Human Translational Genomics
My research is focused on leveraging the resources provided by the Geisinger MyCode and DiscovEHR projects to study the role of individual genetic variation in health and disease. MyCode is a system-wide biorepository of blood, serum and DNA samples for broad research use that is linkable to Geisinger’s electronic medical record database. By Fall, 2017 more than 150,000 Geisinger patients had consented to participate; enrollment is ongoing. Through the DiscovEHR collaboration with the Regeneron Genetics Center MyCode samples are used to generate whole exome sequence and whole genome genotype data that is linkable to Geisinger’s longitudinal electronic health record database. As of late 2017, more than 92,000 samples have been analyzed, with a goal of 150,000 analyzed by end of 2018. This genomic data is used for genetic association or phenome wide association studies using validated phenotype algorithms developed using health record data, thus creating a highly versatile pipeline for genomic discovery. Phenotype-first approaches, which seek to find genetic variants associated with a particular clinical trait, and genotype-first approaches, which identify clinical traits associated with specific gene or variants, are utilized.
The availability of exome sequence and whole genome genotype data also allows us to investigate the role of both common and rare genetic variants. Consistent with other large-scale sequencing studies, rare genetic variation (population frequency < 1%) accounts for the preponderance of variants observed in our patient cohort. In genetic association studies rare variants typically have substantially larger effect sizes on the traits of interest compared to common variants.
We are using this approach to investigate the role of genetic variation in a range of diseases, including rare monogenic diseases and common chronic diseases. Examples of the former include cystic fibrosis, rare cancer syndromes, and monogenic diabetes. Examples of common diseases we are studying include cardiovascular disease, type 2 diabetes, and fatty liver disease.
The long-term goal is to use knowledge of gene-phenotype associations to identify previously unknown mechanisms of disease, to quantify individual and population risk of disease, and to identify novel targets for the next generation of therapeutic interventions.
- Carey DJ, Fetterolf SN, Davis FD, Faucett WA, Kircher HL, Mirshahi UL, Murray MF, Smelser DT, Gerhard GS, and Ledbetter DH. The Geisinger MyCode Community Health Initiative: an electronic health record-linked biobank for Precision Medicine research. Genet Med. 2016 Sep;18(9):906-13. PMCID: PMC4981567.
- Dewey FE, Murray MF, Overton JD, Habegger L, Leader JB, Fetterolf SN, O'Dushlaine C, Van Hout CV, Staples J, Gonzaga-Jauregui C, Metpally R, Pendergrass SA, Giovanni MA, Kirchner HL, Balasubramanian S, Abul-Husn NS, Hartzel DN, Lavage DR, Kost KA, Packer JS, Lopez AE, Penn J, Mukherjee S, Gosalia N, Kanagaraj M, Li AH, Mitnaul LJ, Adams LJ, Person TN, Praveen K, Marcketta A, Lebo MS, Austin-Tse CA, Mason-Suares H, Bruse S, Mellis S, Phillips R, Stahl N, Murphy A, Economides A, Skelding KA, Still CD, Elmore JR, Borecki IB, Yancopoulos GD, Davis FD, Faucett WA, Gottesman O, Ritchie MD, Shuldiner AR, Reid JG, Ledbetter DH, Baras A, Carey DJ. Distribution and clinical impact of functional variants in 50,726 whole-exome sequences from the DiscovEHR study. Science. 2016 Dec 23;354(6319). PMID: 28008009.
- Abul-Husn NS, Manickam K, Jones LK, Wright EA, Hartzel DN, Gonzaga-Jauregui C, O'Dushlaine C, Leader JB, Kirchner LH, Lindbuchler DM, Barr ML, Giovanni MA, Ritchie MD, Overton JD, Reid JG, Metpally RP, Wardeh AH, Borecki IB, Yancopoulos GD, Baras A, Shuldiner AR, Gottesman O, Ledbetter DH, Carey DJ, Dewey FE, Murray MF. Genetic identification of familial hypercholesterolemia within a single U.S. health care system. Science. 2016 Dec 23;354(6319). PMID: 28008010.
- Dewey FE, Gusarova V, O’Dushlaine C, Gottesman O, Trejos J, Hunt C, Van Hout CV, Habegger L, Buckler D, Lai KM, Leader JB, Murray MF, Ritchie MD, Kirchner LH, Ledbetter DH, Penn J, Lopez A, Borecki IB, Overton JD, Reid JG, Carey DJ, Murphy AJ, Yancopoulos GD, Baras A, Gromada J, Shuldiner AR. Inactivating variants in ANGPTL4 and risk of coronary artery disease. N Engl J Med. 2016 Mar 24;374(12):1123–33. PMCID: PMC4900689].
- Dewey FE, Gusarova V, Dunbar RL, O’Dushlaine C, Schurmann C, Gottesman O, McCarthy S, Van Hout CV, Bruse S, Dansky HM, Leader JB, Murray MF, Ritchie M, Kirchner HL, Habegger L, Lopez A, Penn J, Zhao A, Shao W, Stahl N, Murphy AJ, Hamon S, Bouzelmat A, Zhang R, Shumel B, Pordy R, Gipe D, Herman GA, Sheu WHH, Lee I, Liang KW, Guo X, Rotter JI, Chen Y, Kraus WE, Shah SH, Damrauer S, Small A, Rader DJ, Berg Wulff A, Nordestgaard BG, Tybjærg-Hansen A, van den Hoek AM, Princen HMG, Ledbetter DH, Carey DJ, Overton JD, Reid JG, Sasiela WJ, Banerjee P, Shuldiner AR, Borecki IB, Teslovich TM, Yancopoulos GD, Mellis SJ, Gromada J, and Baras A. Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease. N Engl J Med. 2017 [DOI: 10.1056/NEJMoa1612790]
EducationPhD, St. Louis University, 1980
Postdoctoral Training, Washington University, 1980-1982