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Myopia (near-sightedness) is an important public health issue. Spending more time outdoors can prevent myopia but the long-term association between this exposure and myopia has not been well characterised. We investigated the relationship between time spent outdoors in childhood, adolescence and young adulthood and risk of myopia in young adulthood. The Kidskin Young Adult Myopia Study (KYAMS) was a follow-up of the Kidskin Study, a sun exposure-intervention study of 1776 children aged 6–12 years. Myopia status was assessed in 303 (17.6%) KYAMS participants (aged 25–30 years) and several subjective and objective measures of time spent outdoors were collected in childhood (8–12 years) and adulthood. Index measures of total, childhood and recent time spent outdoors were developed using confirmatory factor analysis. Logistic regression was used to assess the association between a 0.1-unit change in the time outdoor indices and risk of myopia after adjusting for sex, education, outdoor occupation, parental myopia, parental education, ancestry and Kidskin Study intervention group. Spending more time outdoors during childhood was associated with reduced risk of myopia in young adulthood (multivariable odds ratio [OR] 0.82, 95% confidence interval [CI] 0.69, 0.98). Spending more time outdoors in later adolescence and young adulthood was associated with reduced risk of late-onset myopia (≥ 15 years of age, multivariable OR 0.79, 95% CI 0.64, 0.98). Spending more time outdoors in both childhood and adolescence was associated with less myopia in young adulthood.

Using latent variables in gene expression data can help correct unobserved confounders and increase statistical power for expression quantitative trait Loci (eQTL) detection. The probabilistic estimation of expression residuals (PEER) and principal component analysis (PCA) are widely used methods that can remove unwanted variation and improve eQTL discovery power in bulk RNA-seq analysis. However, their performance has not been evaluated extensively in single-cell eQTL analysis, especially for different cell types. Potential challenges arise due to the structure of single-cell RNA-seq data, including sparsity, skewness, and mean-variance relationship. Here, we show by a series of analyses that PEER and PCA require additional quality control and data transformation steps on the pseudo-bulk matrix to obtain valid latent variables; otherwise, it can result in highly correlated factors (Pearson's correlation r = 0.63 ~ 0.99). Incorporating valid PFs/PCs in the eQTL association model would identify 1.7 ~ 13.3% more eGenes. Sensitivity analysis showed that the pattern of change between the number of eGenes detected and fitted PFs/PCs varied significantly in different cell types. In addition, using highly variable genes to generate latent variables could achieve similar eGenes discovery power as using all genes but save considerable computational resources (~ 6.2-fold faster).

Inflammation and cigarette smoking predispose to macular diseases, and choroidal and retinal thinning. We explored the choroidal and retinal thicknesses in young adults against their 7-year C-reactive protein (CRP) level trajectory and pack-years smoked. Participants from the Raine study, a longitudinal cohort study, had serum CRP levels analysed at the 14-, 17-, and 20-year follow-ups. Group-based trajectory modelling was used to classify participants according to their 7-year CRP levels. At the 20-year follow-up (at 18–22 years old), participants completed questionnaires on their smoking history, and underwent optical coherence tomography imaging to obtain their choroidal and retinal thicknesses at the macula. Three CRP trajectories were identified: consistently low CRP levels (78% of sample), increasing (11%), or consistently high (11%). 340 and 1035 participants were included in the choroidal and retinal thickness analyses, respectively. Compared to those in the “Low” trajectory group, participants in the “Increasing” and “High” groups had 14–21 μm thinner choroids at most macular regions. Every additional pack-year smoked was linked with a 0.06–0.10 μm thinner retina at the inner and outer macular rings, suggesting a dose-dependent relationship between smoking and thinner retinas. These associations may suggest that an increased risk of future visual impairment or eye disease associated with these risk factors may be present since young adulthood.

Optical Coherence Tomography (OCT) enables non-invasive imaging of the retina and is used to diagnose and manage ophthalmic diseases including glaucoma. We present the first large-scale genome-wide association study of inner retinal morphology using phenotypes derived from OCT images of 31,434 UK Biobank participants. We identify 46 loci associated with thickness of the retinal nerve fibre layer or ganglion cell inner plexiform layer. Only one of these loci has been associated with glaucoma, and despite its clear role as a biomarker for the disease, Mendelian randomisation does not support inner retinal thickness being on the same genetic causal pathway as glaucoma. We extracted overall retinal thickness at the fovea, representative of foveal hypoplasia, with which three of the 46 SNPs were associated. We additionally associate these three loci with visual acuity. In contrast to the Mendelian causes of severe foveal hypoplasia, our results suggest a spectrum of foveal hypoplasia, in part genetically determined, with consequences on visual function.

Tin Aung, Christopher Hammond and colleagues report the results of a large genome-wide association study of intraocular pressure. They identify four new loci associated with this trait and show that three of these loci are associated with risk of primary open-angle glaucoma. Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma, and variability in IOP might herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma Genetics Consortium (IGGC), comprising 35,296 multi-ancestry participants for IOP. We confirm genetic association of known loci for IOP and primary open-angle glaucoma (POAG) and identify four new IOP-associated loci located on chromosome 3q25.31 within the FNDC3B gene ( P = 4.19 × 10 −8 for rs6445055), two on chromosome 9 ( P = 2.80 × 10 −11 for rs2472493 near ABCA1 and P = 6.39 × 10 −11 for rs8176693 within ABO ) and one on chromosome 11p11.2 (best P = 1.04 × 10 −11 for rs747782). Separate meta-analyses of 4 independent POAG cohorts, totaling 4,284 cases and 95,560 controls, showed that 3 of these loci for IOP were also associated with POAG.

The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, UK, and USA comprising 52,506 individuals. We confirm known loci including MTAP , PLA2G6 , and IRF4 , and detect novel SNPs in KITLG and a region of 9q32. In a bivariate analysis combining the nevus results with a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1 , PPARGC1B , HDAC4 , FAM208B, DOCK8 , and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level. Overall, we conclude that most nevus genes affect melanoma risk ( KITLG an exception), while many melanoma risk loci do not alter nevus count. For example, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis. Melanocytic nevus count is associated with melanoma risk. In this study, a meta-analysis of 11 nevus GWAS studies identifies novel SNPs in KITLG and 9q32, and bivariate analysis with melanoma GWAS meta-analysis reveals that most nevus genes affect melanoma risk, while melanoma risk loci do not alter the nevus count.

Changes in retinal thickness are common in various ocular diseases. Transverse magnification due to differing ocular biometrics, in particular axial length, affects measurement of retinal thickness in different regions. This study evaluated the effect of axial length and refractive error on measured macular thickness in two community-based cohorts of healthy young adults. A total of 2160 eyes of 1247 community-based participants (18-30 years; 23.4% myopes, mean axial length = 23.6mm) were included in this analysis. Macular thickness measurements were obtained using a spectral-domain optical coherence tomography (which assumes an axial length of 24.385mm). Using a custom program, retinal thickness data were extracted at the 9 Early Treatment of Diabetic Retinopathy Study (ETDRS) regions with and without correction for transverse magnificent effects, with the corrected measurements adjusting according to the participant's axial length. Linear mixed models were used to analyse the effect of correction and its interaction with axial length or refractive group on retinal thickness. The raw measures (uncorrected for axial length) underestimated the true retinal thickness at the central macula, while overestimating at most non-central macular regions. There was an axial length by correction interaction effect in all but the nasal regions (all p<0.05). For each 1mm increase in axial length, the central macular thickness is overestimated by 2.7-2.9μm while thicknesses at other regions were underestimated by 0.2-4.1μm. Based on the raw thickness measurements, myopes have thinner retinas than non-myopes at most non-central macular. However, this difference was no longer significant when the corrected data was used. In a community-based sample, the raw measurements underestimate the retinal thickness at the central macula and overestimate the retinal thickness at non-central regions of the ETDRS grid. The effect of axial length and refractive error on retinal thickness is reduced after correcting for transverse magnification effects resulting from axial length differences.

SIX1/SIX6 polymorphism has been shown to be associated with glaucoma. Studies have also found that, in older adults, retinal nerve fibre layer (RNFL) thickness is significantly thinned with each copy of the risk allele in SIX1/SIX6 . However, it is not known whether these genetic variants exert their effects in younger individuals. Comparing a healthy young adult with an older adult cohort (mean age 20 vs 63 years), both of Northern European descent, we found that there was no significant RNFL thinning in each copy of the risk alleles in SIX1/SIX6 in the eyes of younger individuals. The older cohort showed an unexpectedly thicker RNFL in the nasal sector with each copy of the risk allele for both the SIX1 (rs10483727) and SIX6 (rs33912345) variants. In the temporal sector, thinner RNFL was found with each copy of the risk allele in rs33912345 with a decrease trend observed in rs10483727. Our results suggest that SIX1/SIX6 gene variants exert their influence later in adult life.

Background Recent changes in communication technologies, including increased reliance on mobile phones and the internet, may present challenges and/or opportunities to re-engaging inactive study cohorts. We evaluate our ability to recruit participants for the Kidskin Young Adult Myopia Study (KYAMS), a follow-up of the Kidskin Study. Methods KYAMS participants were recruited from the Kidskin Study, a sun exposure-intervention study for 5–6 year-olds running from 1995 to 1999 with most recent follow-up in 2005. From 2015 to 2019, the KYAMS used mail-outs, phone calls and social media to contact Kidskin Study participants. Multivariable logistic regression was used to identify variables associated with successful contact of a Kidskin Study participant or family member and KYAMS participation. Results Of 1695 eligible participants, 599 (35.5%) participants (or a family member) were contacted and 303 (17.9%) participated in the KYAMS. KYAMS participation was more likely in those who participated in the 2005 follow-up (odds ratio [OR] = 5.09, 95% confidence interval [CI]: 3.67–7.06) and had a mobile phone number on record (OR = 2.25, CI: 1.57–3.23). Of those contacted, participants who were the first point of contact (OR = 4.84, CI: 2.89–8.10) and who were contacted by letter in the first (OR = 6.53, CI: 3.35–12.75) or second (OR = 5.77, CI: 2.85–11.67) round were more likely to participate in the KYAMS, compared to contact by landline phone. Conclusions We recruited approximately one-fifth of Kidskin Study participants for the KYAMS. Participants were more likely to participate in the KYAMS if they were contacted directly, rather than through a family member, and if they were contacted by invitation letter. Trial registration ACTRN12617000812392 .

Background To generate and validate a method to estimate axial length estimated (AL est ) from spherical equivalent (SE) and corneal curvature [keratometry (K)], and to determine if this AL est can replace actual axial length (AL act ) for correcting transverse magnification error in optical coherence tomography angiography (OCTA) images using the Littmann-Bennett formula. Methods Data from 1301 participants of the Raine Study Gen2-20 year follow-up were divided into two datasets to generate (n = 650) and validate (n = 651) a relationship between AL, SE, and K. The developed formula was then applied to a separate dataset of 46 participants with AL, SE, and K measurements and OCTA images to estimate and compare the performance of AL est against AL act in correcting transverse magnification error in OCTA images when measuring the foveal avascular zone area (FAZA). Results The formula for AL est yielded the equation: AL est  = 2.102K − 0.4125SE + 7.268, R 2  = 0.794. There was good agreement between AL est and AL act for both study cohorts. The mean difference [standard deviation (SD)] between FAZA corrected with AL est and AL act was 0.002 (0.015) mm 2 with the 95% limits of agreement (LoA) of − 0.027 to 0.031 mm 2 . In comparison, mean difference (SD) between FAZA uncorrected and corrected with AL act was − 0.005 (0.030) mm 2 , with 95% LoA of − 0.064 to 0.054 mm 2 . Conclusions AL act is more accurate than AL est and hence should be used preferentially in magnification error correction in the clinical setting. FAZA corrected with AL est is comparable to FAZA corrected with AL act , while FAZA measurements using images corrected with AL est have a greater accuracy than measurements on uncorrected images. Hence, in the absence of AL act , clinicians should use AL est to correct for magnification error as this provides for more accurate measurements of fundus parameters than uncorrected images.