July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
Integrative analysis of GWAS and eQTLs proposes new genetic associations and causal genes for Primary Open Angle Glaucoma
Author Affiliations & Notes
  • Ayellet Segre
    Ocular Genomics Institute and Department of Ophthalmology, Massachusetts Eye and Ear, Boston, Massachusetts, United States
    Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
  • Andrew Hamel
    Ocular Genomics Institute and Department of Ophthalmology, Massachusetts Eye and Ear, Boston, Massachusetts, United States
    Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
  • John Rouhana
    Ocular Genomics Institute and Department of Ophthalmology, Massachusetts Eye and Ear, Boston, Massachusetts, United States
    Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
  • Anthony P Khawaja
    NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, United Kingdom
    Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom
  • Mark James Simcoe
    Department of Ophthalmology, King’s College London, St. Thomas’ Hospital, London, United Kingdom
    Department of Twin Research & Genetic Epidemiology, King’s College London, St. Thomas’ Hospital, London, United Kingdom
  • Christopher J Hammond
    Department of Ophthalmology, King’s College London, St. Thomas’ Hospital, London, United Kingdom
  • Pirro G Hysi
    Department of Ophthalmology, King’s College London, St. Thomas’ Hospital, London, United Kingdom
    Department of Twin Research & Genetic Epidemiology, King’s College London, St. Thomas’ Hospital, London, United Kingdom
  • GTEx consortium
    Broad Institute of Harvard and MIT, Massachusetts, United States
  • Janey L Wiggs
    Ocular Genomics Institute and Department of Ophthalmology, Massachusetts Eye and Ear, Boston, Massachusetts, United States
    Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Ayellet Segre, None; Andrew Hamel, None; John Rouhana, None; Anthony Khawaja, None; Mark Simcoe, None; Christopher Hammond, None; Pirro Hysi, None; GTEx consortium, None; Janey Wiggs, None
  • Footnotes
    Support  NIH/NEI R01 EY022305, P30 EY014104
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 4252. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Ayellet Segre, Andrew Hamel, John Rouhana, Anthony P Khawaja, Mark James Simcoe, Christopher J Hammond, Pirro G Hysi, GTEx consortium, Janey L Wiggs; Integrative analysis of GWAS and eQTLs proposes new genetic associations and causal genes for Primary Open Angle Glaucoma. Invest. Ophthalmol. Vis. Sci. 2019;60(9):4252.

      Download citation file:


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

      ×
  • Supplements
Abstract

Purpose : Genome-wide association studies (GWAS) have led to the discovery of 30 genomic loci with common variants associated with Primary Open Angle Glaucoma (POAG) risk, explaining ~5% of POAG heritability. The majority of these associations lie in noncoding regions, suggesting that genetic regulation of gene expression plays a primary role in disease risk. It is also difficult to decipher the causal genes in these often, multi-genic regions. To address these challenges, we tested whether expression quantitative trait loci (eQTLs) or splicing QTLs (sQTLs) in human tissues could be used to prioritize causal genes in association regions and detect new genetic associations with POAG.

Methods : We developed a statistical method (eQTLEnrich.v2) that tests whether different types of QTLs are enriched for genetic associations (genome-wide significant and subthreshold) with a given complex disease or trait compared to expectation, correcting for confounding factors, e.g., MAF, distance to TSS, and linkage disequilibrium. If enrichment is found, a second step is applied to test if target genes of QTLs with top ranked GWAS p-values (e.g. P<0.05) are enriched in signaling or metabolic pathways, gene ontologies, or mouse phenotype ontologies (eGeneEnrich.v2). We applied this method to the NEIGHBORHOOD POAG GWAS meta-analysis and the UK Biobank GWAS of intraocular pressure (IOP), using eQTLs and sQTLs from 49 tissues in the Genotype-Tissue Expression (GTEx) project.

Results : We found significant enrichment of POAG and IOP associations amongst eQTLs in relevant tissues (P<5E-04, adjusted fold-enrichment=1.1-1.4), e.g., artery and nerve, proposing hundreds of new genetic associations with regulatory effects on POAG risk. The target genes of the top ranked eQTLs (GWAS p<0.05) were enriched in several biological pathways, pointing to putative causal genes underlying the associations. Replication of the new associations will be tested in a large, independent POAG GWAS (UK Biobank). Enrichment amongst sQTLs and the relative contribution of eQTLs and sQTLs to POAG heritability will also be presented.

Conclusions : This work demonstrates that variation in transcriptional regulation substantially contributes to POAG risk and IOP, and proposes new causal genes for glaucoma. Future eQTL studies in ocular tissues will help refine the pathogenic processes and tissues implicated by genetics of POAG.

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

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×