July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
Disease mechanisms elucidated by genetic regulation of human RPE gene expression
Author Affiliations & Notes
  • Douglas Vollrath
    Department of Genetics, Stanford University School of Medicine, Stanford, California, United States
  • Boxiang Liu
    Department of Biology, Stanford University, Stanford, California, United States
  • Melissa A Calton
    Department of Genetics, Stanford University School of Medicine, Stanford, California, United States
  • Nathan S. Abell
    Department of Genetics, Stanford University School of Medicine, Stanford, California, United States
  • Gillie Benchorin
    Department of Genetics, Stanford University School of Medicine, Stanford, California, United States
  • Michael J. Gloudemans
    Program in Biomedical Informatics, Stanford University School of Medicine, Stanford, California, United States
  • Ming Chen
    Department of Genetics, Stanford University School of Medicine, Stanford, California, United States
  • Jane Hu
    Department of Ophthalmology, Jules Stein Eye Institute, UCLA, Los Angeles, California, United States
  • Xin Li
    Department of Pathology, Stanford University School of Medicine, Stanford, California, United States
  • Brunilda Balliu
    Department of Pathology, Stanford University School of Medicine, Stanford, California, United States
  • Dean Bok
    Department of Ophthalmology, Jules Stein Eye Institute, UCLA, Los Angeles, California, United States
  • Stephen B. Montgomery
    Department of Genetics, Stanford University School of Medicine, Stanford, California, United States
    Department of Pathology, Stanford University School of Medicine, Stanford, California, United States
  • Footnotes
    Commercial Relationships   Douglas Vollrath, None; Boxiang Liu, None; Melissa Calton, None; Nathan Abell, None; Gillie Benchorin, None; Michael Gloudemans, None; Ming Chen, None; Jane Hu, None; Xin Li, None; Brunilda Balliu, None; Dean Bok, None; Stephen Montgomery, None
  • Footnotes
    Support  M2014137 (BrightFocus), R01EY025790, P30EY026877, T32EY20485, R33HL120757, U01HG009431, R01MH101814, R01HG008150, 2016YFD0400800 (PRC)
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 1759. doi:
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    • Get Citation

      Douglas Vollrath, Boxiang Liu, Melissa A Calton, Nathan S. Abell, Gillie Benchorin, Michael J. Gloudemans, Ming Chen, Jane Hu, Xin Li, Brunilda Balliu, Dean Bok, Stephen B. Montgomery; Disease mechanisms elucidated by genetic regulation of human RPE gene expression. Invest. Ophthalmol. Vis. Sci. 2019;60(9):1759.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : To identify potential common modifier alleles of monogenic ocular diseases and uncover mechanisms for risk variants associated with complex eye phenotypes

Methods : We performed a detailed characterization of the transcriptome of 23 differentiated low passage primary human fetal RPE (fRPE) lines across two culture conditions (glucose or galactose). We identified genes and pathways modulated by metabolic perturbation using GSEA and GO enrichment. We compared the fRPE gene expression profile to that of 53 GTEx tissues. We performed high-density genotyping and imputation, followed by RASQUAL, LeafCutter and FastQTL analysis to discover shared and condition-specific expression and splicing quantitative trait loci (e/sQTL). We used eCAVIAR to assess co-localization between e/sQTL signals and GWAS data for myopia and AMD. We treated differentiated RPE cells with cycloheximide to assess a role for nonsense-mediated decay (NMD) in the origin of a particular e/sQTL.

Results : We identified 100 protein coding and 30 long non-coding fRPE-selective genes (expression > 4 S.D. from GTEx mean). fRPE-selective genes are enriched for genes related to monogenic ocular diseases. Variants near fRPE-selective genes explain a larger fraction of risk for both AMD and myopia than variants near genes enriched in GTEx tissues. Increased mitochondrial oxidation (galactose condition) promoted fRPE expression of lipid synthesis genes implicated in AMD. We found 726 shared, 272 glucose-specific, and 191 galactose-specific eQTL (FDR < 0.05), including two not previously described in any tissue. We discovered 210 and 193 sQTL for the glucose and galactose conditions, respectively. Variant rs3138141 in an intron of RDH5 is associated with an sQTL and an eQTL in the RDH5 transcript. The minor allele correlates with increased skipping of the adjacent coding exon, NMD of the aberrant transcript, and three-fold lower minor allele-specific expression. The e/sQTL marked by this common variant colocalizes with high statistical significance with GWAS loci for both AMD and myopia, but with opposing directions of effect.

Conclusions : Our study highlights the unique transcriptomic characteristics of fRPE, lays the foundation for connecting e/sQTL in a critical ocular cell type to monogenic and complex eye disorders, and describes a molecular mechanism by which the same common variant of RDH5 contributes to both increased AMD risk and decreased myopia risk.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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