Genome-Wide Association Study for Glucocorticoid-Induced Ocular Hypertension

We aim to identify genetic variants associated with glucocorticoid (GC)-induced intraocular pressure (IOP) change utilizing genome-wide association study (GWAS) and whole exome sequencing (WES) analyses. The primary outcome was IOP change from baseline to the maximum IOP measurement within 6 months of GC treatment.

Study participants were derived from two cohorts: the Fluocinolone Acetonide in Diabetic Macular Edema (FAME) clinical trial and Massachusetts Eye and Ear Infirmary and Retina Health Center (MEE/RHC) clinical sites. The discovery analysis was conducted using the FAME samples (GWAS: n=532, WES: n=534) and replication analysis was done using the MEE/RHC samples (GWAS: n=603, WES: n=601).

IOP was measured at baseline and throughout the first 6 months of GC exposure. DNA samples were collected through blood and underwent genome-wide genotyping on Illumina's Global Screening Array (GSA) and WES using a custom exome bait from TWIST Biosciences on the Agilent Bravo automated platform. Rare variant gene burden analyses were applied across all ancestries and in the European subgroup after adjusting for covariates. Gene-level and pathway analyses were performed using MAGMA and expression/splicing quantitative trait loci (eQTL/sQTL) colocalization was completed using eCAVIAR.

Demographic and phenotypic information of the 1166 participants enrolled are available in this dbGaP deposition, including information on the GC medications, IOP measurements within the 6 month follow up period, and ocular hypertension/glaucoma history. Array derived genotypes, genotype calls derived from sequencing, and whole exome sequencing data will also be available.

• Study Design:
  • Case-Control
• Study Type:
  • Case-Control
  • Exome Sequencing
  • GWAS
  • Individual-Level Genomic Data
  • Meta-Analysis
• dbGaP estimated ancestry using GRAF-pop
• Total number of consented subjects: 1142
• Subject Sample Telemetry Report (SSTR)

• PubMed

Participants from the discovery cohort (FAME) were recruited for a clinical trial to examine the efficacy of intravitreal inserts of fluocinolone acetonide for diabetic macular edema. Inclusion and exclusion criteria have been described previously (PMID: 21459216 and 27183546).

For the replication cohorts (MEE/RHC):

Inclusion criteria:

• Exposure to GC

Exclusion criteria:

• Age over 18 years
• Active uveitis during the 6-month follow up period
• History of ocular surgery within 3 months of GC exposure
• Hypotony
• Endophthalmitis, and/or ocular trauma

• Primary Phenotype: Genome-wide association study
• Whole Exome Sequencing
• Intraocular Pressure
• Ocular Hypertension
• Glucocorticoids

• Principal Investigator
  • Lucia Sobrin. Department of Ophthalmology at Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
• Co-Principal Investigator
  • Ayellet V Segrè. Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
• Funding Sources
  • National Eye Institute Grant EY030127. Boston, MA, USA.
  • Research to Prevent Blindness Physician Scientist Award (LS). Boston, MA, USA.