The mission of the newly created Department of Molecular and Functional Genomics (MFG) is to apply advanced laboratory research approaches and techniques to investigate fundamental mechanisms of human disease, with the goal of creating knowledge that leads to improved health. The application of next generation sequencing and other genomic technologies have generated enormous excitement around the potential to use genomic information to guide individual health care, as articulated in the national Precision Medicine Initiative. Interpreting this genomic data presents many challenges, however, and will become a rate-limiting step in using it effectively in the health care arena. Elucidation of the molecular and biological consequences of genetic variation will be required to harness the value of genomic information to improve health. A major focus of the Department of Molecular and Functional Genomics is to investigate the functional consequences of genetic variation to elucidate the molecular basis of observed gene-phenotype associations. MFG faculty leverage Geisinger Health System’s unique resources, including the MyCode Community Health Initiative, an electronic health record-linked biorepository with more than 100,000 consented participants and a database of more than 50,000 exome sequences (expected to be 100,000 by the end of 2016). This data is being used to identify genes and pathways associated with a host of important clinical traits and diseases, such as obesity, diabetes, cardiovascular disease, and brain and behavioral disorders.
Investigators in the Department of Molecular and Functional Genomics work closely with colleagues in other Geisinger research programs, including the Department of Bioinformatics and Data Science, and Department of Epidemiology and Health Services Research, and clinician-investigators in numerous clinical departments at Geisinger. The Department currently consists of five faculty level investigators, plus several research associates and adjunct faculty.
In 2012 the Department of Health of the Commonwealth of Pennsylvania awarded Geisinger Health System a major grant through the PA-CURE Translational Genomics Program. This project creates a score for patients to estimate their risk of developing an abdominal aortic aneurysm (AAA) based on their genetic profile and clinical risk factors such as age, smoking history and presence of other diseases. Estimating risk is critical to diagnosing AAAs, since aneurysms often cause no symptoms until they rupture.
Current guidelines for AAA screening by abdominal ultrasonography often exclude individuals who later develop an AAA. As part of this project, Geisinger's team, in collaboration with a statistical genetics group from University of Pittsburgh, developed and are testing guidelines for population screening that combine genetic risk factor data with a more comprehensive set of clinical risk factor data. The project also includes patient and provider education about AAA screening and genetic testing. Overall, this project will help identify patient, provider and system barriers to AAA screening; develop interventions to overcome these barriers; and implement personalized strategies for prevention, screening and treatment of AAA and similar diseases.
More than three percent of people are born with a congenital heart defect; for some babies, these are life threatening from birth, while other defects are silent until adulthood and then become a source of serious heart problems that require surgery. This project is focused on understanding the developmental origins of congenital heart defects. We have generated the entire spectrum of defects observed in humans as well as in animal models and use these models to discover the genetic and molecular pathways that control normal and abnormal heart development. We have discovered pathways that control both the structural and electrical features of heart. These studies also provide new insight into diseases of other organs such as the lungs, kidneys and brain. The long term goal is to provide better treatment of congenital heart defects and strategies for prevention.
The Electronic Medical Records and Genomics (eMERGE) Network is a national consortium organized by NHGRI to develop, test and disseminate approaches to research that combine DNA biorepositories with electronic medical record (EMR) systems for large-scale, high-throughput genetic research, with the ultimate goal of returning genomic testing results to patients in a clinical care setting. The network is exploring more than three dozen clinical phenotypes. Various models of returning clinical results have been implemented at sites across the network. Genomic discovery, clinical implementation, privacy and community engagement are of particular interest to eMERGE.
In Phase III, which started in September of 2015, the focus is on gene sequencing. All sites will provide approximately 2,500 patient samples for sequencing on a next-generation sequencing chip that contains about 100 genes, as well as other selected variants. These genes and variants have been chosen through a collaborative process with attention to a balance between clinical actionability and discovery. A key aspect of eMERGE III is returning results to participants that can alter clinical care and measuring the impact of this return of results. This marks a major change for eMERGE, which in the first two phases focused on discovery of new gene-disease associations. This will complement the ongoing efforts of the Genomic Medicine Institute, which has been returning results from different sequencing projects for several years.
Geisinger launched the MyCode® Community Health Initiative in 2007 to create a system-wide repository of blood, serum and DNA samples from Geisinger patients who consented to the use of their samples for research, including genomic analysis, and linking to clinical data in their Geisinger EMR. Participants are enrolled through both primary and specialty care clinics. The samples are processed and stored in the Geisinger Genomics Core in the Weis Center for Research. The eligibility criteria are sufficiently broad, consents rates are high (80-95 percent among various clinics), and the cohort of consented patients is large enough (more than 114,000 consented participants) to provide a representative sample of the Geisinger outpatient population. MyCode® enrollment is ongoing, with a current rate of accrual of approximately 2,000 participants per month and a goal of at least 250,000 additional participants over the next several years.
The mission of the Translational Medicine Initiative is to discover the genetic and molecular bases of human disease and to translate this new knowledge into clinical practice. The primary goal is to carry out transformative research into the genetic and molecular bases of human diseases using new and innovative approaches such as phenome-wide association studies (PheWAS). This research identifies novel associations between genes and clinical traits of interest, and performs biological, cellular and molecular studies of gene function to elucidate the disease mechanism. Creation of a novel cell repository and animal models are critical to understanding the origin of human disease and testing novel therapies. Initial projects underway include cardiogenomics studies and investigation of the genomics of pain.
Geisinger and the Regeneron Genetic Center are collaborating to perform whole exome sequence analysis of DNA samples from Geisinger patients who consented to participate in the Geisinger MyCode® Community Health Initiative. The collaboration also links the genomic variant data to clinical phenotype data in the participant's electronic medical record (EMR) to facilitate discovery of novel gene-disease associations. The long-term goal is to analyze the exomes of at least 250,000 individuals.
The use of EMR data for this purpose provides enormous flexibility with respect to the number and variety of clinical traits that can be studied, and at reduced cost and accelerated timeframe compared to traditional methods. GHS has substantial experience and expertise in the use of EMR data to identify patients with clinical phenotypes of interest.
The data that are available enable both "phenotype-first' and "genotype-first" approaches to genomic discovery. The former could include genetic association studies of cases and controls for clinical phenotypes of interest. The genome-first approach is based on identification of genomic variants of interest and searching for associated clinical traits. An example is a phenome-wide association study, which looks for associations between genomic variants and an array of clinical traits.
Weis Center for Research Summer Undergraduate Research Program (SURP)
The Weis Center for Research Summer Undergraduate Research Program (SURP) provides an exceptional opportunity for undergraduate students to conduct laboratory research under the mentorship of our nationally and internationally recognized scientists. This program is designed for undergraduates with a strong background in the sciences who are considering a career in biomedical research. Participants experience the joy of scientific discovery as well as the challenges inherent in scientific research while investigating the molecular and genetic basis of human disease. Specifically, participants develop skills in scientific reasoning, laboratory methods and scientific communication through interaction with our scientific staff. Learn more and apply.