Shared Genetic Architectures Identified Across 5 Ocular Diseases

Research that focused on genome analysis of 5 different ocular diseases distinguished the genetic architectures that the diseases shared. The findings can further the understanding of the underlying molecular mechanisms related to these diseases.

Ocular conditions often present with similar clinical symptoms and epidemiological comorbidity, and yet, not much is known about the extent of pleiotropic mechanisms across the spectrum of diseases. Zhengbo Xue, and a team of investigators, decided to dive deeper into the genome associations.

"The shared genetic structure and pleiotropic mechanisms in ocular diseases interprets their clinical associations to some extent," investigators wrote. "Our results suggest that abnormalities in retinal development, Wnt signalling, and glucose metabolism may be the underlying mechanisms leading to susceptibility to multiple ocular diseases."

Age-Related Macular Degeneration, Diabetic Retinopathy, Glaucoma, Retinal Detachment, & Myopia

Age-related macular degeneration (AMD, diabetic neuropathy (DR), glaucoma, retinal detachment (RD), and myopia, were the 5 ocular diseases the team analyzed. The meta-analysis included information gathered from the large-scale UK Biobank on 43,877 cases and 44,373 controls and estimated their genetic relationships.

Approximately 96 million genotypes were imputed with Haplotype Reference Consortium and UK10K haplotype resources. Before standard quality control, investigators reviewed close to 500,000 patient cases genotyped for 805,426 markers on the UK BiLEVE Axiom array and UK Biobank Axiom array. Then, they identified pleitropic loci.

Genome-wide association analyses were performed for each individual disease and were adjusted for age, sex, and first 10 principal components. A subset-based approach, ASSETT, was employed to combine the association evidence and identify the genomic loci multiple ocular diseases shared.

The Genetic Structure of Ocular Disease

A meaningful genetic structure within the diseases was found in the genetic correlation of common single nucleotide polymorphisms (SNPs) which allowed investigators to identify the genetic correlations between AMD, DR, and glaucoma. Additionally, 23 pleitropic loci associated with at least 2 ocular dieases was revealed in cross-trait meta-analysis, along with 14 loci unique to individual non-pleitropic conditions.

The genes associated with these shared genetic loci were associated with functions including neuron differentiation and eye development systems, according to investigators. Data yieled by single cell RNA sequencing revealed heightened gene expression from multipotent progenitors to other differentiated retinal cells during the developmental process of the retina.

"These results highlighted the potential common genetic architectures among these ocular diseases and can deepen the understanding of the molecular mechanisms underlying the related diseases," investigators wrote.

The study "Genome-wide association meta-analysis of 88,250 individuals highlights pleiotropic mechanisms of five ocular diseases in UK Biobank" was published in The Lancet.