Clinical Trial Summary
Despite the overwhelming focus on genetic and genomic causes of human disease over the past
two decades, it has been estimated that genetics is currently known to explain only 20% and
40% of the etiology of common disease. Thus, it is becoming increasingly apparent that human
disease is a consequence of both genetic susceptibility and environmental exposures.
Importantly, while individuals cannot change their genetic composition, we do have the
ability both personally and as a society, to influence our environment, promoting health and
decreasing the risk of disease. The Personalized Environment and Genes Study (PEGS) aims to
determine how the environment and gene-environment interactions can inform our understanding
of human health and disease. As science has evolved, so too has the science of this project.
This evolution was reflected in a change in the title of this project from the Environmental
Polymorphisms Registry (EPR) to the Personalized Environment and Genes Study (PEGS) to more
accurately reflect the science that can be conducted. PEGS is a unique resource because of
the depth of environmental phenotyping which includes extensive information from exposome
surveys, as well as whole genome sequencing on a significant number of participants in the
cohort. While it is small relative to genomic cohorts, none of these have the extensive
environmental data that is present in PEGS. In addition, other cohorts with deep
environmental data lack the depth of genomic data that is present in PEGS. Importantly, PEGS
has already provided important analytic advances that are of great interest to and can be
confirmed in larger cohorts such as All of Us.
The Personalized Environment and Genes Study (PEGS) aims to provide a resource for
environmental health translational research by examining gene-environment interactions in
health and disease. PEGS is an extension of two previous efforts where it began as a pilot
study, the Environmental Polymorphisms Study (EPS; IRB# 02E9004) and was approved
subsequently as a full protocol titled the Environmental Polymorphisms Registry (EPR) (IRB
#04-E-N0053 and transitioned to its current ID# 04-E-0053). The EPR was envisioned as a
phenotype-by-genotype registry of participants who had donated DNA samples, and who had
agreed to be contacted for follow-up clinical translational studies based on their DNA
genotypes. At the time, the only information available was a participant s age, sex, race,
and ethnicity. Further phenotyping of a participant and/or any biospecimens obtained were
investigated during a follow-up translational clinical study on participants recruited based
on their genotype (hence phenotype-by-genotype) and the PEGS was the first recruit-by-
genotype study at the NIH. Following a period focused on recruiting approximately 15,000
participants to enable genotyping of rare (approximately 1% minor allele frequency) single
nucleotide polymorphisms (SNPs), the PEGS Consortium Project was undertaken in 2010- 2011 to
examine, using the DNA of nearly 4,000 participants, approximately 700 SNPs in approximately
80 environmental response genes that work in concert with environmental exposures to elicit a
phenotype. Several clinical follow-up studies, genotype-phenotype association studies, and
publications have resulted from the PEGS Consortium Project.
To expand phenotype information available to researchers, the Health and Exposure
Questionnaire was administered between 2013-2014. In 2017, a more detailed Exposome
Questionnaire which includes questions relating to the external and internal exposome was
administered. This was an important resource through which to integrate exposures with
genotype-phenotype association studies.
Whole genome sequencing has now been performed on approximately 4700 participants who were
reconsented for this purpose, as indicated above. Questionnaire data was fully adjudicated
and combined in a robust and searchable database. With the increased power of the data
available, the project was renamed as the Personalized Environment and Genes Study (PEGS) and
rolled out in Sept. 2021.
Study Description: The Personalized Environment and Genes Study (PEGS) integrates genetic and
environmental data to understand disease etiology, identify disease risk factors, and improve
disease prevention.
Objectives: The objective of PEGS is to provide a resource for environmental health
translational research by examining environment and geneenvironment interactions in health
and disease. PEGS will incorporate exposure and health information with or without genomic
information to address the following objectives.
- Primary Objective: To uncover novel environmental risk factors for the most prevalent
health conditions and diseases.
- Secondary Objective: To use an environmental precision medicine framework to uncover
genetic susceptibilities to specific environmental exposures that can ultimately be used
to provide a fuller understanding of individual risks for diseases.
Endpoints:
Primary Endpoints:
1. Dichotomous phenotype (multiple analyses; each analysis is focused on a single
dichotomous phenotype of clinical interest,
or a group of mechanistically related dichotomous phenotypes) Example: asthma;
2. Continuous phenotype (multiple analyses; each analysis is focused on a clinically
relevant continuous phenotype). Example: FEV1, an indicator of asthma severity.
Secondary Endpoints:
1. Phenome (simultaneous assessment of all clinically relevant phenotypes);
2. Exposome.
