The Sigfried and Janet Weis Center for Research provides a focus for laboratory-based translational research and research training. The primary mission of the Weis Center for Research is to conduct original and innovative research that elucidates the cellular, molecular and genetic basis of disease, with the ultimate goal of translating this new knowledge into patient care. Ongoing research programs investigate a range of topics in cardiovascular biology, metabolic disease, neuroscience, cancer and other areas. Our research program stresses a collaborative approach to scientific investigation that leverages Geisinger's unique combination of resources including an integrated health system, a supportive patient population, advanced electronic health record and a large biorepository of patient samples.
- Breitwieser, Gerda E, PhD
- Gogoi, Radhika, MD, PhD
- Mirshahi, Tooraj, PhD
- Moon, Anne, MD, PhD
- Tapinos, Nikolaos, MD, PhD
- Williams, Heinric, MD
- Wolk, Donna M, MHA, PhD, D(ABMM)
Initiatives & Projects
Abdominal Aortic Aneurysm (AAA)
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, will develop and test new guidelines for population screening that combine genetic risk factor data with a more comprehensive set of clinical risk factor data. This new risk score will then be evaluated in Geisinger's patient population. 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 currently 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 78,000 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.
Molecular neuroscience & neuro-oncology
Glial cells constitute the majority of the cells in the nervous system and are emerging as major regulators of nervous system development, function and health. Despite their abundance, we know surprisingly little about any aspect of their biological functions. Molecular neuroscience & neuro-oncology projects employ multidisciplinary approaches and out-of-the box thinking to discover mechanisms that regulate myelination, plasticity, cellular motility and oncogenic transformation of glial cells. Projects related to the molecular neuroscience of the peripheral nervous system include:
- Role of nuclear ErbB3 in PNS myelination;
- Role of Lck during nerve injury response and the generation of the regenerating Schwann cell phenotype; and
- Identification and role of a natural occurring long antisense RNA against the Egr2 promoter during nerve injury response and in demyelinating diseases.
Molecular neuro-oncology projects include:
- Modeling of human glioma stem cell migration - role of glioma cell pseudopodia;
- Novel glioma therapies: Methods to attract and trap migrating glioma cells; and
- RNA epigenetics of human glioma stem cells.
Translational Medicine Initiative
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.
Whole Exome Sequencing Collaboration
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 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.
Announcements & Resources
Research & Educational Training Opportunities
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.
- Barrie ES, Weinshenker D, Verma A, Pendergrass SA, Lange LA, Ritchie MD, Wilson JG, Kuivaniemi H, Tromp G, Carey DJ, Gerhard GS, Brilliant MH, Hebbring SJ, Cubells JF, Sadee W. Regulatory polymorphisms in DBH affect peripheral gene expression and sympathetic phenotypes. Circ Res. 2014 Dec 5;115(12):1017-25.
- Bieniek J, Childress C, Swatski MD, Yang W. (2014) COX-2 inhibitors arrest prostate cancer cell cycle progression by down-regulation of kinetochore/centromere proteins. Prostate. 74(10):999-1011
- Breitwieser GE. The calcium sensing receptor life cycle: trafficking, cell surface expression, and degradation. Best Practice & Research Clinical Endocrinology & Metabolism. 2013 Jun. 27(3):303-313.
- Breitwieser GE. Pharmacoperones and the calcium sensing receptor: Exogenous and endogenous regulators. Pharmacol Res. 2014 May;83;30-7.
- Cheng J, Koenig SN, Kuivaniemi HS, Garg V, Hans CP: Pharmacological inhibitor of notch signaling stabilizes the progression of small abdominal aortic aneurysm in a mouse model. Journal of the American Heart Association. 2014 Oct 27. 3:e001064.
- Chernousov MA, Stahl RC, Carey DJ. Tetraspanins are involved in Schwann cell-axon interaction. Journal of Neuroscience Research 2013 Nov. 91(11); 1419-1428.
- Cronin RM, Field JR, Bradford Y, Shaffer CM, Carroll RJ, Mosley JD, Bastarache L, Edwards TL, Hebbring SJ, Lin S, Hindorff LA, Crane PK, Pendergrass SA, Ritchie MD, Crawford DC, Pathak J, Bielinski SJ, Carrell DS, Crosslin DR, Ledbetter DH, Carey DJ, Tromp G, Williams MS, Larson EB, Jarvik GP, Peissig PL, Brilliant MH, McCarty CA, Chute CG, Kullo IJ, Bottinger E, Chisholm R, Smith ME, Roden DM, Denny JC. Phenome Wide Association Studies demonstrating pleiotropy of genetic variants within FTO with and without adjustment for body mass index. Front Genet. 2014 Aug 5;5:250. doi: 10.3389/fgene.2014.00250.
- Crosslin DR, Tromp G, Burt A, Kim DS, Verma SS, Lucas AM, Bradford Y, Crawford, DC, Armasu SM, Heit JA, Hayes MG, Kuivaniemi H, Ritchie MD, Jarvik GP, de Andrade, M, The electronic Medical Records and Genomics (eMERGE) Network. Controlling for population structure and genotyping platform bias in the eMERGE multi-institutional biobank linked to electronic health records. Frontiers in Genetics. 2014. 5:532.
- Crosslin DR, Carrell DS, Burt A, Kim DS, Underwood JG, Hanna DS, Comstock BA, Baldwin E, de Andrade M, Kullo IJ, Tromp G, Kuivaniemi H, Borthwick KM, McCarty CA, Peissig PL, Doheny KF, Pugh E. Kho A, Pacheco J, Hayes MG, Ritchie MD, Verma SS, Armstrong G, Stallings S, Denny JC, Carroll RJ, Crawford DC, Crane PK, Mukherjee S, Bottinger E, Li R, Keating B, Mirel DB, Carlson CS, Harley JB, Larson EB, Jarvik GP. Genetic variation in the HLA region is associated with susceptibility to herpes zoster. Genes and Immunity. 2015 16,1-7 doi:10.1038/gene.2014.51.
- Jarvik GP, Amendola LM, Berg JS, Brothers K, Clayton EW, Chung W, Evans BJ, Evans JP, Fullerton SM, Gallego CJ, Garrison NA, Gray SW, Holm IA, Kullo IJ, Lehmann LS, McCarty C, Prows CA, Rehm HL, Sharp RR, Salama J, Sanderson S, Van Driest SL, Williams MS, Wolf SM, Wolf WA, eMERGE Act-ROR Committee and CERC Committee: Sundaresan A, Tromp G, Faucett A, Ledbetter D, Williams J, CSER Act-ROR Working Group, Burke W. Return of genomic results to research participants: the floor, the ceiling, and the choices in between. American Journal of Human Genetics. 2014 Jun 5. 94(6):818-826.
- Kuivaniemi H, Ryer EJ, Elmore JR, Hinterseher I, Smelser DT, Tromp G. Update on abdominal aortic aneurysm research: from clinical to genetic studies. Scientifica. 2014 Apr 17. 2014.
- Kullo IJ, Haddad R, Prows CA, Holm I, Sanderson SC, Garrison NA, Sharp RR, Smith ME, Kuivaniemi H, Bottinger EP, Connolly JJ, Keating BJ, McCarty CA, Williams MS, Jarvik GP. Return of results in genomic medicine projects of the eMERGE network. Frontiers in Genetics. 2014 Mar. 5(50):1-8.
- Kumar P P, Franklin S, Emechebe U, Hu H, Moore B, Lehman C, Yandell M, Moon AM. TBX3 Regulates Splicing In Vivo: A Novel Molecular Mechanism for Ulnar-Mammary Syndrome. PLoS Genet. 2014 Mar 27;10(3):e1004247.
- Kumar PP, Emechebe U, Smith R, Franklin S, Moor B, Yandell M, Lessnick SL, Moon AM. Coordinated control of senescence by lncRNA and a novel T-box3 co-repressor complex. eLife. 2014 May 29;3.
- Lipsky EB, King BR, Tromp G. Node-Oriented Workflow (NOW): A Command Template Workflow Management Tool for High Throughput Data Analysis Pipelines. Journal of Data Mining in Genomics & Proteomics. 5:159. August 2014.
- Makrygiannis G, Courtois A, Drion P, Defraigne JO, Kuivaniemi H, Sakalihasan N. Sex Differences in Abdominal Aortic Aneurysm: the Role of Sex Hormones. Ann Vasc Surg. 2014 Nov;28(8):1946-58.
- Matsumaru D, Haraguchi R, Moon AM, Satoh Y, Nakagata N, Yamamura K, Takahashi N, Kitazawa S, Yamada G. Genetic analysis of the role of Alx4 in the coordination of lower body and external genitalia formation. Eur J Hum Genet. 2014 Mar;22(3):350-7.
- Mi W, Lin Q, Childress C, Sudol M, Robishaw J, Berlot C, Shabahang M, Yang W. (2014) Geranylgeranylation signals to the Hippo pathway for breast cancer cell proliferation and migration. Oncogene. 2014 Aug 11 [Epub ahead of print].
- Mirshahi T, Murray MF, Carey DJ. The metabolic syndrome and DYRK1B. N Engl J Med. 2014 Aug 21;371(8):784-5.
- Moon AM, Stauffer AM, Schwindinger WF, Sheridan K, Firment A, Robishaw JD. Disruption of G-Protein γ5 Subtype Causes Embryonic Lethality in Mice. PLoS One. 2014 Mar 5;9(3).
- Moore BS, Mirshahi UL, Yost EA, Stepanchick AN, Bedrin MD, Styer AM, Jackson KK, Still CD, Breitwieser GE, Gerhard GS, Carey DJ, Mirshahi T. Long-term weight-loss in gastric bypass patients carrying melanocortin 4 receptor variants. PLoS One. 2014 Apr 4;9(4):e93629.
- Morris DR, Biros E, Cronin O, Kuivaniemi H, Golledge J. The association of genetic variants of matrix metalloproteinases with abdominal aortic aneurysm: a systematic review and meta-analysis. Heart 100:295-302, 2014. PMID: 23813847
- Muthalagu A, Pacheco JA, Aufox S, Peissig PL, Fuehrer JT, Tromp G, Kho AN, Ramussen-Torvik LJ. A rigorous algorithm to detect and clean inaccurate adult height records within EHR systems. Appl Clin Inform 2014 Feb 19;5(1):118-26.
- Pan Y, Carbe C, Kupich S, Pickhinke U, Ohlig S, Frye M, Seelige R, Pallerla SR, Moon AM, Lawrence R, Esko JD, Zhang X, Grobe K. Heparan sulfate expression in the neural crest is essential for mouse cardiogenesis. Matrix Biol. 2014 Apr;35:253-65.
- Rasmussen LV, Thompson WK, Pacheco JA, Kho AN, Carrell DS, Pathak J, Peissig PL, Tromp G, Denny JC, Starren JB. Design patterns for the development of electronic health record-driven phenotype extraction algorithms. Journal of Biomedical Informatics.
- Robishaw JD. Preferential assembly of G-αβγ complexes directed by the γ subunits Subcell Biochem. 2012;63:181-91.
- Ryer EJ, Garvin RP, Schworer CM, Bernard-Eckroth KR, Tromp G, Franklin DP, Elmore JR, Kuivaniemi H. Proinflammatory role of stem cells in abdominal aortic aneurysms. Journal of Vascular Surgery. 2014 Jul 2 doi:10.1016/j.jvs2014.04.067 [Epub ahead of print].
- Schrodi SJ, Mukherjee S, Shan Y, Tromp G, Sninsky JJ, Callear AP, Carter TC, Ye Z, Haines JL, Brilliant MH, Crane PK, Smelser DT, Elston RC, Weeks DE. Genetic-based prediction of disease traits: prediction is very difficult, especially about the future. Frontiers in Genetics. 2014 Jun 2. 5:162.
- Segal MM, Abdellateef M, El-Hattab AW, Hilbush BS, De La Vega FM, Tromp G, Williams MS, Betensky RA, Gleeson J. Clinical Pertinence Metric Enables Hypothesis-Independent Genome-Phenome Analysis for Neurologic Diagnosis. J Child Neurol. 2014 Aug 24. [Epub ahead of print].
- Tao Y, Zhang M, Li L, Bai Y, Zhou Y, Moon AM, Kaminski HJ, Martin JF. Pitx2, an Atrial Fibrillation Predisposition Gene, Directly Regulates Ion Transport and Intercalated Disc Genes. Circ Cardiovasc Genet. 2014 Feb;7(1):23-32.
- Tromp G, Weinsheimer S, Ronkainen A, Kuivaniemi H. Molecular basis and genetic predisposition to intracranial aneurysm. Annals of Medicine 2014 Dec; 46(8):597-606.
- Zhang L, Nomura-Kitabayashi A, Sultana N, Cai W, Cai X, Moon AM, Cai CL. Mesodermal Nkx2.5 is necessary and sufficient for early second heart field development. Developmental Biology. 2014 Jun 1. 390(1):68-79.