The overarching theme of research in the Roden laboratory is how genomic variation affects variability in disease susceptibility and response to drug treatment.
The protocol for an ongoing project could implement the following methodology. 
Our focus at the bench is on abnormalities of cardiac rhythm, and individual projects incorporate the expertise of the laboratory in mining electronic health records (EHRs) and in basic electrophysiologic methods, including the use of emerging medium and high-throughput approaches for functional genomics. The lab has a strong tradition in translating discovery from the bedside to the bench and back. Dr. Dan Roden has been Principal Investigator for Vanderbilt’s large BioVU resource that links DNA samples from almost 300,000 patients to their deidentified EHRs since the program was launched in 2007. 
He has also co-directed the Vanderbilt site in the National Human Genome Research Institute’s Electronic Medical Records and Genomics (eMERGE) network since 2007, and he currently serves as co-Principal Investigator for the Data and Research Center in All of Us, a national effort aiming to recruit at least a million Americans, with their EHRs and biosamples, from diverse backgrounds. He directed Vanderbilt’s site in the NIH’s Pharmacogenetics Research Network (PGRN) and in the American Heart Association’s Strategically Focused Atrial Fibrillation Research Network (AF-SFRN).
Large genome-wide association studies (GWAS) have identified hundreds of common variants that each contribute a small risk for disease susceptibility. Combining these variants into a Polygenic Risk Score shows promise in identifying individuals at unusually high risk for common disease. The eMERGE network’s long-term goal is to understand how best to implement genomic discovery to enable “Genomic Medicine”, the idea that genomic information will be used to guide individual treatments. The current (2020-2025) cycle of eMERGE will combine Polygenic Risk Scores, family history, and clinical risk factors to identify and inform patients at unusually high risk for 10 common diseases including breast cancer, type 2 diabetes, or atrial fibrillation. Advice on suggested preventive approaches will be provided to high-risk patients and their physicians. The study is recruiting 2,500 patients per site at Vanderbilt and 9 other centers nationwide.
The All of Us initiative aims to recruit at least 1,000,000 Americans, including those not usually represented in biomedical research. Participants will contribute their EHRs, biospecimens for laboratory study (including whole genome sequencing), and responses to survey questionnaires. Importantly, results obta
ined by the study, including genetic variants known to affect disease susceptibility or drug response, are being returned to participants. The Data and Research Center is a partnership among Vanderbilt, Google Verily, and the Broad Institute. Our goals are to acquire, curate, and secure the data, and then make the data and analysis tools available to a very broad research community in a cloud environment.
A common experiment in the lab has been to study function of genetic variants in key ion channels controlling cardiac electrical behavior, often discovered in the Genetic Arrhythmia Clinic where Dr. Roden sees patients. The conventional approach has been to compare mutant and wild-type function using heterologous expression, but the lab has in the last decade turned increasingly to human cardiac cells derived from induced pluripotent stem cells. This model has the advantage that it allows the study of how individual genetic changes affect overall cellular function, and can be especially powerful when combined with DNA editing. Experiments are conducted using conventional patch-clamping as well as newer automated approaches that allow simultaneous study of up to 384 cells.
The availability of genetic sequencing is changing clinical management for patients with genetic arrhythmia syndromes and their families. However, a major barrier to the widespread application of sequencing to practice is that the function of the vast majority of variants that we discover have never been seen or studied before, so we don’t actually know their function. Dr. Roden is co-Principal Investigator in the large CardioVar consortium that aims to use novel high-throughput functional approaches to determine pathogenicity of nearly all missense variants in key arrhythmia genes, as well as other genes important for cardiac function.
One-third of human adults will develop atrial fibrillation (AF) in their lifetimes. Atrial Fibrillation causes burdensome symptoms, stroke, and increased mortality, but for the past 20 years we have not had truly important changes in treatment or prognosis. We need new approaches. Many factors, such as aging, diabetes, high blood pressure, or having an affected family member, increase AF risk. But not everyone with AF has all these risk factors and some have none.
T
he Roden lab has discovered specific molecules generated by inflammation that cause atrial tissue damage and increase AF risk. Our Center will build on these findings to test how inflammation contributes to AF risk across all patients, and test a new therapy designed to prevent the tissue damage leading to AF.
Population Project (Roden lab): Identifying AF subtypes driven by inflammation: While atrial fibrillation is a very common problem, it comes in many 'flavors': some patients have incapacitating symptoms and others have none. Some patients have many recognized risk factors, others have none. Some patients respond well to certain drugs, others don't.
Our goal in the Population Project is to use advanced computer-based techniques to identify subgroups of patients with AF in whom specific risk factors are causing AF, or in whom specific treatments 'like the anti-inflammatory approaches being developed in other Projects at this Center may be especially effective. In this work, we will build a large collection of patients with and without AF so other groups can work with us to answer other questions related to AF, its treatment, and its outcomes.
It is a given in clinical medicine that patients vary in their responses to drug therapy: lack of efficacy is common and serious adverse drug reactions (ADRs) remain a leading cause of morbidity and mortality. In our Center, three interlinked projects are targeted to improve the prediction of drug action, with the aim of improving current approaches to individual patient therapeutics and drug development.
The project focuses on:
A new paradigm for identifying patients and drugs at risk for QT prolongation
Understanding and preventing HLA-associated drug reactions