This article was reviewed by Bennet J. McComish, PhD
In the largest study of its kind in keratoconus published so far, researchers conducting a genome-wide association study found a region of chromosome 11 in which multiple genetic variants were significantly more common in keratoconus patients than in unaffected individuals.
Functional annotation of the associated variants indicated that several of the genes in the identified locus are likely involved in apoptotic pathways.
The findings were published in the February issue of JAMA Ophthalmology [McComish BJ, et al. JAMA Ophthalmol. 2020;138(2):174-181.] Bennet J. McComish, PhD, research fellow, Menzies Institute for Medical Research, University of Tasmania, Tasmania, Australia, is lead author of the article.
“Our study, which was an international collaboration between groups in Australia, the United States, and the United Kingdom, aimed to identify genetic variants involved in the risk of developing keratoconus,” he said. “This information will allow us to better understand the biochemical pathways that are disrupted in keratoconus. It will help in the identification of potential therapeutic targets for this disease that is relatively common and can cause severe visual impairment.”
Dr. McComish said the region of chromosome 11 that researchers identified contains at least five protein-coding genes.
“The next step will be to determine which of those genes is implicated in the disease, recognizing that other genetic variations nearby can ‘hitchhike’ with the variants that cause the disease,” he said.
Data used for the study were collected from individuals seen between January 2006 and March 2019 at eye clinics in Australia, the United States, and Northern Ireland.
First, in a discovery phase, data were analyzed from 522 Australians with keratoconus and 655 unaffected individuals representing a control group. Subjects for the control group were taken from cohorts of the Australian Blue Mountains Eye Study and a previous study of glaucoma.
Genotyping for 551,839 variants was done using the HumanCoreExome single-nucleotide polymorphism (SNP) array (Illumina). The SNPs with P values <1.00 x 10-6 that were identified in the discovery cohort were assessed in three independent replication cohorts using the MassARRAY System (Agena Bioscience).
The replication cohorts included 818 affected subjects with keratoconus and 3,858 unaffected controls. They were comprised of individuals included in a previous keratoconus GWAS data set from the United States, a cohort of subjects with keratoconus and unaffected controls from Australia and Northern Ireland, and a case-control cohort from Victoria, Australia.
In the discovery cohort as well as in the three replication cohorts, the majority of keratoconus subjects were males (55% to 61%) and mean age for the cases in each cohort ranged from 35 to 45 years. The proportion of males among controls in the discovery cohort was greater than in the replication cohorts (47% versus ~38%). Mean age of the controls in all four cohorts was 17 to 28 years older than the mean age of their keratoconus counterparts.