Genetic Associations of Primary Angle-Closure Disease: A Systematic Review and Meta-Analysis

Yu Jing Liang; Yu Yao Wang; Shi Song Rong; Zhen Ji Chen; Shu Ying Chen; Jenson A Tham; Poemen P Chan; Jason C Yam; Janey L Wiggs; Chi Pui Pang; Clement C Tham; Li Jia Chen

doi:10.1001/jamaophthalmol.2024.0363

. 2024 Mar 28;142(5):437–444. doi: 10.1001/jamaophthalmol.2024.0363

Genetic Associations of Primary Angle-Closure Disease

A Systematic Review and Meta-Analysis

Yu Jing Liang ¹, Yu Yao Wang ¹, Shi Song Rong ⁴, Zhen Ji Chen ¹, Shu Ying Chen ¹, Jenson A Tham ¹, Poemen P Chan ^1,², Jason C Yam ^1,², Janey L Wiggs ⁴, Chi Pui Pang ¹, Clement C Tham ^1,^2,³, Li Jia Chen ^1,^2,^3,^✉

¹Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China

²Hong Kong Eye Hospital, Hong Kong, China

³Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Hong Kong, China

⁴Department of Ophthalmology, Mass Eye and Ear, Mass General Brigham, Boston, Massachusetts

Accepted for Publication: January 12, 2024.

Published Online: March 28, 2024. doi:10.1001/jamaophthalmol.2024.0363

^✉

Corresponding Author: Li Jia Chen, PhD, Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, 147K Argyle St, Kowloon, Hong Kong, China (lijia_chen@cuhk.edu.hk).

Author Contributions: Dr Chen had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Ms Liang, Ms Wang, and Dr Rong contributed equally to this work.

Concept and design: Liang, Rong, Z. Chen, S. Chen, Pang, C. Tham, L. Chen.

Acquisition, analysis, or interpretation of data: Liang, Wang, Rong, Z. Chen, S. Chen, J. Tham, Chan, Yam, Wiggs, L. Chen.

Drafting of the manuscript: Liang, Rong, J. Tham, Chan.

Critical review of the manuscript for important intellectual content: Liang, Wang, Rong, Z. Chen, S. Chen, Chan, Yam, Wiggs, Pang, C. Tham, L. Chen.

Statistical analysis: Liang, Wang, Rong, Z. Chen, S. Chen, J. Tham, Chan.

Obtained funding: Pang, L. Chen.

Administrative, technical, or material support: Yam, Pang, L. Chen.

Supervision: Rong, Chan, Pang, C. Tham, L. Chen.

Conflict of Interest Disclosures: Dr Wiggs reported grants from the National Institutes of Health and consulting fees from CRISPR Therapeutics and Broadwing Bio outside the submitted work. No other disclosures were reported.

Funding/Support: This work was supported by grants from the Health and Medical Research Fund Hong Kong (07180256; Dr Chen), the General Research Fund, Hong Kong (14102122 and 14105320; Prof C. Tham and 14105916 and 2141022; Prof Pang), and the Endowment Fund for Lim Por-Yen Eye Genetics Research Centre, Hong Kong.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 2.

^✉

Corresponding author.

PMCID: PMC10979365 PMID: 38546604

Key Points

Question

What are the genetic risk factors associated with primary angle-closure disease, its subtypes and progression, regarding both common single-nucleotide variants and rare variants?

Findings

This systematic review and meta-analysis revealed association between primary angle-closure glaucoma and 7 genes or loci not found to be associated with primary angle-closure glaucoma in previous systematic reviews or genome-wide association studies of primary angle-closure glaucoma. Single reported common and rare variants in the coding region of 16 genes associated with primary angle-closure disease were cataloged.

Meaning

This study supports the genetic complexity of primary angle-closure glaucoma, involving multiple common single-nucleotide variants and rare coding variants.

This systematic review and meta-analysis evaluates associations of common single-nucleotide variants and rare coding variants with primary angle-closure disease.

Abstract

Importance

Effects of genetic variants on primary angle-closure disease remained uncertain.

Objective

To systematically review the associations of common single-nucleotide variants (SNVs) and rare coding variants with primary angle-closure disease, its subtypes (including primary angle-closure glaucoma, primary angle-closure suspect, and primary angle-closure) and progression.

Data Sources

Eligible studies from PubMed, Embase, and Web of Science were retrieved up to April 3, 2023. SNV information was extracted from eligible reports and 2 genome-wide association studies summary statistics, UK BioBank and FinnGen.

Study Selection

Studies providing analyzable genotype or allele data in a case-control design for primary angle-closure disease association and longitudinal case-only design for primary angle-closure disease progression.

Data Extraction and Synthesis

PRISMA guidelines were used for literature screening and the Newcastle Ottawa Scale for data quality assessment. Pooled effect size with 95% CIs of SNV associations were calculated using fixed- or random-effect models according to I² statistics.

Main Outcomes and Measures

SNVs reported in 2 or more studies were meta-analyzed to generate pooled odds ratios and P values. Common and rare coding variants from single reports were summarized.

Results

Sixty-nine citations were eligible for meta-analysis on overall primary angle-closure disease, involving 206 SNVs in 64 genes or loci. Seventeen SNVs in 15 genes or loci showed associations with primary angle-closure disease, and 15 SNVs in 13 genes or loci showed associations with primary angle-closure glaucoma. Two SNVs, ABCA1 rs2422493 and ZNRF3 rs3178915, were associated only with primary angle-closure disease. Two SNVs, PCMTD1-ST18 rs1015213 and COL11A1 rs3753841, were associated with primary angle-closure suspect, and 1 SNV, MMP9 rs3918249, was associated with primary angle-closure. This systematic review and meta-analysis newly confirmed 7 genes or loci associated with primary angle-closure glaucoma: ATOH7, CALCRL, FBN1, IL6, LOXL1, MMP19, and VAV3. Common and rare coding variants in 16 genes or loci that have been associated with primary angle-closure disease were cataloged. Stratification analysis revealed different primary angle-closure disease–associated genes in different ethnic populations. Only 1 study regarding the genetic association of primary angle-closure glaucoma progression was identified.

Conclusions and Relevance

This study revealed the genetic complexity of primary angle-closure disease, involving common SNVs and rare coding variants in more than 30 genes or loci, with ethnic and phenotypic diversities. Further replication, genotype-phenotype correlation, and pathway analyses are warranted.

Introduction

Glaucoma is a leading cause of irreversible blindness worldwide, estimated to have affected 60.6 to 79.6 million people between 2010 and 2020.¹ Angle closure glaucoma accounts for approximately 26% of all types of glaucoma.² Primary angle-closure glaucoma affected approximately 17.14 million individuals globally in 2020,³ and the number is expected to double by 2040.⁴

Major risk factors for primary angle-closure glaucoma include older age, female sex, ethnicity (eg, African and East Asian), and genetic factors.⁵ Direct evidence for the genetic basis of primary angle-closure glaucoma came from genome-wide association studies (GWASs), which have identified 8 susceptibility loci for primary angle-closure glaucoma: EPDR1, CHAT, CLIS3, FERMT2, DPM2-FAM102A, PLEKHA7, COL11A1, and PCMTD1-ST18.^6,7 In addition, more than 80 candidate genes have been assessed for their associations with primary angle-closure glaucoma, as well as primary angle-closure and primary angle-closure suspect, which together form a continuum of phenotypes known as primary angle-closure disease.

Since the first systematic review and meta-analysis on primary angle-closure disease published in 2016,⁸ a primary angle-closure glaucoma GWAS with a larger sample size⁷ and a number of new candidate gene studies have been reported. In addition, sequencing studies have identified multiple variants in coding regions associated with primary angle-closure disease or related traits.^{9,10,11,12,13,14,15,16,17,18} However, the association profiles for these genes or loci, including effect allele frequency, statistical significance, and effect size, varied across the study cohorts. Therefore, their roles in primary angle-closure glaucoma remained inconclusive. Moreover, genetic associations of primary angle-closure and primary angle-closure suspect have been much less studied than primary angle-closure glaucoma, while genetic studies on primary angle-closure glaucoma progression have not been systematically reviewed.

In this study, we conducted a 2-staged systematic review and meta-analysis to evaluate and summarize the effects of all reported genes and variants, including both common single-nucleotide variants (SNVs) and rare coding variants, on overall primary angle-closure disease, its subtypes (ie, primary angle-closure glaucoma, primary angle-closure and primary angle-closure suspect), and disease progression.

Methods

Study Inclusion

We conducted this systematic review and meta-analysis in 2 stages. Stage 1 focused on the genetic associations of primary angle-closure disease and subtypes and stage 2 on the genetic associations of primary angle-closure disease progression. We performed literature searches independently for each stage in PubMed, Web of Science, Embase, and GWAS catalog databases, using predefined search strategies (eAppendix 1 in Supplement 1). No language filter was applied. The last search was conducted on April 3, 2023, for both stages.

Eligibility Criteria

At stage 1, we selected studies that (1) were original case-control studies with unrelated individuals from defined populations, (2) reported the genetic associations of primary angle-closure disease and its subtypes, and (3) reported odds ratios (ORs) with 95% CIs and SEs or allelic and/or genotypic frequencies that allowed the calculation of ORs, CIs, and SEs. To summarize common and rare coding variants in primary angle-closure disease, we included targeted gene sequencing, whole-exome sequencing and whole-genome sequencing studies in sporadic or familial cases. We excluded animal studies, case reports, reviews, conference proceedings, editorials, and studies with incomplete data. Common and rare variants in coding regions presented in single reports that could not be meta-analyzed were cataloged. At stage 2, in addition to criteria 2 and 3 in stage 1, we selected case-only longitudinal studies that tested the genetic associations of explicitly defined primary angle-closure disease progression.

Study Selection, Quality Assessment, Data Extraction, and Data Analysis

At stage 1, 2 reviewers (Y.J.L. and Y.Y.W.) independently screened all identified records. Disagreements were resolved through discussion with a third reviewer (S.S.R.). After identifying eligible articles, 2 reviewers (Y.J.L. and Y.Y.W.) independently assessed the quality of each study using the Newcastle Ottawa Scale. We gave 1 star to a study if it met 1 Newcastle Ottawa Scale requirement from any of the 3 dimensions (selection, comparability, and exposure). We considered a study having low risk of inducing bias when it had 7 or more stars.^8,19 We meticulously evaluated the methodologies and diagnostic criteria adopted in each study and confirmed in most of these studies that the diagnosis of primary angle-closure disease and its subtypes was done by ophthalmologists.

Two reviewers (Y.J.L. and Y.Y.W.) independently extracted data from all identified studies using a customized datasheet, including the first author, date of publication, title of articles, study cohorts and populations, disease subgroups and corresponding sample sizes, SNV identification and genes, effect allele, allele counts and/or frequencies, genotypic counts and/or frequencies, ORs and 95% CIs (or SEs) of the tested variants, and results of Hardy-Weinberg Equilibrium test in control groups. For studies including more than 1 cohort, we treated each cohort as an independent entry. For 2 studies comparing different primary angle-closure disease subtypes with the same group of controls,^20,21 we combined the cases from the 2 studies into 1 case-control comparison.

Of note, we identified 2 published single-cohort GWAS summary statistics, UK Biobank and FinnGen,^22,23 which provided includable data for meta-analysis. We extracted SNVs tested in candidate gene studies within these 2 data sets and combined the data with non-European cohorts to minimize the risk of sample overlapping. Any SNVs that were reported in 2 or more cohorts were meta-analyzed. For each SNV, we meta-analyzed the data from candidate gene studies and UK Biobank and FinnGen if available. If an SNV has been reported in the primary angle-closure glaucoma GWAS,⁷ we meta-analyzed it further with the GWAS data. This is to test whether the SNV is replicable in independent studies (eFigure 1 in Supplement 1).

The primary outcome of this study is the pooled-allelic association of individual variants with primary angle-closure disease. Intercohort heterogeneity was evaluated using the I² test. During meta-analysis, the fixed-effect model was used when a low heterogeneity (I² < 25%) was detected, otherwise a random effect model was used.^8,24,25 Pooled ORs, 95% CIs, and P values were generated accordingly. We performed sensitivity analysis to examine whether the pooled association of individual SNV was robust. We excluded cohorts that deviated from Hardy-Weinberg Equilibrium in controls and studies with fewer than 7 stars in the Newcastle Ottawa Scale (eTable 1 in Supplement 1). We then omitted each cohort entry at 1 time and recalculated the pooled outcomes. If an association was dominated by 1 entry, it failed the sensitivity test and should be interpreted with caution. We adopted funnel plots to assess the publication biases (data not shown). RevMan version 5.4 (Cochrane) and R version 4.3.1 (R Foundation) were used for statistical analyses. Significance was set at 2-sided P less than .05.

Results

Identification of Eligible Studies

At stage 1, we identified 62 276 records published between January 1953²⁶ and April 3, 2023. After removing 12 152 duplicates, we screened 50 124 records from the literature and 2 GWAS datasets, UK Biobank and FinnGen. In total, we identified 98 studies for full review (eFigure 2 in Supplement 1), including 83 candidate gene studies, 2 GWASs,^6,7 2 single-cohort GWAS summary statistics,^22,23 5 genetic linkage analysis,^{11,12,16,18,27} 3 mitochondrial sequencing studies,^28,29,30 and 3 whole-exome sequencing studies^10,15,31 (eFigure 3 in Supplement 1). In these 98 studies, 4 linkage analysis, 3 mitochondrial sequencing, and 3 whole-exome sequencing studies were not eligible for meta-analysis as they did not provide analyzable data or replications. Among the 83 candidate gene studies, 19 were excluded because 4 of them contained gene variants without replication,^32,33,34,35 12 did not provide analyzable genotype or allele data,^{9,14,17,36,37,38,39,40,41,42,43,44} and 3 involved cohorts that had been reported before.^45,46,47 Primary angle-closure glaucoma GWASs were eligible for the meta-analysis. But given the heavily overlapped cohorts between 2 primary angle-closure glaucoma GWASs,^6,7 we selected the latest one⁷ for calculation (eFigures 2 and 4 in Supplement 1). Moreover, 2 single cohort GWAS summary statistics were eligible for analysis.^22,23 Although no SNV achieved genome-wide significance in these 2 GWAS summary statistics, they enabled the assessment of primary angle-closure disease genetics in the European populations. Eventually, 64 candidate gene studies, 1 linkage study with genotype data,²⁷ and 3 GWAS data sets^7,22,23 were included for meta-analysis (eFigure 4 in Supplement 1).

The flow of study inclusion for genetic association of primary angle-closure disease progression is shown in eFigure 5 in Supplement 1. Among 5253 records screened, only 1 study was found to test the genetic association of primary angle-closure glaucoma progression in longitudinal design.⁴⁸ Therefore, meta-analysis was not conducted.

Association of Primary Angle-Closure Disease

From the 69 eligible studies, a total of 267 comparisons between 206 SNVs in 64 genes or loci and primary angle-closure disease (including primary angle-closure glaucoma, primary angle-closure, primary angle-closure suspect, and the overall primary angle-closure disease; eTables 2-5 in Supplement 1) were conducted in different populations, including Australian, Chinese, Egyptian, European, Indian, Iranian, Nepalese, Pakistani, Saudi Arabian, and Singaporean (eAppendix 2 in Supplement 1). Of note, for the SNVs in 8 loci (namely EPDR1, CHAT, CLIS3, FERMT2, DPM2-FAM102A, PLEKHA7, COL11A1, and PCMTD1-ST18) that were associated with primary angle-closure glaucoma in the latest GWAS,⁷ we first pooled the data from replication studies and the 2 GWAS summary statistics, then meta-analyzed altogether with the original GWAS (eFigure 1, eTables 2-5 in Supplement 1).

Fifteen SNVs in 13 loci were associated with primary angle-closure glaucoma in replication studies. Four of these (CHAT rs1258267, PLEKHA7 rs11024102, PCMTD1-ST18 rs1015213, and COL11A1 rs3753841) were previously reported in the GWAS.⁷ The other 11 were located in 10 loci reported in candidate gene studies, namely ABCC5, ATOH7, CALCRL, FBN1, HGF, IL6, LOXL1, MMP19, PLEKHA7, and VAV3 (Table 1).

Table 1. Allelic Association With Primary Angle-Closure Glaucoma (PACG).

Gene	SNV	No. of cohorts	PACD subtype	A1/A2^a	Population^b	Pooled sample size		FEM or REM^c		I², %
Gene	SNV	No. of cohorts	PACD subtype	A1/A2^a	Population^b	Case	Control	P value	OR (95% CI)	I², %
CHAT	rs1258267	5	PACG	A/G	Multiple	2684	815 288	1.50 × 10⁻⁸	1.34 (1.21-1.48)	0
PLEKHA7	rs11024102	10	PACG	G/A	Multiple	3975	817 714	1.99 × 10⁻³	1.19 (1.07-1.33)	75
PCMTD1-ST18 ^d	rs1015213	7	PACG	A/G	Multiple	3254	816 706	2.59 × 10⁻³	1.36 (1.11-1.65)	61
LOXL1	rs3825942	3	PACG/PACD	A/G	Multiple	1886	814 237	3.02 × 10⁻³	0.88 (0.80-0.96)	0
COL11A1	rs3753841	10	PACG	G/A	Multiple	3975	817 714	5.49 × 10⁻³	1.16 (1.05-1.29)	75
HGF	rs5745718	6	PACG/PACD	A/G	Multiple	2704	815 403	9.64 × 10⁻³	1.51 (1.10-2.05)	94
IL6	rs1800796	3	PACG/PACD	C/G	Multiple	2251	814 581	1.38 × 10⁻²	1.21 (1.04-1.40)	0
ATOH7	rs1900004	3	PACG/PACD	T/C	Multiple	1915	814 365	1.41 × 10⁻²	1.10 (1.02-1.18)	0
MMP19	rs2291267	3	PACG/PACD	A/G	Multiple	1868	814 218	1.57 × 10⁻²	1.20 (1.03-1.39)	0
PLEKHA7	rs11024060	4	PACG	T/C	Multiple	2447	815 105	1.89 × 10⁻²	0.93 (0.87-0.99)	0
ABCC5	rs1401999	3	PACG/PACD	C/G	Multiple	6566	833 653	2.38 × 10⁻²	1.08 (1.01-1.15)	44
HGF	rs3735520	5	PACG/PACD	A/G	Multiple	2634	815 343	2.53 × 10⁻²	1.07 (1.01-1.13)	0
CALCRL	rs9288141	5	PACG/PACD	G/A	Multiple	2210	814 829	3.37 × 10⁻²	1.14 (1.01-1.29)	0
FBN1	rs363830	3	PACG/PACD	T/C	Multiple	2290	814 852	4.04 × 10⁻²	0.76 (0.59-0.99)	0
VAV3	rs6689476	3	PACG/PACD	C/T	Multiple	1901	814 417	4.14 × 10⁻²	1.22 (1.01-1.49)	41

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Abbreviations: ABCC5, adenosine 5′-triphosphate–binding cassette subfamily C member 5; ATOH7, atonal basic helix–loop–helix transcription factor 7; CALCRL, calcitonin receptor–like receptor; CHAT, choline O-acetyltransferase; COL11A1, collagen type XI alpha 1 chain; FBN1, fibrillin 1; IL6, interleukin 6; LOXL1, lysyl oxidase like 1; MMP19, matrix metallopeptidase 19; PACD, primary angle-closure disease; PCMTD1, protein-L-isoaspartate (D-aspartate) O-methyltransferase domain containing 1 ST18; PLEKHA7, pleckstrin homology domain containing A7; SNV, single-nucleotide variant; ST18, C2H2C-type zinc finger transcription factor; VAV3, vav guanine nucleotide exchange factor 3.

^{^a}

A1 refers to effect allele, A2 refers to reference allele.

^{^b}

Multiple refers to more than 3 different populations.

^{^c}

If the I² value was larger than 25%, a random-effects model was used; otherwise, a fixed-effects model was adopted.

^{^d}

PCMTD1-ST18 suggests that the SNV is located in the intergenic region of these genes.

Compared to the previous systematic review⁸ and the latest GWAS,⁷ 7 SNVs were newly confirmed for their associations with primary angle-closure glaucoma: LOXL1 rs3825942 (odds ratio [OR], 0.88; 95% CI, 0.80-0.96; P = 3.02 × 10⁻³), IL6 rs1800796 (OR, 1.21; 95% CI, 1.04-1.40; P = 1.38 × 10⁻²), ATOH7 rs1900004 (OR, 1.10; 95% CI, 1.02-1.18; P = 1.41 × 10⁻²), MMP19 rs2291267 (OR, 1.20; 95% CI, 1.03-1.39; P = 1.57 × 10⁻²), CALCRL rs9288141 (OR, 1.14; 95% CI, 1.01-1.29; P = 3.37 × 10⁻²), FBN1 rs363830 (OR, 0.76; 95% CI, 0.59-0.99; P = 4.04 × 10⁻²), and VAV3 rs6689476 (OR, 1.22; 95% CI, 1.01-1.49; P = 4.14 × 10⁻²) (Table 1). Moreover, in the GWAS loci, 1 new SNV, PLEKHA7 rs11024060 (OR, 0.93; 95% CI, 0.87-0.99; P = 1.89 × 10⁻²) (Table 1), was identified. Two candidate SNVs, HGF rs5745718 and ABCC5 rs1401999, which were identified to be associated with primary angle-closure glaucoma in the previous systematic review,⁸ were further verified in this study with larger combined sample sizes. Moreover, another SNV on HGF, rs3735520 (OR, 1.07; 95% CI, 1.01-1.13; P = 2.53 × 10⁻²), was newly identified to be associated with primary angle-closure glaucoma in the current meta-analysis (Table 1).

Regarding primary angle-closure disease, 2 SNVs reported in primary angle-closure glaucoma GWAS, CHAT rs1258267 (OR, 1.25; 95% CI, 1.15-1.37; P = 3.23 × 10⁻⁷) and PLEKHA7 rs11024102 (OR, 1.11; 95% CI, 1.05-1.17; P = 1.24 × 10⁻⁴), showed substantial association in replication cohorts, along with 15 other SNVs (Table 2). Among these 17 SNVs, 15 were shared between primary angle-closure disease and primary angle-closure glaucoma, while ABCA1 rs2422493 and ZNRF3 rs3178915 were associated with primary angle-closure disease only. Regarding other primary angle-closure disease subtypes, 2 SNVs, PCMTD1-ST18 rs1015213 (OR, 1.71; 95% CI, 1.13-2.59; P = 1.10 × 10⁻²) and COL11A1 rs3753841 (OR, 1.10; 95% CI, 1.00-1.22; P = 4.60 × 10⁻²), were associated with primary angle-closure suspect (eTable 4 in Supplement 1), while only one SNV, MMP9 rs3918249 (OR, 0.81; 95% CI, 0.69-0.95; P = 1.10 × 10⁻²), was associated with primary angle-closure (eTable 5 in Supplement 1). The effect allele frequencies of SNVs associated with primary angle-closure glaucoma and primary angle-closure disease in different populations are shown in eTable 6 in Supplement 1.

Table 2. Allelic Association With Primary Angle-Closure Disease (PACD).

Gene	SNV	No. of cohorts	PACD subtype	A1/A2^a	Population^b	Pooled sample size		FEM or REM^c		I², %
Gene	SNV	No. of cohorts	PACD subtype	A1/A2^a	Population^b	Case	Control	P value	OR (95% CI)	I², %
CHAT	rs1258267	7	PACD	A/G	Multiple	4917	816 518	3.23 × 10⁻⁷	1.25 (1.15-1.37)	16
PLEKHA7	rs11024102	13	PACD	G/A	Multiple	6937	819 661	1.24 × 10⁻⁴	1.11 (1.05-1.17)	21
PCMTD1-ST18 ^d	rs1015213	10	PACD	A/G	Multiple	5838	818 653	2.44 × 10⁻⁴	1.50 (1.21-1.87)	86
COL11A1	rs3753841	13	PACD	G/A	Multiple	6937	819 661	1.43 × 10⁻³	1.15 (1.05-1.25)	71
LOXL1	rs3825942	3	PACG/PACD	A/G	Multiple	1886	814 237	3.02 × 10⁻³	0.88 (0.80-0.96)	0
HGF	rs5745718	6	PACG/PACD	A/G	Multiple	2704	815 403	9.64 × 10⁻³	1.51 (1.10-2.05)	94
IL6	rs1800796	3	PACG/PACD	C/G	Multiple	2251	814 581	1.38 × 10⁻²	1.21 (1.04-1.40)	0
ATOH7	rs1900004	3	PACG/PACD	T/C	Multiple	1915	814 365	1.41 × 10⁻²	1.10 (1.02-1.18)	0
MMP19	rs2291267	3	PACG/PACD	A/G	Multiple	1868	814 218	1.57 × 10⁻²	1.20 (1.03-1.39)	0
PLEKHA7	rs11024060	4	PACD	T/C	Multiple	2814	815 105	1.69 × 10⁻²	0.93 (0.87-0.99)	0
ABCA1	rs2422493	4	PACD	A/G	Multiple	3401	816 163	2.20 × 10⁻²	0.93 (0.88-0.99)	0
ABCC5	rs1401999	3	PACG/PACD	C/G	Multiple	6566	833 653	2.38 × 10⁻²	1.08 (1.01-1.15)	44
HGF	rs3735520	5	PACG/PACD	A/G	Multiple	2634	815 343	2.53 × 10⁻²	1.07 (1.01-1.13)	0
ZNRF3	rs3178915	4	PACD	A/G	Multiple	2511	815 148	3.25 × 10⁻²	1.07 (1.01-1.13)	0
CALCRL	rs9288141	5	PACG/PACD	G/A	Multiple	2210	814 829	3.37 × 10⁻²	1.14 (1.01-1.29)	0
FBN1	rs363830	3	PACG/PACD	T/C	Multiple	2290	814 852	4.04 × 10⁻²	0.76 (0.59-0.99)	0
VAV3	rs6689476	3	PACG/PACD	C/T	Multiple	1901	814 417	4.14 × 10⁻²	1.22 (1.01-1.49)	41

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Abbreviations: ABCA1, adenosine 5′-triphosphate–binding cassette subfamily A member 1; ABCC5, adenosine 5′-triphosphate–binding cassette subfamily C member 5; ATOH7, atonal basic helix–loop–helix transcription factor 7; CALCRL, calcitonin receptor–like receptor; CHAT, choline O-acetyltransferase; COL11A1, collagen type XI alpha 1 chain; FBN1, fibrillin 1; IL6, interleukin 6; LOXL1, lysyl oxidase like 1; MMP19, matrix metallopeptidase 19; PACG, primary angle-closure glaucoma; PCMTD1, protein-L-isoaspartate (D-aspartate) O-methyltransferase domain containing 1 ST18; PLEKHA7, pleckstrin homology domain containing A7; SNV, single-nucleotide variant; VAV3, vav guanine nucleotide exchange factor 3; ST18, C2H2C-type zinc finger transcription factor; ZNRF3, zinc and ring finger 3.

^{^a}

A1 refers to effect allele, A2 refers to reference allele.

^{^b}

Multiple refers to more than 3 different populations.

^{^c}

If the I² value was larger than 25%, a random-effects model was used; otherwise, a fixed-effects model was adopted.

^{^d}

PCMTD1-ST18 suggests that the SNV is located in the intergenic region of these genes.

After combining with the primary angle-closure glaucoma GWAS, 5 SNVs showed associations with primary angle-closure glaucoma and primary angle-closure disease, namely CHAT rs1258267 (primary angle-closure glaucoma, OR, 1.25; 95% CI, 1.17-1.34; P = 4.03 × 10⁻¹⁰; primary angle-closure disease, OR, 1.23; 95% CI, 1.17-1.29; P = 4.58 × 10⁻¹⁶), PCMTD1-ST18 rs1015213 (primary angle-closure glaucoma, OR, 1.38; 95% CI, 1.22-1.55; P = 2.39 × 10⁻⁷; primary angle-closure disease, OR, 1.49; 95% CI, 1.25-1.78; P = 7.21 × 10⁻⁶), PLEKHA7 rs11024102 (primary angle-closure glaucoma, OR, 1.19; 95% CI, 1.09-1.29; P = 3.90 × 10⁻⁵; primary angle-closure disease, OR, 1.13; 95% CI, 1.08-1.18; P = 1.43 × 10⁻⁸), COL11A1 rs3753841 (primary angle-closure glaucoma, OR, 1.18, 95; CI, 1.08-1.28; P = 1.56 × 10⁻⁴; primary angle-closure disease, OR, 1.16; 95% CI, 1.08-1.25; P = 3.63 × 10⁻⁵), and DPM2-FAM102A rs3739821 (primary angle-closure glaucoma, OR, 1.08; 95% CI, 1.02-1.15; P = 1.29 × 10⁻²; primary angle-closure disease, OR, 1.11; 95% CI, 1.04-1.18; P = 8.89 × 10⁻⁴) (eTable 2-3 in Supplement 1).

In sensitivity analysis, we first excluded reports with fewer than 7 stars in the Newcastle Ottawa Scale assessment (eTable 1 in Supplement 1)^13,27 or cohorts deviating from Hardy-Weinberg Equilibrium in controls,^{20,21,49,50,51} then sequentially omitted each study 1 at a time and recalculated the pooled effect sizes. No significant alterations were observed, suggesting that the results were robust (data not shown).

Stratification Analysis by Population

Among all 199 SNVs that have been investigated in admixed populations, 8 (namely, CHAT rs1258267, COL11A1 rs3753841, GLIS3 rs736893, HGF rs5745718 and rs3735520, MMP9 rs17577, and PLEKHA7 rs216489 and rs11024102) were associated with primary angle-closure glaucoma and overall primary angle-closure disease in East Asian individuals, mainly Chinese individuals. In European individuals, 7 SNVs (namely, ATOH7 rs1900004, FBN1 rs363830, FERMT2 rs7494379, GLIS3 rs736893, IL6 rs1800796, LOXL1 rs3825942, and MMP19 rs2291267) exhibited associations with primary angle-closure glaucoma (eTable 7 in Supplement 1). Only GLIS3 rs736893 showed association in both Asian and European individuals.

Rare Coding Variants in Primary Angle-Closure Disease

We cataloged all coding variants that have been associated with primary angle-closure glaucoma (eTable 8 in Supplement 1). This is because coding variants, which are usually rare, are more likely to be functional and worth further evaluation. We found that all coding variants except for LOXL1 rs3825942 (G153D) and FBN1 rs363830 (Q2296 = ) were reported in single studies without replication. Therefore, they were not eligible for meta-analysis.

In hypothesis-based studies, where candidate genes or variants were sequenced, Asp148Glu in APEX1,¹³ Ser326Cys in OGG1,¹³ Arg92Gly in BEST1,⁹ Thr862Ser in CRB1,⁹ Pro166Ala in MFRP,⁹ 4 variants in MYRF,⁹ 4 variants in PRSS56,¹⁷ 2 variants in LTBP2,¹⁴ 2 variants in MYOC,^11,15 Leu432Val in CYP1B1,¹¹ and 2 sets of biallelic variants in CPAMD8¹⁰ were found to be associated with primary angle-closure glaucoma in Chinese cohorts. In a hypothesis-free whole-exome sequencing study, 2 genes, OPA1 and WDR36, were associated with primary angle-closure glaucoma in unrelated Chinese individuals.¹⁵ Another gene, PCK2, was associated with primary angle-closure glaucoma in a Chinese pedigree.¹⁶ In other populations, SPATA13 was associated with primary angle-closure glaucoma in a British pedigree,¹⁸ while COL18A1 was associated with iridocorneal angle-closure, a feature of primary angle-closure disease, in related Iranian individuals (eTable 8 in Supplement 1).¹²

Genetic Association of Primary Angle-Closure Glaucoma Progression

Our literature search identified only 1 study examining the genetic associations of primary angle-closure glaucoma progression in a Malay population,⁴⁸ precluding further meta-analysis. This study investigated the associations of SNVs rs11024102 in PLEKHA7, rs17217796 in ABCC5, and rs1392912 in KALRN with primary angle-closure glaucoma progression using event-based evidence over 3 years of follow-up. However, no association was found.⁴⁸

Discussion

In this updated systematic review and meta-analysis, we verified the associations of common SNVs in 15 genes or loci with primary angle-closure disease and 13 genes or loci with primary angle-closure glaucoma, cataloged single-reported rare coding variants in 16 genes or loci associated with primary angle-closure glaucoma, and revealed a scarcity of genetic studies on primary angle-closure glaucoma progression. Notably, the genes harboring those common and rare variants did not overlap and most of the associated genes were different between Asian and European individuals, suggesting the genetic complexity of primary angle-closure disease and primary angle-closure glaucoma and possible ethnic diversities.

In this study, only 1 SNV, rs1258267, showed substantial association with primary angle-closure glaucoma, and 2, rs1258267 and rs11024102, with primary angle-closure disease. Both rs1258267 and rs11024102 are located in intronic regions and expression quantitative trait loci analysis provided limited evidence for their biological relevance (eFigures 6 and 7 in Supplement 1). However, the association summarized from multiple populations suggested these SNVs may be genetic biomarkers for glaucoma risk assessment. Other SNVs showing questionable associations may or may not be worth exploring. The lack of a definitive association could be because there truly is no association, although it is possible that the associations lacked precision due to low numbers evaluated. Further studies might be warranted to validate these associations.

In the meta-analysis, 15 SNVs showed associations with both primary angle-closure glaucoma and primary angle-closure disease, while ABCA1 rs2422493 and ZNRF3 rs3178915 were associated with primary angle-closure disease only (Tables 1 and 2). Two 2 SNVs, PCMTD1-ST18 rs1015213 and COL11A1 rs3753841, were associated with primary angle-closure suspect from the meta-analysis (eTable 4 in Supplement 1); these were also associated with overall primary angle-closure disease. In contrast, only 1 SNV, MMP9 rs3918249, was associated with primary angle-closure from the meta-analysis (eTable 5 in Supplement 1), and this SNV is not among those associated with primary angle-closure glaucoma, primary angle-closure, or overall primary angle-closure disease (Figure). The limited number of associations with primary angle-closure suspect or primary angle-closure could be because there is no true associations or that the associations lacked precision due to low numbers evaluated among these subtypes. Results of our meta-analysis suggested that different primary angle-closure disease subtypes may have shared and distinct genetic markers. Further genetic studies involving different primary angle-closure disease subtypes are warranted.

The Figure also demonstrates the overlapping genes between primary angle-closure disease and other glaucoma subtypes, including primary open-angle glaucoma and exfoliation glaucoma. LOXL1 is a major gene associated with exfoliation glaucoma, while the ABCA1, ATOH7, CALCRL, IL6, and VAV3 genes have been associated with primary open-angle glaucoma.^{52,53,54,55,56,57} It has long been suggested that the genetic components of primary angle-closure glaucoma and primary open-angle glaucoma are distinct and independent, at least based on GWAS findings.^6,7 In the present study, the identification of overlapping loci suggested that primary angle-closure disease, primary open-angle glaucoma, and exfoliation glaucoma might share some genetic markers or even pathways. Therefore, further functional characterization of selected genes located in these 6 loci may shed new lights on the pathogenesis of different glaucoma subtypes.

In this study, 2 coding variants among the 15 shared SNVs between primary angle-closure glaucoma and primary angle-closure disease were identified: LOXL1 rs3825942 (G153D) and FBN1 rs363830. LOXL1, a major gene for exfoliation syndrome and exfoliation glaucoma,^58,59 encodes a protein affecting zonule morphology in zebrafish without functional defects.⁶⁰ FBN1 rs363830, a multiallelic variant, results in either a missense (Q2296H) or silent (Q2296) amino acid change. The variant associated with primary angle-closure glaucoma in this study is the silent Q2296. Its functional impact on primary angle-closure glaucoma has yet to be determined. The remaining 13 noncoding SNVs might play a regulatory role or be in linkage disequilibrium with the causal variants. Further resequencing analysis of these loci can help to identify the causal variants and provide new insights into their roles in primary angle-closure disease.

In this study, coding variants in COL18A1,¹⁴ SPATA13,²⁰ and PCK2¹⁸ were identified in related affected individuals in primary angle-closure disease pedigrees (eTable 7 in Supplement 1). Moreover, biallelic variants in CPAMD8 were associated with primary angle-closure glaucoma in a Chinese cohort.¹² The roles of these genes in primary angle-closure glaucoma and primary angle-closure disease should be further confirmed in replication and functional studies. Sequencing analysis in unrelated individuals also identified some shared genes between primary angle-closure glaucoma and primary open-angle glaucoma: WDR36, MYOC, and CYP1B1.⁶¹ This finding added new evidence into the shared mechanisms between primary angle-closure glaucoma and primary open-angle glaucoma, echoing the shared common SNVs between them.

Limitations

This study has limitations. First, many genes have been evaluated in a small number of studies in specific populations, hindering subgroup analysis. Second, coding variants identified in single reports required confirmation in replication cohorts. Third, genetic factors influencing primary angle-closure glaucoma progression remained unclear. Fourth, not all studies included in this meta-analysis applied established diagnostic criteria for primary angle-closure disease and its subtypes, therefore misclassification is likely. Fifth, the SNVs reported may not be the causal variants, indicating a need of further fine-mapping and deep sequencing of respective genes or loci.

Conclusions

This study summarized the associations of common SNVs and rare coding variants in more than 30 genes or loci with primary angle-closure disease, while revealing a lack of genetic markers for primary angle-closure disease progression. The shared and distinct variants among different subtypes of primary angle-closure disease, different populations, and different glaucoma subtypes, suggests the genetic complexity of primary angle-closure disease and the possibility of ethnic and phenotypic diversities. This study provided some candidates for future replication, genotype-phenotype correlation, and pathway analyses of glaucoma.

Supplement 1.

eAppendix 1. Search strategy

eAppendix 2. Candidate genetic studies across populations

eTable 1. Quality assessment using Newcastle-Ottawa Quality Assessment

eTable 2. Allelic associations with primary angle-closure glaucoma

eTable 3. Allelic associations with primary angle-closure disease

eTable 4. Allelic associations with primary angle-closure suspect

eTable 5. Allelic associations with primary angle-closure

eTable 6. Allele frequency across populations

eTable 7. Stratification analysis of gene variants with primary angle-closure disease

eTable 8. Common and rare Variants in coding region associated with primary angle-closure disease

eFigure 1. Diagram on data-analysis procedure

eFigure 2. Flow chart for stage one systematic review and meta-analysis on PACD genetic association

eFigure 3. Landscape of PACD genetic studies published in different years

eFigure 4. Overview of genetic studies of PACD included in meta-analysis

eFigure 5. Flow chart for stage two systematic review on genetic association with PACD progression

eFigure 6. Cis-eQTLs associated with CHAT rs1258267 generated by FIVEx

eFigure 7. Cis-eQTLs associated with PLEKHA7 rs11024102 generated by FIVEx

eReferences

jamaophthalmol-e240363-s001.pdf^{(1.5MB, pdf)}

Supplement 2.

Data sharing statement

jamaophthalmol-e240363-s002.pdf^{(13.3KB, pdf)}

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

eAppendix 1. Search strategy

eAppendix 2. Candidate genetic studies across populations

eTable 1. Quality assessment using Newcastle-Ottawa Quality Assessment

eTable 2. Allelic associations with primary angle-closure glaucoma

eTable 3. Allelic associations with primary angle-closure disease

eTable 4. Allelic associations with primary angle-closure suspect

eTable 5. Allelic associations with primary angle-closure

eTable 6. Allele frequency across populations

eTable 7. Stratification analysis of gene variants with primary angle-closure disease

eTable 8. Common and rare Variants in coding region associated with primary angle-closure disease

eFigure 1. Diagram on data-analysis procedure

eFigure 2. Flow chart for stage one systematic review and meta-analysis on PACD genetic association

eFigure 3. Landscape of PACD genetic studies published in different years

eFigure 4. Overview of genetic studies of PACD included in meta-analysis

eFigure 5. Flow chart for stage two systematic review on genetic association with PACD progression

eFigure 6. Cis-eQTLs associated with CHAT rs1258267 generated by FIVEx

eFigure 7. Cis-eQTLs associated with PLEKHA7 rs11024102 generated by FIVEx

eReferences

jamaophthalmol-e240363-s001.pdf^{(1.5MB, pdf)}

Supplement 2.

Data sharing statement

jamaophthalmol-e240363-s002.pdf^{(13.3KB, pdf)}

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PERMALINK

Genetic Associations of Primary Angle-Closure Disease

Yu Jing Liang, BSc

Yu Yao Wang, MMed

Shi Song Rong, PhD

Zhen Ji Chen, PhD

Shu Ying Chen, MMed

Jenson A Tham

Poemen P Chan, MBBS

Jason C Yam, MD

Janey L Wiggs, MD, PhD

Chi Pui Pang, DPhil

Clement C Tham, BM Bch

Li Jia Chen, PhD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Data Sources

Study Selection

Data Extraction and Synthesis

Main Outcomes and Measures

Results

Conclusions and Relevance

Introduction

Methods

Study Inclusion

Eligibility Criteria

Study Selection, Quality Assessment, Data Extraction, and Data Analysis

Results

Identification of Eligible Studies

Association of Primary Angle-Closure Disease

Table 1. Allelic Association With Primary Angle-Closure Glaucoma (PACG).

Table 2. Allelic Association With Primary Angle-Closure Disease (PACD).

Stratification Analysis by Population

Rare Coding Variants in Primary Angle-Closure Disease

Genetic Association of Primary Angle-Closure Glaucoma Progression

Discussion

Figure. Associated Genes Shared Among Primary Angle-Closure Disease Subtypes and Other Glaucoma Subtypes.

Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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