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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
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