Dwight E. Stambolian
Associate Professor of Ophthalmology
Attending Physician, Penn Presbyterian Medical Center, Philadelphia, PA
Full Member, Institute for Human Gene Therapy, University of Pennsylvania School of Medicine, Institute for Human Gene Therapy, University of Pennsylvania School of Medicine
Attending Physician, Hospital of the University of Pennsylvania
Rm. 313 Stellar-Chance Labs
422 Curie Boulevard
Philadelphia, PA 19104-6069
422 Curie Boulevard
Philadelphia, PA 19104-6069
Graduate Group Affiliations
Lycoming College, Williamsport, PA, 1971.
S.U.N.Y. Downstate at Syracuse, 1976.
University of Pennsylvania, 1983.
Lycoming College, Williamsport, PA, 1971.
S.U.N.Y. Downstate at Syracuse, 1976.
University of Pennsylvania, 1983.
Description of Research ExpertiseResearch Interests
Genome wide association studies of age-related macular degeneration and glaucoma; Next-generation targeted sequencing of age-related macular degeneration in African Americans; Genetics of age-related macular degeneration in the Amish; Whole exome sequencing of families with refractive error; Zebrafish modeling of refractive error and glaucoma; Characterization of mouse models for microphthalmia.
Key Words: Fun Lab, Bioinformatics galore, espirit de corps, collegial atmosphere, challenging projects, molecular genetics.
Description of Research:
Age-related macular degeneration (AMD) in African Americans
Much work has been accomplished on the genetics of AMD in Caucasians to the point that we currently have 10 well-defined loci identified by genome-wide association studies. While we have had amazing successes in Caucasians for AMD, very little has been done in African Americans probably because the disease is much rarer in this group. A GWAS study is not plausible in African Americans because of the decreased frequency of AMD. Therefore, we are using new DNA sequencing technology to identify the reasons that AMD is less severe in African Americans. We have collected a large cohort of African American cases and controls and are currently utilizing targeted next-gen sequencing to identify protective haplotypes that might offer an explanation of resistance to AMD development in African Americans. If these protective SNPs are found, they could serve as new potential drug targets.
Expression differences between normal and AMD eyes
We have been very successful in the identification of susceptibility genes for AMD through GWAS. The next horizon is to understand the expression differences between eyes with AMD and eyes that are normal. To identify differential expression between normal and AMD eyes, we have collected a series of postmortem eyes with and without AMD. RNA and DNA has been isolated from these eyes for the purpose of RNA sequencing and genotyping. Our underlying hypothesis is that there is a difference in normal transcript expression between normal and AMD eyes or a defect in alternative splicing that predisposes to AMD. The RNA-Seq data is being analyzed for expression differences as well as for alternative splicing defects with our new algorithm developed in the lab, SplicePL. Expression will also be correlated with known AMD risk SNPs to assess SNP potential to influence expression.
Genetics of AMD in the Amish
The genetics of AMD has been well studied in unrelated case-control Caucasian cohorts. However, very little has been done to identify genes in families. To that end, we have screened 3000 Amish individuals over the age of 50 years living in Lancaster County, Pa for various eye diseases including AMD. Every subject visiting the Amish clinic received a full eye exam, an epidemiology questionnaire, and a fundus photo along with the donation of a blood sample. We currently have DNA on all these individuals. Our collected Amish cohort currently consists of 750 nuclear families and has tremendous power to identify rare variants. We are currently preparing to do whole exome sequencing in selected families for the purpose of rare variant discovery in AMD. Discovery of rare AMD variants of large effect will have potential impact in the general population.
Genetics of Refractive Error
Refractive error is an abnormality of the eye that results in myopia, hyperopia or astigmatism. It is the leading cause of blindness worldwide. Most studies to date have centered on family linkage studies. Our lab is currently leading an international consortium to identify the genes for refractive error through GWAS and next-gen sequencing. We have just completed a GWAS of 7000 individuals with a few significant hits. We now seek to understand how these significant GWAS SNPs lead to the development of refractive error. We are currently utilizing bioinformatic tools to characterize the function of these SNPS and will move to functional studies in zebrafish after exhausting our bioinformatic tools. In addition, we have collected DNA from large families transmitting myopia and are preparing to perform whole exome sequencing to identify rare variants in these families.
Modeling of Human Disease in Zebrafish
We have developed a system in the lab to assess the refractive error phenotype in zebrafish embryos. Current experiments include knockdown and overexpression of various potential refractive error genes as a validation to the GWAS hits we have identified. Validated results in a zebrafish model will be followed by RNA-Seq of the mutants to provide a framework for a systems biology approach to understanding refractive error.
Characterization of Mouse Models for Microphthalmia
Over the past few years we have been characterizing a mouse model for microphthalmia (Tcm), a phenotype identified in a colony of X-ray irradiated mouse. Genetic mapping refined the causative locus to a 1.3Mb region on mouse Chromosome 4 which contains 5 genes. Further molecular characterization is underway in our lab to identify the founder mutation responsible for the microphthalmic phenotype.
Common techniques in the lab include bioinformatics, DNA cloning, PCR, agarose gel electrophoresis, in situ hybridization, DNA sequencing and library screening.
Description of Itmat ExpertiseDr. Stambolian is interested in human and mouse models for eye disease with a focus on early detection and therapies for age-related macular degeneration.
Selected PublicationsSimpson Claire L, Wojciechowski Robert, Yee Stephanie S, Soni Poorva, Bailey-Wilson Joan E, Stambolian Dwight: Regional replication of association with refractive error on 15q14 and 15q25 in the Age-Related Eye Disease Study cohort. Molecular Vision 19: 2173-86, Nov 2013.
Zhan Xiaowei, Larson David E, Wang Chaolong, Koboldt Daniel C, Sergeev Yuri V, Fulton Robert S, Fulton Lucinda L, Fronick Catrina C, Branham Kari E, Bragg-Gresham Jennifer, Jun Goo, Hu Youna, Kang Hyun Min, Liu Dajiang, Othman Mohammad, Brooks Matthew, Ratnapriya Rinki, Boleda Alexis, Grassmann Felix, von Strachwitz Claudia, Olson Lana M, Buitendijk Gabriëlle H S, Hofman Albert, van Duijn Cornelia M, Cipriani Valentina, Moore Anthony T, Shahid Humma, Jiang Yingda, Conley Yvette P, Morgan Denise J, Kim Ivana K, Johnson Matthew P, Cantsilieris Stuart, Richardson Andrea J, Guymer Robyn H, Luo Hongrong, Ouyang Hong, Licht Christoph, Pluthero Fred G, Zhang Mindy M, Zhang Kang, Baird Paul N, Blangero John, Klein Michael L, Farrer Lindsay A, DeAngelis Margaret M, Weeks Daniel E, Gorin Michael B, Yates John R W, Klaver Caroline C W, Pericak-Vance Margaret A, Haines Jonathan L, Weber Bernhard H F, Wilson Richard K, Heckenlively John R, Chew Emily Y, Stambolian Dwight, Mardis Elaine R, Swaroop Anand, Abecasis Goncalo R: Identification of a rare coding variant in complement 3 associated with age-related macular degeneration. Nature Genetics 45(11): 1375-9, Nov 2013.
Ching-Yu Cheng, Maria Schache, M. Kamran Ikram, Terri L. Young, Jeremy A. Guggenheim, Veronique Vitart, Stuart MacGregor, Virginie J.M. Verhoeven, Veluchamy A. Barathi, Jiemin Liao, Pirro G. Hysi, Joan E. Bailey-Wilson, Beate St. Pourcain, John P. Kemp, George McMahon, Nicholas J. Timpson, David M. Evans, Grant W. Montgomery, Aniket Mishra, Ya Xing Wang, Jie Jin Wang, Elena Rochtchina, Ozren Polasek, Alan F. Wright, Najaf Amin, Elisabeth M. van Leeuwen, James F. Wilson, Craig E. Pennell, Cornelia M. van Duijn, Paulus T.V.M. de Jong, Johannes R. Vingerling, Xin Zhou, Peng Chen, Ruoying Li, Wan-Ting Tay, Yingfeng Zheng, Merwyn Chew, Consortium for Refractive Error and Myopia, Aichi cohort, ALIENOR, ALSPAC, ANZRAG, AREDS1a, AREDS1b, AREDS1c, BATS, Beijing Eye Study, BMES, CIEMS, CROATIA-Korčula, CROATIA-Split, CROATIA-Vis, DCCT, Duke FECD Fuchs Dystrophy GWAS, Duke Myopia Study, Erasmus Rucphen Family Study, Estonian Genome Project / EGCUT, FITSA, Framingham Eye Study, GEMT, Gutenberg Health Study, Hong Kong cohort study, KORA, Kyoto high myopia, LIKI, Myopia Genomics Study (Hong Kong HTI), Ogliastra Genetic Park Study, ORCADES, Penn Family Studies, RAINE, Rotterdam Study, SCES, SCORM, SIMES, SINDI, SP2, STARS, TEST, TwinsUK, Utah Timorese, Wenzhou, WESDR, Yokohama Study, Young Finns Study, Kathryn P. Burdon, Jamie E. Craig, Sudha K. Iyengar, Robert P. Igo Jr., Jonathan H. Lass Jr., The Fuchs’ Genetics Multi-Center Study Group, Emily Y. Chew, Toomas Haller, Evelin Mihailov, Andres Metspalu, Juho Wedenoja, Claire L. Simpson, Robert Wojciechowski, René Höhn, Alireza Mirshahi, Tanja Zeller, Norbert Pfeiffer, Karl J. Lackner, Wellcome Trust Case Control Consortium 2, Data and Analysis Group, DNA, Genotyping, Data QC and Informatics Group, Publications Committee, Thomas Bettecken, Thomas Meitinger, Konrad Oexle, Mario Pirastu, Laura Portas, Abhishek Nag, Katie M. Williams, Ekaterina Yonova-Doing, Ronald Klein, Barbara E. Klein, S. Mohsen Hosseini, Andrew D. Paterson, The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions, and Complications Research Group, Members, Clinical Coordinating Center, Data Coordinating Center, National Institute of Diabetes and Digestive and Kidney Disease Program Office, Central Fundus Photograph Reading Center, Central Biochemistry Laboratory, Central Carotid Ultrasound Unit, Central ECG Reading Unit, Central ECG Reading Unit, Central Neuropsychological Coding Unit, Central ANS Reading Unit, Computed Tomography Reading Center, External Evaluation Committee, Molecular Risk Factors Program Project, Genetic Studies Group, Epigenetics, EDIC Publications, Kari-Matti Makela, Terho Lehtimaki, Mika Kahonen, Olli Raitakari, Nagahisa Yoshimura, Fumihiko Matsuda, Li Jia Chen, Chi Pui Pang, Shea Ping Yip, Maurice K.H. Yap, Akira Meguro, Nobuhisa Mizuki, Hidetoshi Inoko, Paul J. Foster, Jing Hua Zhao, Eranga Vithana, E-Shyong Tai, Qiao Fan, Liang Xu, Harry Campbell, Brian Fleck, Igor Rudan, Tin Aung, Albert Hofman, André G. Uitterlinden, Goran Bencic, Chiea-Chuen Khor, Hannah Forward, Olavi Pärssinen, Paul Mitchell, Fernando Rivadeneira, Alex W. Hewitt, Cathy Williams, Ben A. Oostra, Yik-Ying Teo, Christopher J. Hammond, Dwight Stambolian, David A. Mackey, Caroline C.W. Klaver, Tien-Yin Wong, Seang-Mei Saw, Paul N. Baird: Nine Loci for Ocular Axial Length Identified through Genome-wide Association Studies, Including Shared Loci with Refractive Error. The American Journal of Human Genetics 93: 264-277, August 2013.
Wu Yinghua, Tian Lifeng, Pirastu Mario, Stambolian Dwight, Li Hongzhe: MATCHCLIP: locate precise breakpoints for copy number variation using CIGAR string by matching soft clipped reads. Frontiers in genetics 4: 157, August 2013.
Stambolian Dwight, Wojciechowski Robert, Oexle Konrad, Pirastu Mario, Li Xiaohui, Raffel Leslie J, Cotch Mary Frances, Chew Emily Y, Klein Barbara, Klein Ronald, Wong Tien Y, Simpson Claire L, Klaver Caroline C W, van Duijn Cornelia M, Verhoeven Virginie J M, Baird Paul N, Vitart Veronique, Paterson Andrew D, Mitchell Paul, Saw Seang Mei, Fossarello Maurizio, Kazmierkiewicz Krista, Murgia Federico, Portas Laura, Schache Maria, Richardson Andrea, Xie Jing, Wang Jie Jin, Rochtchina Elena, Viswanathan Ananth C, Hayward Caroline, Wright Alan F, Polasek Ozren, Campbell Harry, Rudan Igor, Oostra Ben A, Uitterlinden André G, Hofman Albert, Rivadeneira Fernando, Amin Najaf, Karssen Lennart C, Vingerling Johannes R, Hosseini S M, Döring Angela, Bettecken Thomas, Vatavuk Zoran, Gieger Christian, Wichmann H-Erich, Wilson James F, Fleck Brian, Foster Paul J, Topouzis Fotis, McGuffin Peter, Sim Xueling, Inouye Michael, Holliday Elizabeth G, Attia John, Scott Rodney J, Rotter Jerome I, Meitinger Thomas, Bailey-Wilson Joan E: Meta-analysis of genome-wide association studies in five cohorts reveals common variants in RBFOX1, a regulator of tissue-specific splicing, associated with refractive error. Human molecular genetics 22(13): 2754-2764, July 2013.
Fritsche Lars G, Chen Wei, Schu Matthew, Yaspan Brian L, Yu Yi, Thorleifsson Gudmar, Zack Donald J, Arakawa Satoshi, Cipriani Valentina, Ripke Stephan, Igo Robert P, Buitendijk Gabriëlle H S, Sim Xueling, Weeks Daniel E, Guymer Robyn H, Merriam Joanna E, Francis Peter J, Hannum Gregory, Agarwal Anita, Armbrecht Ana Maria, Audo Isabelle, Aung Tin, Barile Gaetano R, Benchaboune Mustapha, Bird Alan C, Bishop Paul N, Branham Kari E, Brooks Matthew, Brucker Alexander J, Cade William H, Cain Melinda S, Campochiaro Peter A, Chan Chi-Chao, Cheng Ching-Yu, Chew Emily Y, Chin Kimberly A, Chowers Itay, Clayton David G, Cojocaru Radu, Conley Yvette P, Cornes Belinda K, Daly Mark J, Dhillon Baljean, Edwards Albert O, Evangelou Evangelos, Fagerness Jesen, Ferreyra Henry A, Friedman James S, Geirsdottir Asbjorg, George Ronnie J, Gieger Christian, Gupta Neel, Hagstrom Stephanie A, Harding Simon P, Haritoglou Christos, Heckenlively John R, Holz Frank G, Hughes Guy, Ioannidis John P A, Ishibashi Tatsuro, Joseph Peronne, Jun Gyungah, Kamatani Yoichiro, Katsanis Nicholas, N Keilhauer Claudia, Khan Jane C, Kim Ivana K, Kiyohara Yutaka, Klein Barbara E K, Klein Ronald, Kovach Jaclyn L, Kozak Igor, Lee Clara J, Lee Kristine E, Lichtner Peter, Lotery Andrew J, Meitinger Thomas, Mitchell Paul, Mohand-Saïd Saddek, Moore Anthony T, Morgan Denise J, Morrison Margaux A, Myers Chelsea E, Naj Adam C, Nakamura Yusuke, Okada Yukinori, Orlin Anton, Ortube M Carolina, Othman Mohammad I, Pappas Chris, Park Kyu Hyung, Pauer Gayle J T, Peachey Neal S, Poch Olivier, Priya Rinki Ratna, Reynolds Robyn, Richardson Andrea J, Ripp Raymond, Rudolph Guenther, Ryu Euijung, Sahel José-Alain, Schaumberg Debra A, Scholl Hendrik P N, Schwartz Stephen G, Scott William K, Shahid Humma, Sigurdsson Haraldur, Silvestri Giuliana, Sivakumaran Theru A, Smith R Theodore, Sobrin Lucia, Souied Eric H, Stambolian Dwight E, Stefansson Hreinn, Sturgill-Short Gwen M, Takahashi Atsushi, Tosakulwong Nirubol, Truitt Barbara J, Tsironi Evangelia E, Uitterlinden André G, van Duijn Cornelia M, Vijaya Lingam, Vingerling Johannes R, Vithana Eranga N, Webster Andrew R, Wichmann H-Erich, Winkler Thomas W, Wong Tien Y, Wright Alan F, Zelenika Diana, Zhang Ming, Zhao Ling, Zhang Kang, Klein Michael L, Hageman Gregory S, Lathrop G Mark, Stefansson Kari, Allikmets Rando, Baird Paul N, Gorin Michael B, Wang Jie Jin, Klaver Caroline C W, Seddon Johanna M, Pericak-Vance Margaret A, Iyengar Sudha K, Yates John R W, Swaroop Anand, Weber Bernhard H F, Kubo Michiaki, Deangelis Margaret M, Léveillard Thierry, Thorsteinsdottir Unnur, Haines Jonathan L, Farrer Lindsay A, Heid Iris M, Abecasis Gonçalo R: Seven new loci associated with age-related macular degeneration. Nature genetics 45(4): 433-9, Apr 2013.
Verhoeven Virginie J M, Hysi Pirro G, Wojciechowski Robert, Fan Qiao, Guggenheim Jeremy A, Höhn René, Macgregor Stuart, Hewitt Alex W, Nag Abhishek, Cheng Ching-Yu, Yonova-Doing Ekaterina, Zhou Xin, Ikram M Kamran, Buitendijk Gabriëlle H S, McMahon George, Kemp John P, Pourcain Beate St, Simpson Claire L, Mäkelä Kari-Matti, Lehtimäki Terho, Kähönen Mika, Paterson Andrew D, Hosseini S Mohsen, Wong Hoi Suen, Xu Liang, Jonas Jost B, Pärssinen Olavi, Wedenoja Juho, Yip Shea Ping, Ho Daniel W H, Pang Chi Pui, Chen Li Jia, Burdon Kathryn P, Craig Jamie E, Klein Barbara E K, Klein Ronald, Haller Toomas, Metspalu Andres, Khor Chiea-Chuen, Tai E-Shyong, Aung Tin, Vithana Eranga, Tay Wan-Ting, Barathi Veluchamy A, Chen Peng, Li Ruoying, Liao Jiemin, Zheng Yingfeng, Ong Rick T, Döring Angela, Evans David M, Timpson Nicholas J, Verkerk Annemieke J M H, Meitinger Thomas, Raitakari Olli, Hawthorne Felicia, Spector Tim D, Karssen Lennart C, Pirastu Mario, Murgia Federico, Ang Wei, Mishra Aniket, Montgomery Grant W, Pennell Craig E, Cumberland Phillippa M, Cotlarciuc Ioana, Mitchell Paul, Wang Jie Jin, Schache Maria, Janmahasathian Sarayut, Jr Robert P Igo, Lass Jonathan H, Chew Emily, Iyengar Sudha K, Gorgels Theo G M F, Rudan Igor, Hayward Caroline, Wright Alan F, Polasek Ozren, Vatavuk Zoran, Wilson James F, Fleck Brian, Zeller Tanja, Mirshahi Alireza, Müller Christian, Uitterlinden André G, Rivadeneira Fernando, Vingerling Johannes R, Hofman Albert, Oostra Ben A, Amin Najaf, Bergen Arthur A B, Teo Yik-Ying, Rahi Jugnoo S, Vitart Veronique, Williams Cathy, Baird Paul N, Wong Tien-Yin, Oexle Konrad, Pfeiffer Norbert, Mackey David A, Young Terri L, van Duijn Cornelia M, Saw Seang-Mei,+ Bailey-Wilson Joan E,+ Stambolian Dwight,+ Klaver Caroline C,+ Hammond Christopher J+: Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia. Nature genetics 45(3): 314-8, Mar 2013 Notes: + These authors jointly directed the work.
Sadigh Sam, Cideciyan Artur V, Sumaroka Alexander, Huang Wei Chieh, Luo Xunda, Swider Malgorzata, Steinberg Janet D, Stambolian Dwight, Jacobson Samuel G: Abnormal Thickening as well as Thinning of the Photoreceptor Layer in Intermediate Age-Related Macular Degeneration. Investigative ophthalmology & visual science 54(3): 1603-1612, March 2013.
Wojciechowski Robert, Yee Stephanie S, Simpson Claire L, Bailey-Wilson Joan E, Stambolian Dwight: Matrix Metalloproteinases and Educational Attainment in Refractive Error: Evidence of Gene-Environment Interactions in the Age-related Eye Disease Study. Ophthalmology 120(2): 298-305, Feb 2013.
Zheng Y, Stambolian D, O'Brien J, Gee JC: Optic disc and cup segmentation from color fundus photograph using graph cut with priors. Med Image Comput Comput Assist Interv 16: 75-82, 2013.