Primary Open-Angle Genetics

Increased intraocular pressure (IOP) and primary open-angle glaucoma (POAG) go hand-in-hand; IOP is the most important risk factor for the disease. But why pressure increases has always been a mystery. Now, the largest genome-wide association study (GWAS) on IOP to date – a meta-analysis of 139,555 European participants – has provided over 100 potential clues (1).

In total, 112 genomic loci were identified to be associated with IOP and POAG, of which 68 were novel. Significantly associated genetic loci included ANGPT1, ANGPT2, LRIG1 and FER, which are involved in angiopoietin-receptor tyrosine kinase signaling; ME3, VPS13C, GCAT and PTCD2, which are important for mitochondrial function; and DGKG, which is involved in lipid metabolism. The upshot? The findings open doors for potential screening of at-risk patients, personalized glaucoma care, and the discovery of new mechanisms of IOP regulation. Anthony Khawaja, lead author of the study, tells us more.

The inspiration

“Patients with POAG or ocular hypertension frequently ask why they have high IOP and, until now, we have not been able to answer them. Twin studies have suggested it was partly genetic, but analyzing all the globally available data on nearly 40,000 people only identified eight genetic loci associated with IOP. We were excited to use the huge UK Biobank cohort to discover new loci for IOP, as we can now tell our patients it is a combination of over 100 genetic variants. Each of these contributes a tiny amount to raising IOP but, collectively, they can have a big impact.”

The impact

“A very striking finding of our study was that these genetic loci predicted a substantial proportion of POAG in two independent studies (area under ROC: 75 percent). This opens up possibilities for targeted screening of people with a high genetic risk, which could allow early diagnosis and the prevention of irreversible vision loss. Currently, general population screening for glaucoma is not recommended because false positive rates are too high. We also hypothesize that some genetic variants will predict response to different IOP-lowering modalities.”

The challenges

“Making sense of the 112 loci individually is a challenge. Using a pathway approach helps us identify genes with associated biological functions. Lymphangiogenic factors were identified as important, and this points to Schlemm’s canal [a lymphatic-like vessel in the eye] as an important site of outflow resistance leading to variation in IOP. This finding challenges the previous dogma that the trabecular meshwork is the primary site of outflow obstruction in POAG.”

The future

“We will be examining whether subsets of genetic variants predict response to [laser surgery] and prostaglandin therapy, which could potentially lead to precision glaucoma management. An effort will also determine whether these genetic variants can improve screening of glaucoma in a large population in the Netherlands.”