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Genome-wide scan of everyone possible for Etiologic, Prevention, and Clinical Outcome Research

Principal Investigator

Name
Wen-Yi Jung

Degrees
PhD, MPH

Institution
NCI

Position Title
Senior Investigator

Email
huangw@mail.nih.gov

About this CDAS Project

Study
PLCO (Learn more about this study)

Project ID
2017-9000

Initial CDAS Request Approval
Jan 23, 2018

Title
Genome-wide scan of everyone possible for Etiologic, Prevention, and Clinical Outcome Research

Summary
PLCO has served as a workhorse of cancer genome wide association studies, contributing to nearly three quarters of the known common susceptibility alleles for more than 15 cancers. To date more than 30,000 PLCO participants have received genome wide scans; all as part of nested sets for various cancer types. Such an approach is cost effective, however has limited potential discovery in key ways. For example, genotyping different cancers and controls at different times on different chips has led to a hodge-podge of available genetic data which is hard to harmonize and effectively use. Furthermore, many PLCO participants with less common disease endpoints, microbiome characterization, and biochemical measurements have not yet been genotyped.

With declining genotyping costs, we are now able to efficiently genotype the entire cohort of participants without a recent genome-wide scan (n~85,000) on the new Illumina Global Screening Array (GSA) chip. The resulting dataset (n~110,000 participants with harmonized and imputed GWAS data) will accelerate research in PLCO as all bona fide investigators will have access to the genotyping results, enabling them to pursue diverse scientific hypotheses. The genotyped data will only become more valuable overtime, as disease endpoints increase with continued follow-up and researchers from the scientific community complete ongoing projects and deposit their data back into the study.

In addition to contributing towards discovering common disease loci, a fully genotyped cohort will also generate countless new opportunities, such as genetic risk stratification using polygenic risk scores and risk prediction models that integrate genetic and environmental risk factors.

As this cohort-wide effort provides a unique opportunity to generate a resource of DNA samples extracted by the same platform at the same time, which will be useful for future investigations of markers sensitive to DNA extraction method (e.g., telomere length, methylation, microbiome), we will also extract eligible DNA samples for about 11,000 participants with valid GWAS data who will not be re-genotyped.

Aims

1. Genotype all participants in PLCO with genetic consent, an available source of DNA, and who don’t have a recent GWAS scan
2. Discover common susceptibility alleles related to cancer, other diseases, phenotypes, and biochemical measures
3. Examine gene-environment interactions and perform Mendelian randomization studies
4. Identify and characterize participants with genetic mosaicism
5. Create a harmonized and imputed genomic dataset that can be leveraged by the scientific community
6. Evaluate the impact of genetic risk stratification using polygenic risk scores on screening trial results
7. Generate risk prediction models that integrate information on genetic and environmental risk factors

Collaborators

Neal Freedman (NCI)
Stephen Chanock (NCI)
Wen-Yi Huang (NCI)
Mitchell Machiela (NCI)

Approved Addenda This project has one or more approved addenda.
  • Genotyping participants in PLCO who now have a DNA source because of the additional buccal collection.
  • A pilot study of ONT adaptative sequencing of the X chromosome using residual DNA samples (up to1000 ng) from 10 mosaic loss of X cases

Related Publications

  • Using Mendelian randomization to investigate etiologic heterogeneity across renal cell carcinoma subtypes.
    Winter TD, Jahagirdar O, Renal Cancer Genetics Consortium, , Johansson M, Brennan P, Machiela MJ, Chanock SJ, Purdue MP, Dutta D
    Int J Epidemiol. 2025 Oct 14; Volume 54 (Issue 6) PUBMED
  • Polygenic prediction of body mass index and obesity through the life course and across ancestries.
    Smit RAJ, Wade KH, Hui Q, Arias JD, Yin X, Christiansen MR, Yengo L, Preuss MH, Nakabuye M, Rocheleau G, Graham SE, Buchanan VL, Chittoor G, Graff M, Guindo-Martínez M, Lu Y, Marouli E, Sakaue S, Spracklen CN, Vedantam S, ...show more Wilson EP, Chen SH, Ferreira T, Ji Y, Karaderi T, Lüll K, Machado M, Malden DE, Medina-Gomez C, Moore A, Rüeger S, Akiyama M, Allison MA, Alvarez M, Andersen MK, Appadurai V, Arbeeva L, Bartell E, Bhaskar S, Bielak LF, Bis JC, Bollepalli S, Bork-Jensen J, Bradfield JP, Bradford Y, Brandl C, Braund PS, Brody JA, Broeckel U, Burgdorf KS, Cade BE, Cai Q, Camarda S, Campbell A, Cañadas-Garre M, Chai JF, Chesi A, Choi SH, Christofidou P, Couture C, Cuellar-Partida G, Danning R, Degenhardt F, Delgado GE, Delitala A, Demirkan A, Deng X, Dietl A, Dimitriou M, Dimitrov L, Dorajoo R, Eichelmann F, Eliasen AU, Engmann JE, Erdos MR, Fairhurst-Hunter Z, Farmaki AE, Faul JD, Fernandez-Lopez JC, Forer L, Frank M, Freitag-Wolf S, Fritsche LG, Fuchsberger C, Galesloot TE, Gao Y, Geller F, Giannakopoulou O, Giulianini F, Gjesing AP, Goel A, Gordon SD, Gorski M, Grove J, Guo X, Gustafsson S, Haessler J, Hansen TF, Havulinna AS, Haworth SJ, Heard-Costa N, Hemerich D, Highland HM, Hindy G, Ho YL, Hofer E, Holliday E, Horn K, Hornsby WE, Hottenga JJ, Huang H, Huang J, Huerta-Chagoya A, Huo S, Hwang MY, Hwu CM, Iha H, Ikeda DD, Isono M, Jackson AU, Jansen IE, Jiang Y, Johansson I, Jonsson A, Jørgensen T, Kalafati IP, Kanai M, Kanoni S, Kårhus LL, Kasturiratne A, Katsuya T, Kawaguchi T, Kember RL, Kentistou KA, Kim D, Kim HN, Kim YJ, Kleber ME, Knol MJ, Kurbasic A, Lauzon M, Le P, Lea R, Lee JY, Lee WJ, Leonard HL, Li H, Li SA, Li X, Li X, Liang J, Lin H, Lin K, Liu J, Liu X, Lo KS, Long J, Lores-Motta L, Luan J, Lyssenko V, Lyytikäinen LP, Mahajan A, Malik MZ, Mamakou V, Mangino M, Manichaikul A, Marten J, Mattheisen M, McDaid AF, Mei Q, Meiselbach H, Melendez TL, Milaneschi Y, Miller JE, Millwood IY, Mishra PP, Mitchell RE, Møllehave LT, Mononen N, Mucha S, Munz M, Mykkänen J, Nakatochi M, Nardone GG, Nelson CP, Nethander M, Nho CW, Nielsen AA, Nolte IM, Nongmaithem SS, Noordam R, Ntalla I, Nutile T, Pandit A, Pauper M, Petersen ERB, Petersen LV, Piluso F, Polašek O, Poveda A, Pyarajan S, Raffield LM, Rakugi H, Ramirez J, Rasheed A, Raven D, Rayner NW, Riveros C, Rohde R, Ruggiero D, Ruotsalainen SE, Ryan KA, Sabater-Lleal M, Santin A, Saxena R, Scholz M, Shen B, Shi J, Shin JH, Sidore C, Sidorenko J, Sim X, Slieker RC, Smith AV, Smith JA, Smyth LJ, Southam L, Steinthorsdottir V, Sun L, Takeuchi F, Taylor KD, Tayo BO, Tcheandjieu C, Terzikhan N, Tesolin P, Teumer A, Theusch E, Thompson DJ, Thorleifsson G, Timmers PRHJ, Trompet S, Turman C, Vaccargiu S, van der Laan SW, van der Most PJ, van Klinken JB, van Setten J, Verma SS, Verweij N, Veturi Y, Wang CA, Wang C, Wang JS, Wang L, Wang YX, Wang Z, Warren HR, Bin Wei W, Wen W, Wheeler WA, Wickremasinghe AR, Wielscher M, Winsvold BS, Wong A, Wuttke M, Xia R, Yamamoto K, Yang J, Yao J, 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XO, Simonsick EM, Sims M, Singleton AB, Sinner MF, Smith JG, Snieder H, Spector TD, Spedicati B, Stampfer MJ, Stark KJ, Strachan DP, Tabara Y, Tai ES, Tang H, Tardif JC, Thanaraj TA, Tönjes A, Tuomi T, Tuomilehto J, Tusié-Luna MT, van Dam RM, van der Harst P, Van der Velde N, van Duijn CM, van Schoor NM, Vitart V, Vohl MC, Völker U, Vollenweider P, Völzke H, Vrieze S, Wacher-Rodarte NH, Walker M, Wander GS, Wareham NJ, Watanabe RM, Watkins H, Weir DR, Werge TM, Widen E, Willemsen G, Willett WC, Wilson JF, Wilson PWF, Wong TY, Woo JT, Wright AF, Xu H, Yajnik CS, Yang J, Yokota M, Yuan JM, Zeggini E, Zemel BS, Zheng W, Zhu X, Zillikens MC, Zonderman AB, Zwart JA, 23andMe Research Team, DiscovEHR (DiscovEHR and MyCode Community Health Initiative), eMERGE (Electronic Medical Records and Genomics Network), GPC-UGR, PRACTICAL Consortium, Understanding Society Scientific Group, VA Million Veteran Program, Abecasis GR, Assimes TL, Auton A, Boehnke M, Chasman DI, Esko T, Stefansson K, Lettre G, Lindgren CM, Ng MCY, O'Donnell CJ, Thorsteinsdottir U, Visscher PM, Walters RG, Winkler TW, Wood AR, Deloukas P, Frayling TM, Justice AE, Kilpeläinen TO, Locke AE, Mohlke KL, North KE, Okada Y, Willer CJ, Young KL, Fatumo S, McCaffery JM, Timpson NJ, Hirschhorn JN, Sun YV, Berndt SI, Loos RJF
    Nat Med. 2025 Sep; Volume 31 (Issue 9): Pages 3151-3168 PUBMED
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    J Natl Cancer Inst. 2025 Sep 25 PUBMED
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    Vo JB , Brown DW , Buller ID , Shing JZ , Synnott N , Jones RR , Landi MT , Huang WY , Machiela MJ , Berrington De Gonzalez A , Nolan TS , Kraft P , Williams F , Freedman ND
    J Natl Cancer Inst. 2025 Mar 20 PUBMED
  • Estimation of mosaic loss of Y chromosome cell fraction with genotyping arrays lacking coverage in the pseudoautosomal region.
    Zhou W, Huang WY, Freedman ND, Machiela M
    BMC Bioinformatics. 2025 Feb 19; Volume 26 (Issue 1): Pages 60 PUBMED
  • Vitamin D binding protein genetic isoforms, serum vitamin D, and cancer risk in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial.
    Weinstein SJ, Parisi D, Mondul AM, Layne TM, Huang J, Stolzenberg-Solomon RZ, Ziegler RG, Purdue MP, Huang WY, Abnet CC, Freedman ND, Yu K, Albanes D
    PLoS One. 2024; Volume 19 (Issue 12): Pages e0315252 PUBMED
  • Author Correction: Genetic drivers and cellular selection of female mosaic X chromosome loss.
    Liu A, Genovese G, Zhao Y, Pirinen M, Zekavat SM, Kentistou KA, Yang Z, Yu K, Vlasschaert C, Liu X, Brown DW, Hudjashov G, Gorman BR, Dennis J, Zhou W, Momozawa Y, Pyarajan S, Tuzov V, Pajuste FD, Aavikko M, ...show more Sipilä TP, Ghazal A, Huang WY, Freedman ND, Song L, Gardner EJ, FinnGen, Estonian Biobank Research Team, Breast Cancer Association Consortium, Million Veteran Program, Sankaran VG, Palotie A, Ollila HM, Tukiainen T, Chanock SJ, Mägi R, Natarajan P, Daly MJ, Bick A, McCarroll SA, Terao C, Loh PR, Ganna A, Perry JRB, Machiela MJ
    Nature. 2024 Dec; Volume 636 (Issue 8043): Pages E7 PUBMED
  • Evaluating the Use of Environmental and Polygenic Risk Scores to Inform Colorectal Cancer Risk-Based Surveillance Intervals.
    Landy R, Katki HA, Huang WY, Wang D, Thomas M, Qu F, Freedman ND, Loftfield E, Shi J, Peters U, Hsu L, Schoen RE, Berndt SI
    Clin Transl Gastroenterol. 2024 Dec 1; Volume 15 (Issue 12): Pages e00782 PUBMED
  • Transcriptome- and proteome-wide association studies identify genes associated with renal cell carcinoma.
    Dutta D, Guo X, Winter TD, Jahagirdar O, Renal Cancer Genetics Consortium, Ha E, Susztak K, Machiela MJ, Chanock SJ, Purdue MP
    Am J Hum Genet. 2024 Sep 5; Volume 111 (Issue 9): Pages 1864-1876 PUBMED
  • Genetic drivers and cellular selection of female mosaic X chromosome loss.
    Liu A, Genovese G, Zhao Y, Pirinen M, Zekavat SM, Kentistou KA, Yang Z, Yu K, Vlasschaert C, Liu X, Brown DW, Hudjashov G, Gorman BR, Dennis J, Zhou W, Momozawa Y, Pyarajan S, Tuzov V, Pajuste FD, Aavikko M, ...show more Sipilä TP, Ghazal A, Huang WY, Freedman ND, Song L, Gardner EJ, FinnGen, Estonian Biobank Research Team, Breast Cancer Association Consortium, Million Veteran Program, Sankaran VG, Palotie A, Ollila HM, Tukiainen T, Chanock SJ, Mägi R, Natarajan P, Daly MJ, Bick A, McCarroll SA, Terao C, Loh PR, Ganna A, Perry JRB, Machiela MJ
    Nature. 2024 Jul; Volume 631 (Issue 8019): Pages 134-141 PUBMED
  • Transcriptome-wide association analysis identifies candidate susceptibility genes for prostate-specific antigen levels in men without prostate cancer.
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    HGG Adv. 2024 Jul 18; Volume 5 (Issue 3): Pages 100315 PUBMED
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    Br J Cancer. 2024 May; Volume 130 (Issue 8): Pages 1286-1294 PUBMED
  • Genetically Determined Circulating Lactase/Phlorizin Hydrolase Concentrations and Risk of Colorectal Cancer: A Two-Sample Mendelian Randomization Study.
    Han S , Yao J , Yamazaki H , Streicher SA , Rao J , Nianogo RA , Zhang Z , Huang BZ
    Nutrients. 2024 Mar 12; Volume 16 (Issue 6) PUBMED
  • Genetically adjusted PSA levels for prostate cancer screening.
    Kachuri L, Hoffmann TJ, Jiang Y, Berndt SI, Shelley JP, Schaffer KR, Machiela MJ, Freedman ND, Huang WY, Li SA, Easterlin R, Goodman PJ, Till C, Thompson I, Lilja H, Van Den Eeden SK, Chanock SJ, Haiman CA, Conti DV, Klein RJ, ...show more Mosley JD, Graff RE, Witte JS
    Nat Med. 2023 Jun; Volume 29 (Issue 6): Pages 1412-1423 PUBMED
  • Genome-wide analyses characterize shared heritability among cancers and identify novel cancer susceptibility regions.
    Lindström S, Wang L, Feng H, Majumdar A, Huo S, Macdonald J, Harrison T, Turman C, Chen H, Mancuso N, Bammler T, Breast Cancer Association Consortium (BCAC), Gallinger S, Gruber SB, Gunter MJ, Le Marchand L, Moreno V, Offit K, Colorectal Transdisciplinary Study (CORECT), Colon Cancer Family Registry Study (CCFR), Genetics And Epidemiology Of Colorectal Cancer Consortium (GECCO), De Vivo I, ...show more O'Mara TA, Spurdle AB, Tomlinson I, Endometrial Cancer Association Consortium (ECAC), Fitzgerald R, Gharahkhani P, Gockel I, Jankowski J, Macgregor S, Schumacher J, Barnholtz-Sloan J, Bondy ML, Houlston RS, Jenkins RB, Melin B, Wrensch M, Brennan P, Christiani DC, Johansson M, Mckay J, Aldrich MC, Amos CI, Landi MT, Tardon A, International Lung Cancer Consortium (ILCCO), Bishop DT, Demenais F, Goldstein AM, Iles MM, Kanetsky PA, Law MH, Ovarian Cancer Association Consortium (OCAC), Amundadottir LT, Stolzenberg-Solomon R, Wolpin BM, Pancreatic Cancer Cohort Consortium (Panscan), Klein A, Petersen G, Risch H, Pancreatic Cancer Case-Control Consortium (Panc4), The PRACTICAL Consortium, Chanock SJ, Purdue MP, Scelo G, Pharoah P, Kar S, Hung RJ, Pasaniuc B, Kraft P
    J Natl Cancer Inst. 2023 Jun 8; Volume 115 (Issue 6): Pages 712-732 PUBMED
  • GWAS Explorer: an open-source tool to explore, visualize, and access GWAS summary statistics in the PLCO Atlas.
    Machiela MJ, Huang WY, Wong W, Berndt SI, Sampson J, De Almeida J, Abubakar M, Hislop J, Chen KL, Dagnall C, Diaz-Mayoral N, Ferrell M, Furr M, Gonzalez A, Hicks B, Hubbard AK, Hutchinson A, Jiang K, Jones K, Liu J, ...show more Loftfield E, Loukissas J, Mabie J, Merkle S, Miller E, Minasian LM, Nordgren E, Park B, Pinsky P, Riley T, Sandoval L, Saxena N, Vogt A, Wang J, Williams C, Wright P, Yeager M, Zhu B, Zhu C, Chanock SJ, Garcia-Closas M, Freedman ND
    Sci Data. 2023 Jan 12; Volume 10 (Issue 1): Pages 25 PUBMED
  • PLCOjs, a FAIR GWAS web SDK for the NCI Prostate, Lung, Colorectal and Ovarian Cancer Genetic Atlas project.
    Ruan E , Nemeth E , Moffitt R , Sandoval L , Machiela MJ , Freedman ND , Huang WY , Wong W , Chen KL , Park B , Jiang K , Hicks B , Liu J , Russ D , Minasian L , Pinsky P , Chanock SJ , Garcia-Closas M , Almeida JS
    Bioinformatics. 2022 Jul 28 PUBMED