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Purpose: To evaluate the associations of single-nucleotide polymorphisms (SNPs) in the high-temperature requirement protease A 1 ( HTRA1) gene with myopia., Methods: 25 SNPs in HTRA1 were selected, including 23 haplotype-tagging SNPs, SNP rs2142308 from a previous genome-wide association study (GWAS) of myopia and rs11200638, a SNP strongly associated with age-related macular degeneration (AMD). All SNPs were genotyped in a Hong Kong Chinese cohort of 533 myopia subjects (including 175 high myopia, 189 moderate myopia and 189 mild myopia) and 280 non-myopic controls. The association of individual SNPs were evaluated in overall myopia and different subgroups of myopia using logistic regression., Results: A tagging SNP, rs11200647, was significantly associated with myopia (p=2.17×10 -4 , OR=0.67). Nominal associations were detected for the AMD-associated SNP rs11200638 (p=0.0042, OR=1.37) and tagging SNPs rs12266322 (p=0.0048, OR=0.59) and rs17103569 (p=0.047, OR=1.34). The association of rs11200647 with myopia remained significant after adjusting for rs11200638, rs12266322 and rs17103569. In sub-group analysis, two tagging SNPs, rs11200647 (p=2.24×10 -4 , OR=0.58) and rs12266322 (p=8.31×10 -4 , OR=0.39), showed significant association with moderate myopia. In haplotype association analysis, haplotypes AT (p=1.00×10 -4 , OR=1.77) and haplotype GT (p=0.0019, OR=0.64), defined by rs11200647 and rs66884382, were significantly associated with myopia., Conclusions: This study provided new evidence to support HTRA1 as an associated gene for myopia, especially moderate myopia. The findings suggested that myopia and AMD may have shared genetic components., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: To investigate the associations of genetic variants previously linked to axial length (AL) and spherical equivalent refraction (SE) in adults with refractive error and related endophenotypes in children, at baseline and 3-year follow-up., Methods: 15 candidate single-nucleotide polymorphisms (SNPs), selected from previous Genome-Wide Association Studies and meta-analyses, were genotyped in 2819 Chinese children, who had undergone baseline and 3-year follow-up cycloplegic refraction, ocular biometry and ocular health examinations. Linear regression analyses were conducted to assess the associations of the SNPs with baseline measurements and longitudinal changes in SE, spherical power (SPH), AL, corneal radius of curvature (CR) and AL/CR ratio., Results: SNPs ZMAT4 rs7829127, ZMAT4 rs16890057, TOX rs7837791, GRIA4 rs11601239 and RDH5 rs3138142 were associated with SE (β=0.233, p=4.21×10 -4 ; β=0.221, p=7.87×10 -4 ; β=0.106, p=0.0076; β=0.084, p=0.041; β=0.14, p=0.013, respectively) and SPH (β=0.24, p=2.3×10 -4 ; β=0.232, p=3.8×10 -4 ; β=0.088, p=0.025; β=0.086, p=0.034; β=0.14, p=0.012, respectively). Among them, ZMAT4 rs7829127 and rs16890057, were also associated with AL (β=-0.128, p=5.6×10 -4 ; β=-0.128, p=5.21×10 -4 ) and AL/CR ratio (β=-0.014, p=0.0028; β=-0.014, p=0.0034), whereas TOX rs7837791 was associated with AL (β=-0.062, p=0.0058) and GRIA4 11 601 239 with AL/CR ratio (β=-0.0058, p=0.049). Additionally, CD55 rs1652333 and RDH5 rs3138142 were associated with 3-year longitudinal changes in AL (β=0.062, p=0.018; β=-0.079, p=0.029) and CR (β=0.014, p=0.027; β=-0.018, p=0.035)., Conclusion: Among SNPs previously associated with AL and SE in adults, variants in ZMAT4 , TOX and GRIA4 were associated with AL, SE, SPH, and/or AL/CR ratio, while variants in RDH5 and CD55 showed associations with AL and CR changes in children., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To evaluate the genetic associations of different subtypes of central serous chorioretinopathy (CSCR), neovascular age-related macular degeneration (nAMD), and polypoidal choroidal vasculopathy (PCV)., Design: A case-control genetic association study., Methods: This study enrolled 217 CSCR, 341 nAMD, 288 PCV patients, and 1380 controls. The CSCR patients were classified into those with focal or diffuse leakage, with or without pigment epithelial detachment (PED), and with or without macular neovascularization (MNV). Associations between 11 variants from 8 genes, ADAMTS9, ANGPT2, ARMS2, CFH, NR3C2, PGF, TNFRSF10A and VIPR2, and diseases/subtypes were analyzed by logistic regression analysis adjusted for age and sex, and inter-phenotype comparison by heterogeneity test., Results: The CFH rs800292-A conferred a protective effect for CSCR with MNV (OR=0.44, P = 0.002) and a risk effect for CSCR without MNV (OR=1.31, P = 0.023). CSCR patients carrying rs800292-G had a 3.23-fold of increased risk towards developing secondary MNV (P = 1.45 ×10 -4 ). CFH rs3753394, rs800292 and rs1329428 showed similar effects among CSCR with MNV, nAMD and PCV, but opposite effects on CSCR without MNV. TNFRSF10A rs13278062-T was associated with overall CSCR but not with CSCR subtypes, nAMD or PCV. Moreover, CFH and ARMS2 SNPs showed heterogeneous effects in CSCR without MNV against CSCR with MNV, nAMD and PCV., Conclusions: Genetic associations of CSCR with MNV resembled nAMD and PCV compared to CSCR without MNV, indicating differential genetic effects on neovascularization and choroidopathy. Further investigation of the functional roles of CFH, ARMS2, and TNFRSF10A in CSCR, nAMD and PCV should help elucidate the mechanisms of these maculopathies., Competing Interests: Declaration of Competing Interest No conflicting relationship exists for any author., (Copyright © 2023. Published by Elsevier Inc.)

Purpose: To identify gene variants associated with anisometropia development in children., Methods: This is a population-based, cross-sectional, and longitudinal genetic association study involving 1057 children aged 6 to 10 years with both baseline and 3-year follow-up data. Six single nucleotide polymorphisms (SNPs), ZC3H11B rs4373767, ZFHX1B rs13382811, KCNQ5 rs7744813, SNTB1 rs7839488, PAX6 rs644242, and GJD2 rs524952 were analyzed in all children. Anisometropia was defined by an interocular difference in SE of ≥1 diopter (D) (Aniso-SE) and an interocular difference in axial length (AL) of ≥0.3 mm (Aniso-AL), respectively. Genetic associations of individual SNPs and joint SNP effects were analyzed., Results: ZFHX1B rs13382811 was associated nominally with Aniso-AL (odds ratio [OR], 1.66; P = 0.003) at baseline. At 3 years, rs13382811 was significantly associated with Aniso-AL (OR, 1.49; P = 0.001) and became nominally associated with Aniso-SE (OR, 1.40; P = 0.01). In addition, PAX6 rs644242 was significantly associated with Aniso-AL at 3 years (OR, 1.45; P = 0.002). At the 3-year follow-up, PAX6 rs644242 was associated significantly with Aniso-AL development (OR, 1.61; P = 0.0003) and nominally with Aniso-SE development (P = 0.03) in children who were not anisometropic at baseline, whereas ZFHX1B rs13382811 was associated nominally with Aniso-AL development (P = 0.02). An additive SNP analysis indicated children carrying the risk allele T of ZFHX1B rs13382811 and allele A of PAX6 rs644242 might have a 4.33- and 6.90-fold of increased risk of Aniso-SE and Aniso-AL development by 3 years, respectively., Conclusions: This study identified two susceptible gene variants, ZFHX1B rs13382811 and PAX6 rs644242, for anisometropia development in Hong Kong Chinese children, implicating their role in imbalanced refractive change and axial elongation between both eyes.

Purpose: Central serous chorioretinopathy (CSCR) is a leading cause of central vision impairment in the working-age population with male predilection. Knowledge about the genetic basis of CSCR and its male predilection remained limited. This study aimed to evaluate the association patterns of multiple gene variants in chronic CSCR (cCSCR) in Chinese patients., Methods: This case-control genetic association study included 531 patients with cCSCR and 2383 controls from two independent Chinese cohorts. Nine single-nucleotide polymorphisms (SNPs) of six genes, namely CFH, NR3C2, GATA5, VIPR2, TNFRSF10A, and ARMS2, were genotyped in all subjects. The main outcome measures were the association of individual single-nucleotide polymorphism (SNP) with cCSCR, the sex-stratification effects of individual SNP, and joint effects of different SNPs on cCSCR., Results: Association results in the two cohorts were consistent with low heterogeneities. In the combined analysis, SNPs CFH rs800292 (odds ratio [OR] = 1.25, P = 0.0020), CFH rs1329428 (OR = 1.23, P = 0.0037), and TNFRSF10A rs13278062 (OR = 1.43, P = 0.0014) were significantly associated with cCSCR. In stratification analysis by sex, 3 SNPs in CFH, rs3753394, rs800292, and rs1329428, were associated with cCSCR in male patients, but not in female patients. Joint analysis revealed that subjects homozygous for the risk alleles of CFH rs800292 and TNFRSF10A rs13278062 had over 4-fold of increased risk of cCSCR when compared with subjects homozygous for the non-risk alleles (OR = 4.06, P = 2.30 × 10-5)., Conclusions: This study revealed main and joint effects of SNPs in CFH and TNFRSF10A on cCSCR, and suggested CFH as a potential genetic factor underlying the male predilection of cCSCR. Further replication in other study populations is needed.

Background: To determine the association of the ANGPT2 gene with primary open-angle glaucoma (POAG) in Chinese., Methods: Six single-nucleotide polymorphisms (SNPs) in ANGPT2 (rs2515487, rs2922869, rs13255574, rs4455855, rs13269021, and rs11775442) were genotyped in a total of 2601 study subjects from two cohorts. One is a Hong Kong Chinese cohort of 484 high tension glaucoma (HTG) and 537 normal tension glaucoma (NTG) patients, and 496 non-glaucoma control subjects. Another cohort is a Shantou Chinese cohort of 403 HTG and 135 NTG patients, and 543 non-glaucoma control subjects. Subgroup analysis by sex was conducted. Outcomes from different cohorts were combined for meta-analysis., Results: The association of SNP rs11775442 with NTG in the Hong Kong cohort [P = 0.0498, OR = 1.24, 95% confidence interval (CI) 1.00-1.55] after adjusting for age and sex did not reach statistical significance after Bonferroni correction. Other SNPs were not significantly associated with NTG, HTG and POAG in individual cohort or in the combined analyses (P > 0.05). In the subgroup analysis by sex, SNP rs13269021 in the Shantou cohort, but not in the Hong Kong cohort, was significantly associated with NTG in males (P = 0.0081, OR = 1.67, 95% CI: 1.14-2.43) but not in females (P = 0.874). In the combined analyses by sex, no SNPs were significantly associated with NTG, HTG and POAG., Conclusions: In the subgroup analysis by sex, a significant association was shown in SNP rs13269021 with NTG in Shantou males, but not in Hong Kong males. Further studies are needed to verify the association between ANGPT2 locus (rs13269021) and NTG in Chinese males., (© 2022. The Author(s).)

Objective: To investigate the associations of single-nucleotide polymorphisms (SNPs) in the ZC3H11B, ZFHX1B, VIPR2 , SNTB1 and MIPEP genes with severities of myopia in Chinese populations., Methods: Based on previous myopia genome-wide association studies, five SNPs ( ZC3H11B rs4373767, ZFHX1B rs13382811, VIPR2 rs2730260, SNTB1 rs7839488 and MIPEP rs9318086) were selected for genotyping in a Chinese cohort of 2079 subjects: 252 extreme myopia, 277 high myopia, 393 moderate myopia, 366 mild myopia and 791 non-myopic controls. Genotyping was performed by TaqMan assays. Allelic frequencies of the SNPs were compared with myopia severities and ophthalmic biometric measurements., Results: The risk allele T of ZC3H11B SNP rs4373767 was significantly associated with high myopia (OR=1.39, p=0.007) and extreme myopia (OR=1.34, p=0.013) when compared with controls, whereas ZFHX1B rs13382811 (allele T, OR=1.33, p=0.018) and SNTB1 rs7839488 (allele G, OR=1.71, p=8.44E-05) were significantly associated with extreme myopia only. In contrast, there was no significant association of these SNPs with moderate or mild myopia. When compared with mild myopia, subjects carrying T allele of rs4373767 had a risk of progressing to high myopia (spherical equivalent ≤-6 dioptres) (OR=1.29, p=0.017). Similarly, the T allele of rs13382811 also imposed a significant risk to high myopia (OR=1.36, p=0.007). In quantitative traits analysis, SNPs rs4373767, rs13382811 and rs7839488 were correlated with axial length and refractive errors., Conclusions: We confirmed ZC3H11B as a susceptibility gene for high and extreme myopia, and ZFHX1B and SNTB for extreme myopia in Chinese populations. Instead of myopia onset, these three genes were more likely to impose risks of progressing to high and extreme myopia., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To evaluate the association between single-nucleotide polymorphisms (SNPs) in the ZC3H11B, RSPO1, C3orf26, GJD2, ZNRF3, and WNT7B genes and myopia endophenotypes in children., Methods: Seven SNPs identified in previous genome-wide association studies of axial length (AL) were genotyped in 2883 Southern Han Chinese children. Multiple linear regression analyses were conducted to evaluate the genotype association with AL, spherical equivalent (SE), corneal curvature (CC), and central corneal thickness (CCT)., Results: Two SNPs-namely, rs12144790 in RSPO1 (allele T, P = 0.0066, β = 0.062) and rs10453441 in WNT7B (allele A, P = 8.03 × 10-6, β = 0.103)-were significantly associated with AL. The association of rs4373767 in ZC3H11B (allele C, P = 0.030, β = -0.053) could not withstand the correction for multiple testing. WNT7B rs10453441 showed a strong association with CC (P = 1.17 × 10-14, β = 0.053) and with CCT (P = 0.0026, β = 2.65). None of the tested SNPs was significantly associated with SE. The C allele of SNP rs12321 in ZNRF3 was associated with CC (P = 0.0060, β = -0.018)., Conclusions: This study revealed that the RSPO1 SNP rs12144790 was associated with AL, whereas WNT7B rs10453441 was associated with AL, CC, and CCT in children. A novel association between ZNRF3 rs12321 and CC was discovered. Our data suggest that the RSPO1 and WNT7B genes might exert their effects on multiple aspects of eye growth during childhood. Potential differences in the genetic profiles of AL between children and adults should be explored in larger cohorts.

Background: The CAV1-CAV2 locus has been associated with primary open-angle glaucoma (POAG) and intraocular pressure. However, its association with normal-tension glaucoma (NTG) was inconclusive. Therefore, we evaluated this association in Chinese and Japanese., Methods: Two single-nucleotide polymorphisms (SNPs, rs4236601 and rs1052990) from previous genome-wide association studies of POAG were genotyped in a total of 2220 study subjects: a Hong Kong Chinese cohort of 537 NTG patients and 490 controls, a Shantou Chinese cohort of 102 NTG and 731 controls and an Osaka Japanese cohort of 153 NTG and 207 controls. Subgroup analysis by gender was conducted. Outcomes from different cohorts were combined using meta-analysis., Results: SNP rs4236601 was significantly associated with NTG in the two Chinese cohorts (P meta = .0019, OR = 4.55, I 2 = 0). In contrast, rs4236601 was monomorphic in the Osaka cohort. The association of rs1052990 was insignificant in a meta-analysis combining Chinese and Japanese cohorts (P meta = .81, OR = 1.05; I 2 = 64%), and the OR tended towards opposite directions between Chinese (OR = 1.26) and Japanese (OR = 0.69). Gender-specific effects of the SNPs were not statistically significant in the logistic regression or Breslow-day tests of ORs (P > .05), although rs4236601 was significant in males (P = .0068; OR = 10.30) but not in females (P = .14; OR = 2.65) in the meta-analysis of Chinese subjects., Conclusions: In this study, we confirmed the association of rs4236601 at the CAV1-CAV2 locus with NTG in Chinese. SNP rs4236601 is monomorphic, and rs1052990 tends towards a different direction in the Japanese cohort. Further studies are warranted to verify the ethnic difference and gender-specific effects of this locus., (© 2020 Royal Australian and New Zealand College of Ophthalmologists.)

Background: Sclerocornea is a rare congenital disorder characterized with the opacification of the cornea. Here, we report a nonconsanguineous Chinese family with multiple peripheral sclerocornea patients spanning across three generations inherited in an autosomal dominant manner., Methods: This is a retrospective case series of a peripheral sclerocornea pedigree. Comprehensive ophthalmic examinations were conducted and assessed on 14 pedigree members. Whole-exome sequencing was used to identify the genetic alterations in the affected pedigree members. Lymphoblastoid cell lines (LCLs) were established using blood samples from the family members. Functional tests were performed with these cell lines., Results: Six affected and eight unaffected members of a family with peripheral sclerocornea were examined. All affected individuals showed features of scleralization over the peripheral cornea of both eyes. Mean horizontal and vertical corneal diameter were found significantly decreased in the affected members. Significant differences were also observed on the mean apex pachymetry between affected and unaffected subjects. These ophthalmic parameters did not resemble that of cornea plana. A RAD21 C1348T variant was identified by whole-exome sequencing. Although this variant causes RAD21 R450C substitution at the separase cleavage site, cells from peripheral sclerocornea family members had no mitosis and ploidy defects., Conclusion: We report a family of peripheral sclerocornea with no association with cornea plana. A RAD21 variant was found cosegregating with peripheral sclerocornea. Our results suggest that RAD21 functions, other than its cell cycle and chromosome segregation regulations, could underline the pathogenesis of peripheral sclerocornea., Competing Interests: All authors declare no conflict of interest., (Copyright © 2019 Bi Ning Zhang et al.)

Background: Neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) are sight-threatening maculopathies with both environmental and genetic risk factors. We have previously shown relative risks posed by genes of the complement pathways to neovascular AMD and PCV., Methods: In this study, we investigated the haplotype-tagging single nucleotide polymorphisms (SNPs) in the complement component 5 ( C5 ) gene in 708 unrelated Chinese individuals: 200 neovascular AMD patients, 233 PCV patients and 275 controls. Six tagging SNPs in C5 were genotyped. Univariate single SNP association analysis, haplotype-based association analysis and gene-gene interaction analysis between C5 and other AMD-associated genes were performed., Results: The results revealed none of the six tagging SNPs of the C5 gene had a significant association with neovascular AMD or PCV ( P  > 0.05). We also found insignificant haplotype-based association, and no significant SNP-SNP interaction between C5 and other genes (including C2 - CFB - RDBP - SKIV2L , SERPING1 , CETP , ABCG1 , PGF , ANGPT2 , CFH and HTRA1 ) for neovascular AMD and PCV., Conclusions: This study showed no statistical significance in the genetic association of C5 with neovascular AMD or PCV in a Hong Kong Chinese population. Further studies in large samples from different populations are warranted to elucidate the role of C5 in the genetic susceptibility of AMD and PCV., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s). 2019.)

Purpose: Intronic variants in the placental growth factor (PGF) gene have been associated with neovascular age-related macular degeneration (AMD). This study is to discover and characterize rare variants in the PGF gene for neovascular AMD., Methods: The promoter region, coding sequences and splicing regions of the PGF gene were sequenced in a Hong Kong southern Chinese cohort of 235 neovascular AMD patients and 435 controls. A detected 18 base-pair deletion variant in the promoter region of PGF was analyzed in a Shantou southern Chinese cohort of 189 neovascular AMD patients and 846 controls. The transcription activity of this disease-associated promoter variant was determined in human ARPE-19 cells by promoter-luciferase analysis., Results: A novel 18-base-pair deletion mutation in the promoter region of PGF was identified in 3 (1.28%) patients and 1 (0.23%) control subject (OR = 5.61; 95% CI 0.58-54.26) in the Hong Kong cohort, and in 2 (1.06%) patients and 2 (0.24%) controls (OR = 4.51; 95% CI: 0.63-32.25) in the Shantou cohort. In the combined southern Chinese sample, this deletion had a significant association with neovascular AMD (P = 0.026; OR = 5.08, 95% CI: 1.21-21.36). The 18-base-pair deletion was predicted to alter the transcription factor binding sites in the PGF promoter, and higher luciferase expression was detected in ARPE-19 cells transfected with the deletion variant plasmid than those transfected with wild type plasmid (P = 0.0002)., Conclusions: This study identified a rare, functional promoter variant in the PGF gene that increases PGF transcription activity and confers a 5-fold risk to neovascular AMD., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: To study the roles of sequence alterations in the optineurin ( OPTN ) gene-coding region in normal-tension glaucoma (NTG) among Chinese patients., Methods: Genomic DNA was extracted from 190 NTG patients and 201 control subjects. The thirteen exons of OPTN were amplified by polymerase chain reaction and analyzed by direct sequencing. Detected sequence changes were compared between NTG patients and control subjects., Results: Seven sequence changes in OPTN were identified in both NTG patients and control subjects. Among them, c.464G>A (T34 T), c.509C>T (T49T), c.806G>A (V148V), and c.959T>C (P199P) were synonymous codon changes, whilst c.655T>A (M98K), c.1996G>A (R545Q), and c.1582T>C (I407T) were missense changes. Two previously reported heterozygous mutations, c.458G>A (E50K) in exon 4 and c.691_692insAG in exon 6, were not found in this study. Out of these seven OPTN sequence variants, c.464G>A (T34T) was significantly associated with NTG in both the allelic and genotypic association analyses (allelic association: p = 0.0001, OR = 2.20, 95% CI: 1.46-3.31; genotypic association: p = 0.0001), whereas the association of other variants with NTG did not reach statistical significance ( p > 0.05). Variants c.1582 T>C (I407T) and c.806G>A (V148V) were identified in one and two NTG patients, respectively, but not in the control subjects., Conclusions: This study confirmed the association of the OPTN T34T variant with NTG, suggesting that OPTN is a susceptibility gene for NTG in Chinese. Moreover, a variant with amino acid change (I407T) was identified in NTG but not in controls. Further studies are warranted to assess whether this variant is a causative mutation for NTG.

The purpose of the study was to evaluate the association profiles of the SIX6 locus with primary open-angle glaucoma (POAG) in southern Chinese and Japanese. In this study, we tested single marker and haplotype-based associations of 11 tagging single nucleotide polymorphisms (SNPs) covering the SIX6 locus with POAG in a Hong Kong Chinese cohort (N = 1402). A novel SNP (i.e., rs12436579) and two SNPs (i.e., rs33912345 and rs10483727) from previous genome-wide association studies were further tested in a Chinese cohort from Shantou (N = 888) and a Japanese cohort from Osaka (N = 463). Results from the three cohorts were meta-analysed using a random-effect model. We found rs12436579, which has not been previously reported, was associated with POAG in Hong Kong and Shantou Chinese (P combined  = 4.3 × 10 -5 , OR = 0.72, I 2  = 0). Additionally, we replicated the association of one known SNP, rs33912345 (P combined  = 0.0061, OR = 0.69, I 2  = 45%), with POAG in the Chinese cohorts but not in the Japanese cohort (P > 0.6). Another known SNP, rs10483727, was nominally associated with POAG in the two Chinese cohorts (P combined  = 0.017, OR = 0.70, I 2  = 53%). All these three SNPs were significantly associated with POAG when the three cohorts were combined in meta-analysis (P combined <0.005). Furthermore, two haplotypes, C-C (P combined  = 1.13 × 10 -5 , OR = 1.41, I 2  = 0) and A-A (P combined  = 0.045, OR = 0.68, I 2  = 70%), defined by rs33912345-rs12436579 were associated with POAG in Chinese but not in Japanese. In conclusion, this study confirmed the association between two GWAS SNPs in SIX6 (rs33912345 and rs10483727) and POAG. Also, a SNP, rs12436579, not associated with POAG before, was found to be associated with POAG in Chinese. Further studies are warranted to elucidate the role of this novel SNP in POAG., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Intraocular pressure (IOP) is a major risk factor for glaucoma. Genetic determinants of intraocular pressure can provide critical insights into the genetic architecture of glaucoma and, as a result, open new avenues for therapeutic intervention. We performed a genome-wide association study and replication analysis of 8,552 Chinese participants. In the genome-wide association study, we identified 51 loci that surpassed the significance of P<9×10 -7 , and we formally replicated these loci. A combined discovery and replication meta-analysis identified 21 genome-wide loci that surpassed the genome-wide significance of P<5×10 -8 , including 4 previously reported loci: rs145063132 (7p21.2, ETV1/DGKB), rs548030386 (7q31.2, ST7 near CAV1/CAV2), rs7047871 (9p24.2, GLIS3), and rs2472494 (9q31.1, ABCA1/SLC44A1). Of the 17 newly identified loci, five were reported to have ocular related phenotypes: PTCH2 (rs7525308 in 1p34.1), LRIF1/DRAM2 (rs1282146 in 1p13.3), COLEC11 (rs201143466 in 2p25.3), SPTBN1 (rs4514918 in 2p16.2), and CRK (rs11078446 in 17p13.3). The genetic loci identified in this study not only increase our understanding of the genes involved in intraocular pressure but also provide important genetic markers to improve future genetic screening and drug discovery for intraocular pressure disorders.

Objective: To investigate the associations between 16 single-nucleotide polymorphisms (SNPs) in 14 genetic loci and keratoconus in an independent Chinese cohort., Methods: This cross-sectional, case-control association study included a Chinese cohort of 133 patients with keratoconus and 371 control subjects. In a recent meta-analysis study, we identified association of 16 SNPs in 14 gene loci with keratoconus. In this study, we genotyped these 16 SNPs in all the patients and controls and analysed their association with keratoconus, its clinical severities and progression profiles. We also analysed the genotype-phenotype correlation between individual SNPs and steep keratometry, flat keratometry (Kf), average keratometry (Avg K) and best-fit sphere diameter (BFS) of the anterior and posterior corneal surface., Results: Among the 16 selected SNPs, rs1324183 in the MPDZ-NF1B locus showed a significant association with keratoconus (OR=2.22; 95% CI 1.42 to 3.45, p=4.30×10 -4 ), especially severe keratoconus (OR=5.10, 95% CI 1.63 to 15.93, p=0.005). The rs1324183 A allele was positively associated with anterior Kf (p=0.008), anterior Avg K (p=0.017), posterior Kf (p=0.01) and negatively associated with apex pachymetry (p=0.007) and anterior BFS (p=0.023) in keratoconus. The other 15 SNPs had no significant association with keratoconus or genotype-phenotype correlations., Conclusions: This study confirmed the association of SNP rs1324183 in MPDZ-NF1B with keratoconus and revealed the association of this SNP with keratoconus severity and corneal parameters. It is thus a putative genetic marker for monitoring the progression of keratoconus to a severe form and facilitating early intervention., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

Age-related macular degeneration (AMD) is the leading cause worldwide of severe visual impairment among people older than 55 years of age. This study aimed to investigate the genetic association between coding and untranslated region (UTR) variants in previously reported loci and exudative age-related macular degeneration (wet AMD) in a Han Chinese population. Using our previously published whole exome sequencing dataset of 349 wet AMD patients and 1253 controls, we searched for associations between coding and UTR variants of the 72 genes located within the 47 reported wet AMD loci regions. From these, 25 variants in 18 of the 72 genes with P < 10 × 10 -3 were selected for the first replication of Sequenom mass-array genotyping in 885 wet AMD subjects and 562 controls. Next, four SNPs were selected for further validation by SNaPshot genotyping in a third Chinese cohort with 456 wet AMD subjects and 211 controls. As a result, we identified two new potential coding and UTR variant SNPs (rs189132250 in BBX located in 3q12.1 and rs144351944 in FILIP1L located in 3q12.1) that showed weak associations with wet AMD in the Han Chinese population. These findings provide new information regarding the coding and UTR variants of the known wet AMD loci in the studied Chinese cohort.

Aims: To investigate the association of the paired box gene 6 ( PAX6 ) with different severities of myopia., Methods: A total of four haplotype-tagging single-nucleotide polymorphisms (SNPs; rs2071754, rs3026354, rs3026390 and rs628224) and two previously reported SNPs (rs644242 and rs662702) in the PAX6 gene were analysed in a Hong Kong Chinese cohort of 1288 myopia subjects (including 252 extreme myopia, 277 high myopia, 393 moderate myopia and 366 mild myopia) and 791 no myopia controls. Allelic association analyses were performed for individual SNPs in different subgroups of myopia and in combined myopia, followed by a meta-analysis of our current data with reported data on PAX6 in myopia., Results: The association of tagging SNPs rs2071754 and rs644242 with extreme myopia could not withstand multiple correction (rs2071754: OR=1.25, P value=0.031; rs644242: OR=1.33, P value=0.032). In the meta-analysis, rs644242 showed an enhanced, significant association with extreme myopia (OR=1.27, 95% CI 1.10 to 1.46, P value=0.001; I 2 =0%). In contrast, there was no significant association between the PAX6 SNPs and high, moderate or mild myopia. No linear correlation was found between the PAX6 SNPs and axial length., Conclusion: This study provides additional evidence suggesting that the PAX6 SNP rs644242 is associated with extreme myopia but not lower grade myopia. Thus, PAX6 may be implicated in the development or progression into severe myopia. Further longitudinal studies are warranted., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Purpose: This study evaluates the associations of haplotype-tagging single nucleotide polymorphisms (SNPs) in the PARL-ABCC5-HTR3D-HTR3C region with primary angle closure glaucoma (PACG), with a view to identify the responsible SNP in this region., Methods: Thirty SNPs from the PARL-ABCC5-HTR3D-HTR3C region were genotyped in a Hong Kong Chinese cohort of 422 PACG patients and 400 control subjects, using TaqMan SNP genotyping assays. Single marker and haplotype-based association analyses were performed., Results: Two synonymous ABCC5 SNPs, namely rs939336 (p.Cys594=; P = 0.013; odds ratio [OR] = 1.46; 95% confidence interval [CI], 1.08 to 1.97) and rs1132776 (p.Ala395=; P = 0.009; OR = 1.47; 95% CI: 1.10 to 1.95), were associated with PACG. Mild associations were detected for ABCC5 rs9838667 (P = 0.024) and HTR3D rs12493550 (P = 0.035). Conditional analysis revealed that no SNPs remained significant after adjusting for other SNPs, suggesting none of these tagging SNPs is fully responsible for the association in this region. In subgroup analysis, ABCC5 SNPs rs939336, rs1132776, and rs983667 and HTR3D rs12493550 were associated only with the chronic form of PACG. However, these associations could not withstand the correction for multiple testing., Conclusions: These findings enrich the allelic spectrum of ABCC5 in PACG. We identified no tagging SNP responsible for the association of the whole region. Further deep sequencing analysis of this region should be warranted to uncover whether there is still disease associated variant in this region.

High myopia, which is extremely prevalent in the Chinese population, is one of the leading causes of blindness in the world. Genetic factors play a critical role in the development of the condition. To identify the genetic variants associated with high myopia in the Han Chinese, we conducted a genome-wide association study (GWAS) of 493,947 SNPs in 1088 individuals (419 cases and 669 controls) from a Han Chinese cohort and followed up on signals that were associated with p < 1.0 × 10(-4) in three independent cohorts (combined, 2803 cases and 5642 controls). We identified a significant association between high myopia and a variant at 13q12.12 (rs9318086, combined p = 1.91 × 10(-16), heterozygous odds ratio = 1.32, and homozygous odds ratio = 1.64). Furthermore, five additional SNPs (rs9510902, rs3794338, rs1886970, rs7325450, and rs7331047) in the same linkage disequilibrium (LD) block with rs9318086 also proved to be significantly associated with high myopia in the Han Chinese population; p values ranged from 5.46 × 10(-11) to 6.16 × 10(-16). This associated locus contains three genes-MIPEP, C1QTNF9B-AS1, and C1QTNF9B. MIPEP and C1QTNF9B were found to be expressed in the retina and retinal pigment epithelium (RPE) and are more likely than C1QTNF9B-AS1 to be associated with high myopia given the evidence of retinal signaling that controls eye growth. Our results suggest that the variants at 13q12.12 are associated with high myopia., (Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)