Transcript Dewey - Blumberg Lab

Distribution and clinical impact of
functional variants in 50,726
whole-exome sequences from the
DiscovEHR Study
Dewey et al.
Presented By: Natasha Granneman & Christina Tran
Background
• What is Precision Medicine?
• Considers a person’s environment, lifestyle, and genes when looking for
course treatment
• Theoretically, treatment should be catered to one person
• Goals of Precision Medicine
• Expand cancer treatments
• Use a cohort study to learn more about health and disease
Background
Background
• In 2014, DiscovEHR initiative started by Regeneron Genetics Center and
Geisinger Health Systems (GHS)
• Cohort in this study came from consenting GHS patients who gave blood
and DNA samples as well as clinical phenotypes and records
• 50, 726 participants
• 87 clinical examinations, 658 lab tests, and 7 procedures per participant
Goals of DiscovEHR
• Find genes that affect a large number of diseases and similar traits
between them
• Use these factors to uncover new scientific knowledge
• Possible drug targets
• Analyzing genetic variants to scale the use of precision medicine
Method
• Genome wide array genotyping via Omni Express exome platform
• Sequenced coding regions of 18,852 genes in 50, 726 participants using
Illumina Sequencing
• 20x read depth at > 85% of targeted bases in 96% of samples
• Average of 80% mean read depth in targeted bases
Bead MicroArray Technology
Exome Capture
Method
• Once sequenced, uploaded to DNAnexus to analyze
• Aligned the sequences from Illumina to a reference
• GRCh37.p13
Method
• Used various computer programs to:
• Align exomes to the reference
• Loss of functions variants
• Zygosity
• Build pedigrees
• Compared exome sequences to phenotypes derived from electronic health records
• Lipid levels
• Clinically actionable genetic variants
Results
• Found previously unidentified associations
between pLOFs in various genes and phenotypes
from EHR
• 4.2 million SNV’s and indels (176,000
predicted LOFs)
• 76 clinically actionable genes
• 3.5% of participants had possible pathogenic
variants
•
PCSK9 was the most significant finding
• Normally degrades LDL receptor
blood LDL levels increase
• pLOF in gene results in lower LDL
levels
• Similar to drugs that target the
gene (alirocumab and evolocumab)
Conclusion from Study
• There needs to be large scale sequencing used in health care system
• Allow us to fill gaps in our knowledge regarding role of genetic variation
in health, disease, genomics, and medical care
• Represents a “powerful platform” for human genetics research
• DiscovEHR is merely a “blueprint” for precision medicine and target gene
discovery
Limitations
Our Conclusions
• Precision medicine using this is a great initiative, but might be too big to
accomplish
• Doubtful that this can be used to treat more terminal diseases such as
cancer
• Saw no links to cardiac illnesses in sample even though cardiac illnesses
were in the majority
• Big pharm companies might not find precision medicine as profitable as
it costs too much per person
References/Additional Reading
• Dewey, F.E, et al. Distribution and clinical impact of functional variants in 50,726 wholeexome sequences from the DiscovEHR Study. Science, 354: 1549.
• https://www.illumina.com/techniques/sequencing.html
• https://www.nih.gov/research-training/allofus-research-program
• Additional Reading
• Precision Medicine – Personalized, Problematic, and Promising
• http://www.nejm.org/doi/full/10.1056/NEJMsb1503104
• A New Initiative on Precision Medicine
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5101938/