Stanford awarded NIH funding to support ClinGen efforts in pharmacogenomics, autoimmune diseases, and ancestry and diversity in genetic research

October 5, 2021. Stanford University and Baylor College of Medicine have been awarded more than $25 million over five years from the National Institutes of Health (NIH) to continue building the Clinical Genome (ClinGen) Resource, an effort to collect and archive information about clinically relevant genes and genomic variants for use in precision medicine. 

The National Human Genome Research Institute (NHGRI) established the ClinGen Consortium in 2013 to fill a gap of organized, available information about which genes and genomic variants are relevant to human disease. The Consortium works to identify which genes are associated with disease (through a process known as gene curation) and which variants in those genes are disease-causing (via variant curation). Then, they work to standardize the way researchers document and share information about those variants. 

About Stanford ClinGen

The Stanford ClinGen team, now overseen by Co-Principal Investigator Teri E. Klein, PhD, shares one of the new NIH awards with Baylor Co-PIs Sharon Plon, M.D., PhD, and Aleksandar Milosavljevic, PhD. Dr. Klein is Professor of Biomedical Data Science and of Medicine (BMIR) and Principal Investigator for ClinGen, PharmGKB, CPIC, and PharmCAT. The team includes the following Department of Biomedical Data Science (DBDS) academic community members:

The work of the Stanford team focuses on the development of software infrastructure to support the gene-disease curation and variant curation processes that provide the curated information to build ClinGen’s publicly available knowledgebase. Two such pieces of essential software include: the Gene Curation Interface (GCI), which supports gene-disease curation following ClinGen’s gene-disease clinical validity curation framework, and the Variant Curation Interface (VCI), which supports the FDA-recognized ClinGen variant pathogenicity curation process.

The GCI & VCI enable curators to associate pertinent evidence with gene-disease associations and variant interpretations, to assess evidence per gene and variant curation protocols, to support expert review of the curated data, and to make their assertions publicly available so that they can be used by anyone seeking to improve patient care through genomic medicine. The VCI is a community curation tool, and so all interested variant curators are encouraged to sign up to use it. Director of Stanford ClinGen, Matt W. Wright, PhD states, “The GCI and VCI are essential components of the ClinGen consortium’s work. The Stanford ClinGen team looks forward to further enhancing and scaling these resources over the coming years. It’s extremely gratifying to work on a project that generates genomic data that can help support clinical care decisions.” 

In addition to funding gene and variant curation infrastructure projects, this award will support research from the ClinGen Complex Disease Working Group, chaired by former DBDS postdoctoral fellow and current Assistant Professor of Epidemiology at Johns Hopkins University, Genevieve Wojcik, PhD. This work will focus on developing clinical validity standards for polygenic risk scores (PRS), which are a way for people to learn about their risk of developing a disease based on the total number of genetic variations they have related to the disease. This award will also support efforts led by another former DBDS postdoctoral fellow and current Assistant Professor of Epidemiology at UC Davis, Alice Popejoy, PhD, to continue developing and implementing guidelines on the use of race, ethnicity, and ancestry in clinical genetics. Dr. Popejoy chairs the ClinGen Ancestry and Diversity Working Group. 

Looking to the future

Stanford ClinGen research will also extend into the realm of pharmacogenomics (PGx), which is the study of how a person’s genetics, as coded in their DNA, affects how much they respond to different medications. PharmGKB Director Michelle Whirl-Carrillo, PhD states, “The PharmGKB team is excited for the opportunity to work closely with ClinGen to further integrate pharmacogenomics into clinical genomic medicine. The clinical utility of pharmacogenomics has been established and integration with disease-based genomics is critical to achieving the goal of personalized/precision medicine.”

There are several (NIH NHGRI- and NICHD- funded) PGx projects based at Stanford that will enable this integration of pharmacogenomics into clinical genomic medicine: 

The Pharmacogenomics Knowledgebase (PharmGKB) is a website resource that serves as a portal to many different kinds of PGx information, including summaries that describe the impact of variants on drug response. 

The Klein Lab and Dr. Mary Relling of St. Jude’s Children’s Research Hospital (SJCRH) teamed up to create the Clinical Pharmacogenetic Implementation Consortium (CPIC). CPIC is a consortium, led by Dr. Klein and Dr. Kelly Caudle of SJCRH, that writes peer-reviewed guidelines for clinicians so they can use a patient’s genetic information when prescribing medication. 

The Pharmacogenomics Clinical Annotation Tool (PharmCAT) is a collaboration between the Klein lab and Professor Marylyn Ritchie at the University of Pennsylvania. PharmCAT takes patient genetic information as it is reported by a genotyping test or DNA sequencing and converts it to CPIC guidelines, prescribing recommendations specific to that patient.

Dr. Klein believes “that we have a unique opportunity to create access to clinical genomics for both diagnosis and therapeutic treatment for clinicians in all settings (e.g. academia, community, rural), and that by collecting, disseminating and implementing this knowledge across these independent resources, we can bring genomics into everyday clinical care, making it the standard of care. The success of precision medicine rests on our ability to measure the genome, the environment, and the physiological state of patients, and to choose interventions that maximize efficacy and minimize adverse effects.”