Abstract
Purpose :
Primary angle closure glaucoma (PACG) is one of the leading causes of blindness worldwide with a complex genetic aetiology. For complex genetic disorders, copy number variation (CNV) is anticipated to play an essential role in disease vulnerability. The impact of CNVs on PACG has not been studied yet. In India, ~30% of people show narrow angles but 0.5-1% of people actually develop PACG. To exclude heterogeneity, we compared genome-wide CNVs between older (age ≥60 years) anatomically suspects (PACS) showing narrow angle <15° and PACG individuals having age ≤50 years. In doing so we would therefore be able to identify genes that are involved in the glaucomatous neurodegeneration, which we believe will be separate from genes controlling angle-related parameters.
Methods :
Genome-wide genotyping was performed on 148 PACG (40.15 ± 6.62 years) and 92 PACS (68.03 ± 7.56 years), followed by CNV calling using the PennCNV package's Hidden Markov model-based approach. For all deletions and duplications, CNV frequencies were analyzed statistically through the Wilcoxon test between PACG and PACS. The significant genomic regions were subjected to validation by qPCR and subsequently, bioinformatic analyses were carried out to determine the role of PACG pathophysiology.
Results :
There is no significant deletion was found between two groups but in amplification, we discovered that NLGN1 genic region (Gr37Chr3; bp:173239453-173246813) was overrepresented in PACG (P = 0.008413). That genic area of NLGN1 was successfully validated in qPCR by SYBR green assay. In PACG, the mean Ct values were significantly lower than in PACS (P= 0.079).NLGN1 is highly expressed retinal ganglion cells (PLIER: 44.3257). Gene network analyses showed that the NLGN1 are associated with many neurodegenerative and eye diseases. Moreover, genotype-phenotype correlation revealed that NLGN1 is linked to the assessment of a greater optic-cup area that is positively correlated with glaucomatous neurodegeneration.
Conclusions :
NLGN1 is involved in regulating the activity of NMDA receptors. Amplification of NLGN1 may promote more synaptic clustering of NMDARs in retinal ganglion cells (RGCs). The overexpression of these NMDARs leads to mitochondrial dysfunction of the RGCs. That eventually leads to the death of RGCs and subsequent glaucomatous neurodegeneration.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.