Genetic Factors in Glaucoma
Janey L. Wiggs, M.D., Ph.D., Paul Austin Chandler Professor of Ophthalmology
The Wiggs laboratory works on the identification of genetic factors that predispose to both mendelian and complex forms glaucoma. The identification of genes that can cause glaucoma will provide critical information regarding the biology of the disease as well as provide the basis for accurate methods of diagnosis and new and specific therapies. Current investigations are focused on the genetic etiologies of adult onset primary open angle glaucoma (POAG), pseudoexfoliation glaucoma, pigment dispersion syndrome and pigmentary glaucoma, glaucoma associated with Rieger syndrome and other anterior segment dysgenesis syndromes and juvenile open angle glaucoma. As part of these studies the laboratory has developed a registry of over 2,000 early and adult onset glaucoma patients. Dr. Wiggs has been continuously funded from the National Eye Institute for over 15 years. In addition to current R01 and R21 funding, she is a member of the NEI supported eyeGENE genotyping project for inherited ocular diseases.
Bailey JN, Loomis SJ, Kang JH, Allingham RR, Gharahkhani P, Khor CC, Burdon KP, Aschard H, Chasman DI, Igo RP Jr, Hysi PG, Glastonbury CA, Ashley-Koch A, Brilliant M, Brown AA, Budenz DL, Buil A, Cheng CY, Choi H, Christen WG, Curhan G, De Vivo I, Fingert JH, Foster PJ, Fuchs C, Gaasterland D, Gaasterland T, Hewitt AW, Hu F, Hunter DJ, Khawaja AP, Lee RK, Li Z, Lichter PR, Mackey DA, McGuffin P, Mitchell P, Moroi SE, Perera SA, Pepper KW, Qi Q, Realini T, Richards JE, Ridker PM, Rimm E, Ritch R, Ritchie M, Schuman JS, Scott WK, Singh K, Sit AJ, Song YE, Tamimi RM, Topouzis F, Viswanathan AC, Verma SS, Vollrath D, Wang JJ, Weisschuh N, Wissinger B, Wollstein G, Wong TY, Yaspan BL, Zack DJ, Zhang K, Study EN; ANZRAG Consortium, Weinreb RN, Pericak-Vance MA, Small K, Hammond CJ, Aung T, Liu Y, Vithana EN, MacGregor S, Craig JE, Kraft P, Howell G, Hauser MA, Pasquale LR, Haines JL, Wiggs JL. Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma. Nat Genet. 2016 Feb;48(2):189-94.
Dewundara SS, Wiggs JL, Sullivan DA, Pasquale LR. Is Estrogen a Therapeutic Target for Glaucoma? Semin Ophthalmol. 2016;31(1-2):140-6.
Guy AH, Wiggs JL, Turalba A, Pasquale LR. Translating the Low Translaminar Cribrosa Pressure Gradient Hypothesis into the Clinical Care of Glaucoma. Semin Ophthalmol. 2016;31(1-2):131-9.
Pasquale LR, Borrás T, Fingert JH, Wiggs JL, Ritch R. Exfoliation syndrome: assembling the puzzle pieces. Acta Ophthalmol. 2015 Dec 9.
Pasquale LR, Hanyuda A, Ren A, Giovingo M, Greenstein SH, Cousins C, Patrianakos T, Tanna AP, Wanderling C, Norkett W, Wiggs JL, Green K, Kang JH, Knepper PA. Nailfold Capillary Abnormalities in Primary Open-Angle Glaucoma: A Multisite Study. Invest Ophthalmol Vis Sci. 2015 Nov;56(12):7021-8.
The Wiggs Lab has three main projects supported by the National Eye Institute:
Research Project Name: Genetic Etiologies of Glaucoma
Primary open angle glaucoma (POAG) is a significant cause of blindness worldwide. Compelling evidence supports the hypothesis that specific genes influence susceptibility to the disease. We have previously completed a genome wide screen and follow-up studies that have identified two POAG candidate loci with high likelihood of containing POAG susceptibility genes on chromosomes 14 and 15. The major objective of this proposal is to identify the POAG susceptibility gene(s) located within the defined genetic region on chromosome 14 and determine the relationships between specific genetic defects and clinical phenotype. In addition to providing insight into disease related molecular pathology, this information will be the basis of new treatment and diagnostic modalities. To accomplish this overall goal, the size of the minimal genetic interval on chromosome 14 will be reduced by performing linkage analyses on new multiplex families affected with POAG, as well as identifying areas of linkage disequillibrium within the minimal genetic interval using family-based SNP association studies. Known genes and novel gene fragments within the refined minimal genetic interval will be identified using the annotated human genome sequence and will be prioritized for screening using function and expression information from a variety of sources. Identified DNA sequence variants will be examined for biological significance by case/control analyses using a large cohort of POAG cases and age-matched controls. Haplotypes associated with candidate genes will be analyzed using a case/control approach to identify potential regulatory changes that could be missed by sequencing alone. Specific genetic defects will be correlated with clinical phenotype by investigating familial aggregation of clinical parameters and looking for evidence of gene/gene interactions and how these interactions may influence phenotype.
Recently in collaboration with Dr. Pasquale we have been awarded funding from the National Institute for Genome Research to carry out a whole genome association study using POAG patients and controls.
Research Project Name: Linkage Study of Juvenile Glaucoma
The general hypothesis of this research program is that biological mechanisms responsible for different forms of inherited glaucoma represent different processes that culminate in optic nerve degeneration. Elucidating each mechanism will produce a composite picture of the complex pathophysiology of this disease. The primary objective of this proposal is to characterize genetic defects responsible for inherited glaucoma, and to determine the relationships between specific mutations and clinical phenotype. In addition to providing insight into disease related molecular pathology, this information will be the basis of new treatment and diagnostic modalities. Identifying genes and gene projects that contribute to the disease process will be the first step toward the development of novel treatment based on specific disease mechanisms. The correlation of gene defects with clinical phenotypes will provide the fundamental knowledge needed to devise DNA-based diagnostic and prognostic tests. Screening different populations of glaucoma patients will illustrate the range of phenotypic expression of mutant genes and will indicate mutations that may contribute to the pathogenesis of more complex forms of the disease. Previously, a genome wide scan for juvenile open angle glaucoma (JOAG) was completed identifying two new JOAG loci, the genetic interval of the 7q36 PDS locus has been reduced to 5cM, and a second locus for pigment dispersion syndrome has been identified, the genetic interval for the RIEG2 locus has been reduced to 7cM and candidate genes have been identified and screened, and genotype/phenotype studies have been completed on patients with abnormalities in the TIGR/Myocilin gene, the CYP1B1 gene and the RIEG1 gene (PITX2). Current research efforts are to: 1) Refine the newly identified loci for juvenile open angle glaucoma (JOAG) and identify and screen candidate genes. 2) Screen candidate genes located in the pigment dispersion (PDS) regions located on 7q35 and 18q22. 3) Screen candidate genes located in the RIEG2 region on chromosome 13q14. 4) Correlate mutations in genes known to cause glaucoma with clinical phenotypes.
Research Project Name: India US Genetic Study of Ocular Quantitative Traits
The primary objective of this exploratory grant is to determine the value of consanguineous pedigrees for quantitative trait mapping and to perform initial gene mapping studies for selected quantitative traits that are significant risk factors for common ocular complex disorders such as glaucoma, and macular degeneration. A long-term goal is to use this approach to develop and support a genotype/phenotype database that will enable investigators to discover, assess and validate genes and biomarkers responsible for quantitative traits that contribute to complex human ocular disease. A major motivation for the project is the expectation that the resources obtained will provide new opportunities for the identification of significant risk factors for blinding human disease. In addition to phenotypic and genotypic data, environmental information will be collected to aid studies of gene environment interactions. DNA and plasma from blood samples collected from each study participant will be stored for future genomic, protein and small molecule analysis with the anticipation that this information will lead to the identification of genetic predictors and biomarkers for some complex ocular disorders. The underlying hypothesis of this proposal is that consanguineous pedigrees can provide more information for mapping genes responsible for quantitative traits than families without consanguineous relationships. Preliminary studies have suggested that consanguineous pedigrees of sufficient size and structure will provide more power for quantitative trait mapping than a similarly sized collection of nuclear families. The immediate goals of this pilot project are to use large consanguineous pedigrees for initial analyses to verify their usefulness for quantitative trait mapping, and to examine the inheritance of selected quantitative traits in inbred families. We plan to accomplish the following specific aims: 1) Identify and enroll members from large consanguineous pedigrees living in southern India, 2) Measure selected ocular quantitative traits for all participating individuals, 3) Collect peripheral blood samples on all available family members and prepare DNA and plasma samples, 4) Develop strategies for collecting environmental exposure information on all participating individuals, 5) Perform initial SNP genotyping, and 6) Perform initial mapping of quantitative trait loci.