A genomewide association study on individuals with occludable angles identifies potential risk loci for intraocular pressure

Purpose PACG is one of the leading causes of blindness where lens thickness is a major risk factor for narrow-angle individuals. To our knowledge, no literature has been reported on candidate gene for lens thickness as a quantitative trait (QT). Here, we performed a genome-wide association analysis on lens thickness in the narrow-angle individuals. Materials and Methods We conducted a genome-wide association study (GWAS) in the narrow angle individuals to investigate comprehensive genetic insights on lens thickness. Results In QT-GWAS, we identified 145 genome-wide suggestive significant loci in the discovery cohort. Subsequently, we observed 13 SNPs that showed statistical significance around the region of PTRRM. Regional association analysis for top significant genotyped variants identified PTPRM as the most likely candidate for increased LT. Integrative bioinformatic analyses confirmed that the associated genomic region has potential regulatory roles for modulating transcription as enhancers. In the replication cohort, the sentinel genotype SNP was further associated significantly (P-value =0.000448) with high LT individuals. In both cohorts, the T allele of rs1941137 in the PTPRM gene indicates as a risk allele for the increased LT. Conclusion In this study, we discovered evidence of a genomic association between chromosomal areas around the PTPRM and increased lens thickness, resulting in a narrow angle. The regulatory components corresponding to PTPRM variations might have a role in the thicker lens. We report that the genomic region near PTPRM, a gene of potential interest, is associated with increased lens thickness.

show abstract

“…Multi-Dimensional Scaling (MDS) was used in R to further compress the dimension into two MDS components from the top 40 PCs. 17…”

Section: Methodsmentioning

confidence: 99%

“…Multi-Dimensional Scaling (MDS) was used in R to further compress the dimension into two MDS components from the top 40 PCs. 17 QT-GWAS analysis and covariates. We used age, sex, axial length, MDS1 and MDS2 as ancestry principal components as covariates in a linear regression of each individual's mean LT for both eyes.…”

Section: Phenotype and Subject Selectionmentioning

confidence: 99%

A quantitative trait GWAS on lens thickness identifies novel risk loci on PTPRM in the narrow angle individuals susceptible to PACG

Chakraborty

Pal

Sharma

et al. 2023

European Journal of Ophthalmology

Self Cite

View full text Add to dashboard Cite

show abstract

“…One study ( Ozel et al, 2014 ) that reported borderline genome-wide significance ( p = 8 × 10 −8 ) was included in Table 1 as well. These criteria excluded two IOP studies ( Chen et al, 2015 ; Chakraborty et al, 2021 ) that reported suggestively significant findings ( P ∼ 5.0 × 10 −5 or P ∼ 5.0 × 10 −6 ).…”

Section: Study Inclusion Criteriamentioning

confidence: 99%

10 Years of GWAS in intraocular pressure

et al. 2023

View full text Add to dashboard Cite

Intraocular pressure (IOP) is the only modifiable risk factor for glaucoma, the leading cause of irreversible blindness worldwide. In this review, we summarize the findings of genome-wide association studies (GWASs) of IOP published in the past 10 years and prior to December 2022. Over 190 genetic loci and candidate genes associated with IOP have been uncovered through GWASs, although most of these studies were conducted in subjects of European and Asian ancestries. We also discuss how these common variants have been used to derive polygenic risk scores for predicting IOP and glaucoma, and to infer causal relationship with other traits and conditions through Mendelian randomization. Additionally, we summarize the findings from a recent large-scale exome-wide association study (ExWAS) that identified rare variants associated with IOP in 40 novel genes, six of which are drug targets for clinical treatment or are being evaluated in clinical trials. Finally, we discuss the need for future genetic studies of IOP to include individuals from understudied populations, including Latinos and Africans, in order to fully characterize the genetic architecture of IOP.

show abstract

“…Primary angle closure glaucoma (PACG) is a major blinding eye disease, affecting over 20 million patients globally, more prevalent in east and south-east Asia 1 . It is characterized by progressive closure of the anterior chamber angle, resulting in blocked drainage of aqueous humour and increased intraocular pressure, which ultimately damages the optic nerve 2,3 . Eventually, loss of retinal layers and the degeneration of the optic nerve can result in irreversible vision loss, leading to blindness 4 .…”

Section: Introductionmentioning

confidence: 99%

Post-GWAS functional analyses ofCNTNAP5suggests its role in glaucomatous neurodegeneration

Chakraborty,

Sarma,

Roy

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

Primary angle closure glaucoma (PACG) affects more than 20 million people worldwide, with an increased prevalence in south-east Asia. In a prior haplotype-based GWAS, we identified a novelCNTNAP5genic region, significantly associated with PACG. In the current study, we have extended our perception ofCNTNAP5involvement in glaucomatous neurodegeneration in a zebrafish model, through investigating phenotypic consequences pertinent to retinal degeneration upon knockdown of cntnap5 by translation-blocking morpholinos. While cntnap5 knockdown was successfully validated using an antibody, immunofluorescence followed by western blot analyses in cntnap5-morphant (MO) zebrafish revealed increased expression of acetylated tubulin indicative of perturbed cytoarchitecture of retinal layers. Moreover, significant loss of Nissl substance is observed in the neuro-retinal layers of cntnap5-MO zebrafish eye, indicating neurodegeneration. Additionally, in spontaneous movement behavioural analysis, cntnap5-MO zebrafish have a significantly lower average distance traversed in light phase compared to mismatch-controls, whereas no significant difference was observed in the dark phase, corroborating with vision loss in the cntnap5-MO zebrafish. This study provides the first direct functional evidence of a putative role ofCNTNAP5in visual neurodegeneration.

show abstract

A genomewide association study on individuals with occludable angles identifies potential risk loci for intraocular pressure

Cited by 3 publications

References 17 publications

A quantitative trait GWAS on lens thickness identifies novel risk loci on PTPRM in the narrow angle individuals susceptible to PACG

A quantitative trait GWAS on lens thickness identifies novel risk loci on PTPRM in the narrow angle individuals susceptible to PACG

10 Years of GWAS in intraocular pressure

Post-GWAS functional analyses ofCNTNAP5suggests its role in glaucomatous neurodegeneration

Contact Info

Product

Resources

About