Genetic analysis localizes a novel locus on chromosome 4q for the glaucoma endophenotype, cup-to-disc ratio: The Jiri Eye Study

Authors

Sarah E. Miller, The University of Texas Rio Grande Valley
Nicholas B. Blackburn, The University of Texas Rio Grande ValleyFollow
Suman S. Thapa, Tilgana Institute of Opthalmology
Sandra Laston, The University of Texas Rio Grande Valley
Satish Kumar, The University of Texas Rio Grande Valley
Juan M. Peralta, The University of Texas Rio Grande Valley
Janardan Subedi, Miami University - Oxford
John Blangero, The University of Texas Rio Grande Valley
Sarah Williams-Blangero, The University of Texas Rio Grande Valley
Matthew P. Johnson, The University of Texas Rio Grande Valley

Document Type

Conference Proceeding

Publication Date

5-2019

Abstract

Purpose: Glaucoma is a heterogeneous disease influenced by genetic risk factors. However, not all genetic risk factors have been identified. The aim of this project is to localize genetic factors influencing known glaucoma endophenotypes: intraocular pressure (IOP), central corneal thickness (CCT), and vertical cup-to-disc ratio (VCDR).

Methods: This family-based study design utilizes phenotypic and genomic data from a single well-characterized pedigree residing in the Jiri region of Nepal. Measures of IOP, CCT and VCDR were obtained by Goldmann applanation tonometry, OCT, and slit lamp biomicroscopy, respectively. Using a genome-wide genotype data set (~550,000 SNPs), we performed a genome-wide linkage scan for IOP, CCT, and VCDR adopting a quantitative approach in SOLAR. For localized quantitative trait locus (QTL) signals, we screened all SNPs within the 1-LOD (95% confidence) interval using the classical measured genotype approach to association analysis and allowing for non-independence amongst the pedigree members.

Results: For this study, phenotypic and genotype data from 1,163 (55% female) members of the Jirel population were available. The mean age of the sample is 43.8 (SD=15.7) years. IOP (h²=19%, p=6.1×10^-5), CCT (h²=57%, p=1.6×10^-26), and VCDR (h²=48%, p=9.7×10^-22) were significantly heritable. We localized a significant QTL for VCDR on chromosome 4 (LOD=3.05 at 86.83 Mb). The top association signal within this QTL was for an intronic SNP (rs4148155; p=2.01×10^-6, b=0.24) in the ABCG2 (ATP binding cassette subfamily G member 2) gene, which satisfied our QTL-specific Bonferroni-corrected significance criterion (p<6.59×10^-5). ABCG2 is a known stem cell marker, which is positively expressed in clonal human trabecular meshwork stem cells. Another positional candidate gene of note is SCD5 (Stearoyl-CoA desaturase 5), which is shown to suppress neurite outgrowth, a marker of neuronal differentiation. SCD5 is of significant interest given that expression of myocilin (MYOC) also inhibits neurite outgrowth.

Conclusions: To our knowledge, the VCDR QTL on chromosome 4 is a novel locus and does not overlap with other glaucoma endophenotypes or glaucoma disease status. These results highlight the importance of continued evaluation of genetic factors influencing glaucoma endophenotypes in under-studied populations, such as the Jirels, as new information may be elucidated.

Recommended Citation

Miller, Sarah E., Nicholas B. Blackburn, Suman S. Thapa, Sandra Laston, Satish Kumar, Juan M. Peralta, Janarden Subedi, John Blangero, Sarah Williams-Blangero, and Matthew P. Johnson. “Genetic Analysis Localizes a Novel Locus on Chromosome 4q for the Glaucoma Endophenotype, Cup-to-Disc Ratio: The Jiri Eye Study,” 3. Vancouver, B.C., 2019.

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Publication Title

Association for Research in Vision and Ophthalmology (ARVO) 2019

Academic Level

faculty

Mentor/PI Department

Office of Human Genetics