Colorectal Cancer Study (MECC): NIH (U19 CA148107, R01CA81488, P30CA014089, R01CA197350, P01CA196569, R01CA201407, and N01 CN043302), and NIEHS (T32 ES013678). Additional support was provided by the H. Leslie Hoffman and Elaine S. Hoffman Chair in Cancer Research, the Jane and Kris Popovich Chair in Cancer Research, and a gift from Daniel and Maryann Fong. MECC was initiated and developed by Drs. Gruber and Rennert. Memorial Sloan Kettering Cancer Center (MSKCC): The Robert and Kate Niehaus Center for Inherited Cancer Genomics and the Romeo Milio Foundation. Nurses Health Study II (NHSII): We thank the participants and staff of the Nurses’ Health Study and the Health Professionals Follow-Up Study for their valuable contributions, as well as the following state cancer registries: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, and WY. This study was approved by the Connecticut Department of Public Health (DPH) Human Investigations Committee. Certain data used in this publication were obtained from the DPH. We assume full responsibility for analyses and interpretation of these data. Health Professionals Follow-Up Study (HPFS): NIH (P01CA055075, UM1CA167552, R01137178, and P50CA127003), Nurses’ Health Study (NHS) by NIH (UM1 CA186107, R01 CA137178, P01CA087969, and P50CA127003). NHS II: NIH (R01050385CA and UM1 CA176726). Physicians’ Health Study (PHS): NIH (R01CA042182). Puerto Rico Familial Colorectal Cancer Registry PURIFICAR—NIMHD and NIAID (MD007587); NCI (CA130034 and CA096297/CA096300); and the Center for Collaborative Research in Health Disparities RCMI (G12MD007600). Studies of Epidemiology and Risk Factors in Cancer Heredity SEARCH: Cancer Research UK (C490/A16561). UK Biobank: UK Biobank Resource under Application Number 8614. The Spanish study—CRCGEN: Instituto de Salud Carlos III, co-funded by FEDER funds: a way to build Europe (PI14-613, PI09-1286), Catalan Government DURSI (2014SGR647), and Junta de Castilla y Leon (LE22A10-2). The Swedish Low-risk Colorectal Cancer Study: The Swedish Research Council (K2015-55X-22674-01-4, K2008-55X-20157-03-3, and K2006-72X-20157-01-2) and the Stockholm County Council (ALF project). Cohort of Swedish Men (COSM) and Swedish Mammography Cohort (SMC): The Swedish Council for Working Life and Social Research and the Swedish Research Council/Committee for Infrastructure. TAIWAN: Taiwan Ministry of Health and Wealth (MOHW105). CIDR genotyping was conducted under contract 268201200008I (to K. Doheny), 101HG007491-01 (to C. I. Amos). The Norris Cotton Cancer Center (P30CA023108), The Quantitative Biology Research Institute (P20GM103534), and the Coordinating Center for Screen Detected Lesions (U01CA196386) also supported the efforts of C. I. Amos. This work was also supported by NCI (U01CA1817700 and R01 CA144040). Asia Colorectal Cancer Consortium (ACCC): NIH (R01CA188214, R37CA070867, UM1CA182910, and R01CA148667) and Anne Potter Wilson funds from Vanderbilt University School of Medicine. Shanghai Women’s Health Study (R37 CA070867 and UM1CA182910), Shanghai Men’s Health Study (UM1CA173640), and the Hwasun Cancer Epidemiology Study–Colon and Rectum Cancer (HCES-CRC; grants from Chonnam National University Hwasun Hospital, HCRI15011-1). Funders had no role in the design of the study; the collection, analysis, or interpretation of the data; the writing of manuscripts from the CORECT data; or the decision to submit manuscripts for publication. dbGaP Lung: Funding for this research was provided in part by the following grants: TRICL (Transdisciplinary Research for Cancer of Lung—NIH U19CA148127, PI: Amos), Canadian Cancer Society Research Institute (no. 020214, PI: Hung). Funding for the Lung Cancer and Smoking study was provided by NIH, GEI Z01 CP 010200, NIH U01HG004446, and NIH GEI U01HG 004438. CIDR conducted genotyping. The Oncoarray consortium was supported by research proposal X01HG007491—Genome-Wide Association Study of Common Cancers, the GAME-On Consortium. The Oncoarray genotyping proposal at CIDR was supported by contract HHSN268201200008I. dbGaP Ovary: Funding support for the Follow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI) was provided through the National Cancer Institute’s Cancer Post-GWAS Initiative, Genetic Associations and Mechanisms in Oncology (GAME-ON; U19-CA148112). The FOCI/Ovarian Cancer Association Consortium (OCAC) Oncoarray genotyping project was funded through NIH (CA1X01HG007491-01, U19-CA148112, R01-CA149429, R01-CA058598). dbGaP Prostate: Aarhus: The Danish Strategic Research Council (now Innovation Fund Denmark) and the Danish Cancer Society. The Danish Cancer Biobank is acknowledged for its biological material. A. Hammermeister Suger: NCI (Z01CP010119). ATBC: NIH Intramural Research Program and NCI, US Public Health Service contracts N01-CN-45165, N01-RC-45035, N01-RC-37004, HHSN261201000006C, and NCI HHSN261201500005C. BioVu: The dataset(s) used for the analyses described were obtained from Vanderbilt University Medical Center’s BioVU which is supported by institutional funding and by the National Center for Research Resources, Grant UL1RR024975-01 (which is now at the National Center for Advancing Translational Sciences, Grant 2 UL1TR000445-06). Canary PASS: PASS was supported by the Canary Foundation and the NCI Early Detection Research Network (U01CA086402) CCI: Prostate Cancer Canada, Movember Foundation(D2013-36). The CCI group would like to thank David Murray, Razmik Mirzayans, and April Scott for their contribution to this work. COH: SLN is partially supported by the Morris and Horowitz Families Endowed Professorship COSM: The Swedish Research Council, the Swedish Cancer Foundation CPCS1 & CPCS2: Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev Ringvej 75, DK-2730 Herlev, DenmarkCPCS1 would like to thank the participants and staff of the Copenhagen General Population Study for their important contributions. CPDR: Uniformed Services University for the Health Sciences HU0001-10-2-0002 (PI: David G. McLeod) CPS-II: The American Cancer Society funds the creation, maintenance, and updating of the Cancer Prevention Study II cohort. CPS-II thanks the participants and Study Management Group for their invaluable contributions to this research. We would also like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries, and cancer registries supported by the National Cancer Institute Surveillance Epidemiology and End Results program. EPIC: The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by the Danish Cancer Society (Denmark); the Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation, Greek Ministry of Health; Greek Ministry of Education (Greece); the Italian Association for Research on Cancer (AIRC) and National Research Council (Italy); the Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), and World Cancer Research Fund (WCRF); the Statistics Netherlands (The Netherlands); the Health Research Fund (FIS), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, Spanish Ministry of Health ISCIII RETIC (RD06/0020), Red de Centros RCESP, C03/09 (Spain); the Swedish Cancer Society, Swedish Scientific Council and Regional Government of Skåne and Västerbotten, Fundacion Federico SA (Sweden); and the Cancer Research UK, Medical Research Council (United Kingdom). EPICAP: The EPICAP study was supported by grants from Ligue Nationale Contre le Cancer, Ligue départementale du Val de Marne; Fondation de France; Agence Nationale de sécurité sanitaire de l’alimentation, de l’environnement et du travail (ANSES)The EPICAP study group would like to thank all urologists, Antoinette Anger and Hasina Randrianasolo (study monitors), Anne-Laure Astolfi, Coline Bernard, Oriane Noyer, Marie-Hélène De Campo, Sandrine Margaroline, Louise N'Diaye, Sabine Perrier-Bonnet (Clinical Research nurses) ERSPC: This study was supported by the DutchCancerSociety(KWF94-869, 98-1657, 2002-277, 2006-3518, and 2010-4800); The Netherlands Organisation for HealthResearch and Development (ZonMW-002822820, 22000106, 50-50110-98-311, and 62300035), The Dutch Cancer Research Foundation(SWOP), and an unconditional grant from Beckman–Coulter–HybritechInc. ESTHER: The Baden Württemberg Ministry of Science, Research and Arts. The ESTHER group would like to thank Hartwig Ziegler, Sonja Wolf, Volker Hermann, Heiko Müller, Karina Dieffenbach, Katja Butterbach for their valuable contributions to the study. FHCRC: NIH (R01CA056678, R01CA082664, and R01CA092579) and support from the Fred Hutchinson Cancer Research Center. FHCRC would like to thank all the men who participated in these studies. Gene-PARE: NIH (1R01CA134444), the Prostate Cancer Research Program of the Department of Defense (PC074201 and W81XWH-15-1-0680), and the American Cancer Society (RSGT-05-200-01-CCE). HPFS: The Health Professionals Follow-up Study was supported by grants UM1CA167552, CA133891, CA141298, and P01CA055075. HPFS are grateful to the participants and staff for their valuable contributions, as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, and WY. IMPACT: The IMPACT study was funded by The Ronald and Rita McAulay Foundation, CR-UK Project (C5047/A1232), Cancer Australia, AICR Netherlands (A10-0227), Cancer Australia and Cancer Council Tasmania, NIHR, EU Framework 6, Cancer Councils of Victoria and South Australia, and Philanthropic donation to Northshore University Health System. We acknowledge support from NIHR to the Biomedical Research Centre at The Institute of Cancer Research and Royal Marsden Foundation NHS Trust. IMPACT acknowledges the study steering committee, collaborating centers, and participants. IPO-Porto: Fundação para a Ciência e a Tecnologia (FCT; UID/DTP/00776/2013 and PTDC/DTP-PIC/1308/2014) and IPO-Porto Research Center (CI-IPOP-16-2012 and CI-IPOP-24-2015). MC and MPS are research fellows from Liga Portuguesa Contra o Cancro, Núcleo Regional do Norte. SM was a research fellow from FCT (SFRH/BD/71397/2010). IPO-Porto would like to express our gratitude to all patients and families who have participated in this study. Karuprostate: The Frech National Health Directorate and by the Association pour la Recherche sur les Tumeurs de la ProstateKarusprostate thanks Séverine Ferdinand. KULEUVEN: F.C. and S.J. are holders of grants from FWO Vlaanderen (G.0684.12N, G.0830.13N), the Belgian federal government (National Cancer Plan KPC_29_023), and a Concerted Research Action of the KU Leuven (GOA/15/017). TVDB is the holder of a doctoral fellowship at the FWO. LAAPC: NCI R01CA84979 (S.A. Ingles). Malaysia: University Malaya High Impact Research Grant (HIR/MOHE/MED/35). Malaysia thanks all associates in the Urology Unit, University of Malaya, Cancer Research Initiatives Foundation (CARIF), and the Malaysian Men's Health Initiative (MMHI). MCCS: VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553, and 504711 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database. MCC-Spain: Partially funded by the Accion Transversal del Cancer, approved on the Spanish Ministry Council, by the Instituto de Salud Carlos III-FEDER (PI08/1770, PI09/00773-Cantabria, PI11/01889-FEDER, PI12/00265, PI12/01270, and PI12/00715), by the Fundación Marqués de Valdecilla (API 10/09), by the Spanish Association Against Cancer (AECC) Scientific Foundation, and by the Catalan Government DURSI (2009SGR1489). Samples: Biological samples were stored at the Parc de Salut MAR Biobank (MARBiobanc; Barcelona) which is supported by Instituto de Salud Carlos III FEDER (RD09/0076/00036). Sample collection was supported by the Xarxa de Bancs de Tumors de Catalunya sponsored by Pla Director d'Oncologia de Catalunya (XBTC). MCC-Spain acknowledges the contribution from Esther Gracia-Lavedan in preparing the data. We thank all the subjects who participated in the study and all MCC-Spain collaborators. MD Anderson: Prostate Cancer Case-Control Studies at MD Anderson (CA68578, ES007784, DAMD W81XWH-07-1-0645, and CA140388). MEC: NIH (U19CA148537 and U01CA164973). MIAMI (WFPCS): ACS MOFFITT: NCI (R01CA128813, PI: JY Park). NMHS: NIH (R01CA121060). The North Carolina–Louisiana Prostate Cancer Project (PCaP) and the Health Care Access and Prostate Cancer Treatment in North Carolina (HCaP-NC) study are carried out as collaborative studies supported by the Department of Defense (DAMD 17-03-2-0052) and American Cancer Society (RSGT-08-008-01-CPHPS). The authors thank the staff, advisory committees, and research subjects participating in the PCaP and HCaP-NC studies for their important contributions. PCMUS: Bulgarian National Science Fund, Ministry of Education and Science (DOO-119/2009; DUNK01/2-2009; DFNI-B01/28/2012) with additional support from the Science Fund of Medical University - Sofia (51/2009; 8I/2009; 28/2010). PHS: The Physicians’ Health Study was supported by grants CA34944, CA40360, CA097193, HL26490, and HL34595. PHS members are grateful to the participants and staff of the Physicians’ Health Study and Health Professionals Follow-Up Study for their valuable contributions, as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, and WY. PLCO: NCI Intramural Research Program. NIHPLCO thanks Drs. Christine Berg and Philip Prorok, NCI, the screening center investigators and staff of the PLCO Cancer Screening Trial for their contributions to the PLCO Cancer Screening Trial. We thank Thomas Riley, Craig Williams, Matthew Moore, and Shannon Merkle at Information Management Services, Inc., for their management of the data and Barbara O’Brien and staff at Westat, Inc., for their contributions to the PLCO Cancer Screening Trial. We also thank the PLCO study participants for their contributions to making this study possible. PROCAP: Swedish Cancer Foundation (08-708, 09-0677). PROCAP thanks and acknowledges all of the participants in the PROCAP study. We thank Carin Cavalli-Björkman and Ami Rönnberg Karlsson for their dedicated work in the collection of data. Michael Broms is acknowledged for his skillful work with the databases. KI Biobank is acknowledged for handling the samples and for DNA extraction. We acknowledge The NPCR steering group: Pär Stattin (chair), Anders Widmark, Stefan Karlsson, Magnus Törnblom, Jan Adolfsson, Anna Bill-Axelson, Ove Andrén, David Robinson, Bill Pettersson, Jonas Hugosson, Jan-Erik Damber, Ola Bratt, Göran Ahlgren, Lars Egevad, and Roy Ehrnström. PROGReSS: The Instituto de Salud Carlos III (FIS PI10/00164, FIS PI13/02030) and Fondo Europeo de Desarrollo Regional (FEDER 2007-2013). ProMPT: CRUK, NIHR, MRC, Cambridge Biomedical Research Centre ProtecT: Founded by NIHRProtecT and ProMPT would like to acknowledge the support of The University of Cambridge, Cancer Research UK. Cancer Research UK grants (C8197/A10123, C8197/A10865). We would also like to acknowledge the support of the National Institute for Health Research which funds the Cambridge Biomedical Research Centre, Cambridge, UK. We would also like to acknowledge the support of the National Cancer Research Prostate Cancer: Mechanisms of Progression and Treatment (PROMPT) collaborative (G0500966/75466). We are grateful to the staff at the Welcome Trust Clinical Research Facility, Addenbrooke’s Clinical Research Centre, Cambridge, UK for their help in conducting the ProtecT study. We also acknowledge the support of the NIHR Cambridge Biomedical Research Centre, the DOH HTA (ProtecT grant), and the NCRI/MRC (ProMPT grant) for help with the bio-repository. The UK Department of Health funded the ProtecT study through the NIHR Health Technology Assessment Programme (96/20/06 and 96/20/99). The ProtecT trial and its linked ProMPT and CAP (Comparison Arm for ProtecT) studies are supported by the Department of Health, England; Cancer Research UK (C522/A8649), Medical Research Council of England (G0500966), ID 75466 and The NCRI, UK. The epidemiological data for ProtecT were generated through funding from the Southwest National Health Service Research and Development. DNA extraction in ProtecT was supported by the USA Dept of Defense (W81XWH-04-1-0280), Yorkshire Cancer Research, and Cancer Research UK. The authors would like to acknowledge the contribution of all members of the ProtecT study research group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Department of Health of England. The bio-repository from ProtecT is supported by the NCRI (ProMPT) Prostate Cancer Collaborative and the Cambridge BMRC grant from NIHR. PROtEuS: PROtEuS was supported financially through grants from the Canadian Cancer Society [13149, 19500, 19864, 19865] and the Cancer Research Society, in partnership with the Ministère de l'enseignement supérieur, de la recherche, de la science et de la technologie du Québec, and the Fonds de la recherche du Québec–Santé. PROtEuS would like to thank its collaborators and research personnel and the urologists involved in the subjects’ recruitment. We also wish to acknowledge the special contribution made by Ann Hsing and Anand Chokkalingam to the conception of the genetic component of PROtEuS. QLD: NHMRC Australia Project Grants (390130 and 1009458) and NHMRC Career Development Fellowship and Cancer Australia PdCCRS funding to J Batra. NHMRC Australia Project Grants (390130 and 1009458) and NHMRC Career Development Fellowship and Cancer Australia PdCCRS funding to J Batra. RAPPER: RAPPER is funded by Cancer Research UK [C1094/A11728; C1094/A18504] and Experimental Cancer Medicine Centre funding [C1467/A7286]. The RAPPER group thank Rebecca Elliott for project management. SABOR: NIH/NCI Early Detection Research Network (U01 CA0866402-12). Also supported by the NCI Cancer Center Support Grant to the Cancer Therapy and Research Center (P30 CA054174) SCCS: NIH (R01 CA092447). The SCCS sample preparation was conducted at the Epidemiology Biospecimen Core Lab, which is supported in part by the Vanderbilt-Ingram Cancer Center (P30 CA68485). Data on SCCS cancer cases used in this publication were provided by the Alabama Statewide Cancer Registry; Kentucky Cancer Registry, Lexington, KY; Tennessee Department of Health, Office of Cancer Surveillance; Florida Cancer Data System; North Carolina Central Cancer Registry, North Carolina Division of Public Health; Georgia Comprehensive Cancer Registry; Louisiana Tumor Registry; Mississippi Cancer Registry; South Carolina Central Cancer Registry; Virginia Department of Health, Virginia Cancer Registry; Arkansas Department of Health, Cancer Registry, 4815 W. Markham, Little Rock, AR 72205. The Arkansas Central Cancer Registry is fully funded by a grant from the National Program of Cancer Registries, CDC. Data on SCCS cancer cases from Mississippi were collected by the Mississippi Cancer Registry which participates in the National Program of Cancer Registries (NPCR) of the CDC. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the CDC or the Mississippi Cancer Registry. SCPCS: CDC (S1135-19/19). The SCPCS sample preparation was conducted at the Epidemiology Biospecimen Core Lab, which is supported in part by the Vanderbilt-Ingram Cancer Center (P30 CA68485). SEARCH: The Cancer Research UK (C490/A10124) and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. SNP_Prostate_Ghent: The study was supported by the National Cancer Plan, financed by the Federal Office of Health and Social Affairs, Belgium. SPAG: Wessex Medical ResearchHope for Guernsey, MUG, HSSD, MSG, Roger Allsopp STHM2: STHM2 was supported by grants from The Strategic Research Programme on Cancer (StratCan), Karolinska Institutet; the Linné Centre for Breast and Prostate Cancer (CRISP, number 70867901), Karolinska Institutet; The Swedish Research Council (number K2010-70X-20430-04-3) and The Swedish Cancer Society (numbers 11-0287 and 11-0624); Stiftelsen Johanna Hagstrand och Sigfrid Linnérs minne; Swedish Council for Working Life and Social Research (FAS), number 2012-0073STHM2 acknowledges the Karolinska University Laboratory, Aleris Medilab, Unilabs and the Regional Prostate Cancer Registry for performing analyses and help to retrieve data. Carin Cavalli–Björkman and Britt-Marie Hune for their enthusiastic work as research nurses. Astrid Björklund for skilful data management. We wish to thank the BBMRI.se biobank facility at Karolinska Institutet for biobank services. SWOG-PCPT & SELECT: NCI Public Health Service (U10CA37429 and 5UM1CA182883). SWOG and SELECT thank the site investigators and staff and, most importantly, the participants who donated their time to this trial. TAMPERE: The Academy of Finland (251074), The Finnish Cancer Organisations, Sigrid Juselius Foundation, and the Competitive Research Funding of the Tampere University Hospital (X51003). The PSA screening samples were collected by the Finnish part of the European Study of Screening for Prostate Cancer. TAMPERE would like to thank Riina Liikanen, Liisa Maeaettaenen, and Kirsi Talala for their work on samples and databases. UKGPCS: UKGPCS would also like to thank the following for funding support: The Institute of Cancer Research and The Everyman Campaign, The Prostate Cancer Research Foundation, Prostate Research Campaign UK (now Prostate Action), The Orchid Cancer Appeal, The National Cancer Research Network UK, NCRI UK. We are grateful for the support of NIHR funding to the NIHR Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. UKGPCS should also like to acknowledge the NCRN nurses, data managers, and consultants for their work in the UKGPCS study. UKGPCS would like to thank all urologists and other persons involved in the planning, coordination, and data collection of the CAPS study. ULM: The German Cancer Aid (Deutsche Krebshilfe). WUGS/WUPCS: WUGS would like to thank the following for funding support: The Anthony DeNovi Fund, the Donald C. McGraw Foundation, and the St. Louis Men’s Group Against Cancer.