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We investigated axial length (AL) distributions in inherited retinal diseases (IRDs), comparing them with reference cohorts.AL measurements from IRD natural history study participants were included and compared with reference cohorts (TwinsUK, Raine Study Gen2-20, and published studies). Comparing with the Raine Study cohort, formal odds ratios (ORs) for AL ≥ 26 mm or AL ≤ 22 mm were derived for each IRD (Firth's logistic regression model, adjusted for age and sex).Measurements were available for 435 patients (median age, 19.5 years). Of 19 diseases, 10 had10 participants: ABCA4 retinopathy; CNGB3- and CNGA3-associated achromatopsia; RPGR-associated disease; RPE65-associated disease; blue cone monochromacy (BCM); Bornholm eye disease (BED); TYR- and OCA2-associated oculocutaneous albinism; and GPR143-associated ocular albinism. Compared with the TwinsUK cohort (n = 322; median age, 65.1 years) and Raine Study cohort (n = 1335; median age, 19.9 years), AL distributions were wider in the IRD groups. Increased odds for longer ALs were observed for BCM, BED, RPGR, RPE65, OCA2, and TYR; increased odds for short AL were observed for RPE65, TYR, and GPR143. In subanalysis of RPGR-associated disease, longer average ALs occurred in cone-rod dystrophy (n = 5) than rod-cone dystrophy (P = 0.002).Several diseases showed increased odds for longer AL (highest OR with BCM); some showed increased odds for shorter AL (highest OR with GPR143). Patients with RPE65- and TYR-associated disease showed increased odds for longer and for shorter eyes. Albinism genes were associated with different effects on AL. These findings add to the phenotype of IRDs and may yield insights into mechanisms of refractive error development.

PURPOSE: To identify genetic risk factors contributing to central corneal thickness (CCT) in individuals from South India, a population with a high prevalence of ocular disorders. METHODS: One hundred ninety-five individuals from 15 large South Indian pedigrees were genotyped using the Omni2.5 bead array. Family-based association for CCT was conducted using the score test in MERLIN. RESULTS: Genome-wide association study (GWAS) identified strongest association for single nucleotide polymorphisms (SNPs) in the first intron of WNT7B and CCT (top SNP rs9330813; β = −0.57, 95% confidence interval CI: −0.78 to −0.36; P = 1.7 × 10−7). We further investigated rs9330813 in a Latino cohort and four independent European cohorts. A meta-analysis of these data sets demonstrated statistically significant association between rs9330813 and CCT (β = −3.94, 95% CI: −5.23 to −2.66; P = 1.7 × 10−9). WNT7B SNPs located in the same genomic region that includes rs9330813 have previously been associated with CCT in Latinos but with other ocular quantitative traits related to myopia (corneal curvature and axial length) in a Japanese population (rs10453441 and rs200329677). To evaluate the specificity of the observed WNT7B association with CCT in the South Indian families, we completed an ocular phenome-wide association study (PheWAS) for the top WNT7B SNPs using 45 ocular traits measured in these same families including corneal curvature and axial length. The ocular PheWAS results indicate that in the South Indian families WNT7B SNPs are primarily associated with CCT. CONCLUSIONS: The results indicate robust evidence for association between WNT7B SNPs and CCT in South Indian pedigrees, and suggest that WNT7B SNPs can have population-specific effects on ocular quantitative traits.

The investigation of the genetic basis of refractive error and myopia entered a new stage with the introduction of genome-wide association studies (GWAS). Multiple GWAS on many ethnic groups have been published over the years, providing new insight into the genetic architecture and pathophysiology of refractive error. This is a review of the GWAS published to date, the main lessons learned, and future possible directions of genetic studies of myopia and refractive error.

Glaucoma is a major cause of blindness in the world. Recent genome-wide association studies (GWAS) have identified common genetic variants for glaucoma, but still a significant heritability gap remains. We hypothesized that copy number variants (CNVs) might influence part of the susceptibility to glaucoma or its related quantitative endophenotypes.THIS STUDY EXAMINED THE ASSOCIATION BETWEEN CNVS AND INTRAOCULAR PRESSURE (IOP), THE MAJOR MODIFIABLE RISK FACTOR FOR PRIMARY OPEN-ANGLE GLAUCOMA (POAG), IN THREE POPULATION PANELS OF EUROPEAN ANCESTRY: the TwinsUK cohort (n = 1047), the Australian Twin Eye Study (n = 561), and the Wellcome Trust Case-Control Consortium 2 (WTCCC2)/Blue Mountains Eye Study (BMES) (n = 1660). We also used PCR-based assays to investigate a locus of interest that we found associated with IOP in a POAG case-control panel of European ancestry from London, United Kingdom.WE IDENTIFIED ASSOCIATIONS BETWEEN IOP AND TWO CNV REGIONS IN THE TWINSUK COHORT: 5q21.2 (P = 0.003) overlapping the gene RAB9BP1 and 12p13.3 (P = 0.03) overlapping the genes SLC2A14 and SLC2A3. The Australian Twin Eye Study and BMES both replicated the 5q21.2 CNV association and direction of effect (P = 0.001 and P = 0.02, respectively). A meta-analysis across all the cohorts showed that presence of a copy number change at this locus increased IOP by 1.56 mm Hg (P = 1.24 × 10(-6)). In the case-control study, the 5q21.2 CNV locus did not show association with high-pressure (≥21 mm Hg) POAG cases.The 5q21.2 CNV locus could represent a novel locus controlling IOP. Interestingly, this IOP locus is located in close vicinity to the previously widely replicated GLC1G linkage locus for glaucoma, for which subsequent studies have not reached consensus on the causal gene.

PURPOSE Myopia, or nearsightedness, is a common ocular genetic disease for which over 20 candidate genomic loci have been identified. The high-grade myopia locus, MYP3, has been reported on chromosome 12q21-23 by four independent linkage studies. METHODS We performed a genetic association study of the MYP3 locus in a family-based high-grade myopia cohort (n = 82) by genotyping 768 single-nucleotide polymorphisms (SNPs) within the linkage region. Qualitative testing for high-grade myopia (sphere ≤ -5 D affected, > -0.5 D unaffected) and quantitative testing on the average dioptric sphere were performed. RESULTS Several genetic markers were nominally significantly associated with high-grade myopia in qualitative testing, including rs3803036, a missense mutation in PTPRR (P = 9.1 × 10(-4)) and rs4764971, an intronic SNP in UHRF1BP1L (P = 6.1 × 10(-4)). Quantitative testing determined statistically significant SNPs rs4764971, also found by qualitative testing (P = 3.1 × 10(-6)); rs7134216, in the 3' untranslated region (UTR) of DEPDC4 (P = 5.4 × 10(-7)); and rs17306116, an intronic SNP within PPFIA2 (P < 9 × 10(-4)). Independently conducted whole genome expression array analyses identified protein tyrosine phosphatase genes PTPRR and PPFIA2, which are in the same gene family, as differentially expressed in normal rapidly growing fetal relative to normal adult ocular tissue (confirmed by RT-qPCR). CONCLUSIONS In an independent high-grade myopia cohort, an intronic SNP in UHRF1BP1L, rs4764971, was validated for quantitative association, and SNPs within PTPRR (quantitative) and PPFIA2 (qualitative and quantitative) approached significance. Three genes identified by our association study and supported by ocular expression and/or replication, UHRF1BP1L, PTPRR, and PPFIA2, are novel candidates for myopic development within the MYP3 locus that should be further studied.

Purpose To identify heritable genetic factors altering susceptibility to refractive error in the general population. Methods This was a genetic association study of refractive error investigating genetic polymorphisms in regions previously reported through linkage. Two study panels were drawn from the British 1958 Birth Cohort, composed of 2211 persons 44 years of age at the time of visit. Two main outcomes were considered: refractive error as a continuous outcome (spherical equivalent) and myopia as a diagnosis (defined as spherical equivalent equal to or worse than-1.00 diopter). Genotyping was initially performed in 1188 subjects from the outer tertiles of the population distribution, using customized arrays of single nucleotide polymorphisms (SNPs) saturating regions of previously reported highly significant linkage. In a second stage, SNPs most significantly associated were validated in 1023 more persons. Findings were investigated further through human fetal expression studies. Results Polymorphisms within the SERPINI2 gene were associated with refractive error in two different European subgroups from the 1958 British Birth Cohort (meta-analysis P = 7.4E-05 for rs9810473). Association was also significant for myopia (best association: OR = 0.80; 95% CI, 0.69-0.93; P = 0.003 for rs10936538). Expression profiling of SERPINI2 revealed that the gene is expressed in the retina and in other eye and CNS tissues. Conclusions The novel association of SERPINI2 with refractive error and myopia is suggestive of a possible link between physiological pathways controlling eye growth and development and those controlling glucose metabolism. The findings indicate that SERPINI2 is a promising candidate for further investigations of the genetic susceptibility to myopia.