Evaluation of a glaucoma genetic risk score through in-depth phenotyping of ocular traits in high and low genetic risk groups

Glaucoma is an adult-onset ocular disorder which can lead to irreversible
blindness if not treated in time; this blindness is due to insidious
destruction of the optic nerve as initial symptoms often go unnoticed (Janssen
et al. 2013; Bailey et al. 2016). An accurate screening procedure to target
at-risk individuals could be clinically valuable, as proactive treatment can
slow the progression of this disorder. Currently no nationwide population-based
screening program exists in the Netherlands for glaucoma, as it is not a
cost-effective procedure currently due to the low prevalence of the disease,
~2% in Caucasians (Stoutenbeek et al. 2008). Tailoring glaucoma screening based
on an individual*s genetic risk for the disorder has the capacity to find cases
earlier, and the resultant early medical intervention could prolong eye health
(Stoutenbeek and Jansonius 2006; de Vries et al. 2012). There are at least five
causal genes as well as more than 68 genetic variants that have been identified
as being linked to glaucoma in Caucasians - making this a classic example of a
complex multifactorial disease (Janssen et al. 2013; Bailey et al. 2016). A
glaucoma genetic risk score (GRS) can be applied to a sample, representative of
the general population (i.e. the Lifelines genotyped cohort) to stratify
individuals as high and low genetic risk for glaucoma (Klijs et al. 2015). The
LifeLines genotyped cohort was not involved in any previous glaucoma gene
finding (GWAS) or replication studies, thus is an ideal population to assess
independently the feasibility to pre-screen based on a glaucoma GRS. Genotyped
Lifelines participants identified with sufficiently high/low genetic risk for
glaucoma will be invited to come in for an in-depth phenotyping of ocular
traits and general eye health; they will not be made aware of their genetic
risk for glaucoma.The GRS will be evaluated via the OR of having glaucoma for
the highest quintile of the GRS versus the lowest quintile. The phenotyping
will occur within the UMCG and will be set up as a carousel of examinations
performed by medical students who will be trained to have ocular examination
skills.

To evaluate the performance of an optimized glaucoma genetic risk score (GRS)
by inviting genotyped individuals from the population-based Lifelines cohort
for in-depth ophthalmic examinations.

cross-sectional, observational

Participants will have one visit to the laboratory of experimental
ophthalmology (LEO) within the UMCG to undergo ocular phenotyping. The
participants do not know their genetic risk, nor do those who assess the
participants. The examinations are as follows: Visual acuity and refraction,
non-contact eye pressure measurement, Frequency Doubling Technique (FDT) to
test visual field, Optical Coherence Tomography (OCT) scan to image structural
layers of the eye including cornea and retina, fundus photograph to image the
fundus of the eye, and quantification of eye moisture levels. All of the
proposed ocular examinations are non-invasive. If abnormal results are found
with any examination (in case of perimetry only if also present on retest,
which will be performed immediately), an on-site ophthalmologist will
confirm/falsify the findings and discuss them with the participant. The
participant will be referred to their GP if the disease status is confirmed by
thorough review of all examination results by an ophthalmologist, otherwise
he/she will be reassured. The total time required for the participants is
approximately half an hour for reception and ocular examinations. There may be
psychological stress if abnormal results are found. However, this is minimized
through quick confirmation/falsification and explanation. Moreover, if glaucoma
is found, participants will benefit from earlier treatment, which will preserve
eye health for longer. Participants will benefit from a free in-depth ocular
examination.