The Potential of Current Polygenic Risk Scores to Predict High Myopia and Myopic Macular Degeneration in Multiethnic Singapore Adults.

PURPOSE: To evaluate the transancestry portability of current myopia polygenic risk scores (PRSs) to predict high myopia (HM) and myopic macular degeneration (MMD) in an Asian population. DESIGN: Population-based study. PARTICIPANTS: A total of 5894 adults (2141 Chinese, 1913 Indian, and 1840 Malay) from the Singapore Epidemiology of Eye Diseases study were included in the analysis. The mean ± standard deviation age was 57.05 ± 9.31 years. A total of 361 adults had a diagnosis of HM (spherical equivalent [SE] < -5.00 diopters [D]) from refraction measurements, 240 individuals had a diagnosis of MMD graded by the International Photographic Classification and Grading System for Myopic Maculopathy criteria from fundus photographs, and 3774 individuals were control participants without myopia (SE > -0.5 D). METHODS: The PRS, derived from 687 289 HapMap3 single nucleotide polymorphisms (SNPs) from the largest genome-wide association study of myopia in Europeans to date (n = 260 974), was assessed on its ability to predict patients with HM and MMD versus control participants. MAIN OUTCOME MEASURES: The primary outcomes were the area under the receiver operating characteristic curve (AUC) to predict HM and MMD. RESULTS: The PRS had an AUC of 0.73 (95% confidence interval [CI], 0.70-0.75) for HM and 0.66 (95% CI, 0.63-0.70) for MMD versus no myopia. The inclusion of the PRS with other predictors (age, sex, educational attainment [EA], and ancestry; age-by-ancestry, sex-by-ancestry, and EA-by-ancestry interactions; and 20 genotypic principal components) increased the AUC to 0.84 (95% CI, 0.82-0.86) for HM and 0.79 (95% CI, 0.76-0.82) for MMD. Individuals with a PRS in the top 5% showed up to a 4.66 (95% CI, 3.34-6.42) times higher risk of HM developing and up to a 3.43 (95% CI, 2.27-5.05) times higher risk of MMD developing compared with the remaining 95% of individuals. CONCLUSIONS: The PRS is a good predictor for HM and facilitates the identification of high-risk children to prevent myopia progression to HM. In addition, the PRS also predicts MMD and helps to identify high-risk adults with myopia who require closer monitoring for myopia-related complications.

Family-focused contextual factors associated with lifestyle patterns in young children from two mother-offspring cohorts: GUSTO and EDEN.

BACKGROUND: Integrated patterns of energy balance-related behaviours of preschool children in Asia are sparse, with few comparative analyses. PURPOSE: Using cohorts in Singapore (GUSTO) and France (EDEN), we characterized lifestyle patterns of children and investigated their associations with family-focused contextual factors. METHODS: Ten behavioural variables related to child's diet, walking, outdoor play and screen time were ascertained by parental questionnaires at age 5-6 years. Using principal component analysis, sex-specific lifestyle patterns were derived independently for 630 GUSTO and 989 EDEN children. Contextual variables were organised into distal (family socio-economics, demographics), intermediate (parental health, lifestyle habits) and proximal (parent-child interaction factors) levels of influence and analysed with hierarchical linear regression. RESULTS: Three broadly similar lifestyle patterns were identified in both cohorts: "discretionary consumption and high screen time", "fruit, vegetables, and low screen time" and "high outdoor playtime and walking". The latter two patterns showed small differences between cohorts and sexes. The "discretionary consumption and high screen time" pattern was consistently similar in both cohorts; distal associated factors were lower maternal education (EDEN boys), no younger siblings (GUSTO boys) and Malay/Indian ethnicity (GUSTO), while intermediate and proximal associated factors in both cohorts and sexes were poor maternal diets during pregnancy, parents allowing high child control over food intake, snacking between meals and having television on while eating. CONCLUSIONS: Three similar lifestyle patterns were observed among preschool children in Singapore and France. There were more common associated proximal factors than distal ones. Cohort specific family-focused contextual factors likely reflect differences in social and cultural settings. Findings will aid development of strategies to improve child health.

Dietary intake and associations with myopia in Singapore children.

PURPOSE: To evaluate associations of dietary factors with myopia, spherical equivalent refractive error (SE) and axial length (AL) in children at age 9 from the Growing Up in Singapore Towards healthy Outcomes (GUSTO) birth cohort. METHODS: We included 467 multi-ethnic children (933 eyes) who participated in the GUSTO prospective birth cohort and were delivered in two major hospitals in Singapore (2009-2010). At the 9-year visit, we assessed the 6-year incidence of myopia (between ages 3 to 9), cycloplegic SE and AL in children without myopia (SE ≤ -0.5 D in either eye) at the 3-year visit. Using a validated 112-item food frequency questionnaire, parents reported each child's average daily intake of dietary factors (nutrients and food groups) in the past month. Paired eyes were analysed using Generalised Estimating Equations with multivariable logistic or linear regression. Bonferroni corrections were applied, correcting for multiple comparisons between the 13 nutrients (p < 0.004) or 8 food groups (p < 0.006) and each outcome. RESULTS: In children aged 9 years (51.0% boys; 56.3% Chinese), the 6-year incidence of myopia was 35.5%. Overall, the mean (SD) SE and AL were -0.3 (1.7) D and 23.4 (1.0) mm, respectively. In multivariable regression, macronutrients or micronutrients were not associated with incident myopia (p ≥ 0.004 for all), adjusting for total energy, gender, ethnicity, time outdoors, near-work and the number of myopic parents (additionally child's height for outcome AL). Similarly, all food groups (including refined grains, sugar-sweetened beverages, protein foods, fruits and vegetables) were not associated with incident myopia (p ≥ 0.006 for all). Additionally, none of the nutrients (p ≥ 0.004 for all) or food groups (p ≥ 0.006 for all) were associated with SE or AL. CONCLUSIONS: Our study findings of no significant association between specific nutrients or food groups and incident myopia or SE or AL suggest that diet may not be associated with myopia in children aged 9 years. Well-conducted prospective studies in other populations may clarify the association.

The longitudinal association between early-life screen viewing and abdominal adiposity-findings from a multiethnic birth cohort study.

IMPORTANCE: Screen viewing in adults has been associated with greater abdominal adiposity, with the magnitude of associations varying by sex and ethnicity, but the evidence is lacking at younger ages. We aimed to investigate sex- and ethnic-specific associations of screen-viewing time at ages 2 and 3 years with abdominal adiposity measured by magnetic resonance imaging at age 4.5 years. METHODS: The Growing Up in Singapore Towards healthy Outcomes is an ongoing prospective mother-offspring cohort study. Parents/caregivers reported the time their child spent viewing television, handheld devices, and computer screens at ages 2 and 3 years. Superficial and deep subcutaneous and visceral abdominal adipose tissue volumes were quantified from magnetic resonance images acquired at age 4.5 years. Associations between screen-viewing time and abdominal adipose tissue volumes were examined by multivariable linear regression adjusting for confounding factors. RESULTS: In the overall sample (n = 307), greater total screen-viewing time and handheld device times were associated with higher superficial and deep subcutaneous adipose tissue volumes, but not with visceral adipose tissue volumes. Interactions with child sex were found, with significant associations with superficial and deep subcutaneous and visceral adipose tissue volumes in boys, but not in girls. Among boys, the increases in mean (95% CI) superficial and deep subcutaneous and visceral adipose tissue volumes were 24.3 (9.9, 38.7), 17.6 (7.4, 27.8), and 7.8 (2.1, 13.6) mL per hour increase in daily total screen-viewing time, respectively. Ethnicity-specific analyses showed associations of total screen-viewing time with abdominal adiposity only in Malay children. Television viewing time was not associated with abdominal adiposity. CONCLUSION: Greater total screen-viewing time (and in particular, handheld device viewing time) was associated with higher abdominal adiposity in boys and Malay children. Additional studies are necessary to confirm these associations and to examine screen-viewing interventions for preventing excessive abdominal adiposity and its adverse cardiometabolic consequences.

A Web-Based Time-Use Application to Assess Diet and Movement Behavior in Asian Schoolchildren: Development and Usability Study of My E-Diary for Activities and Lifestyle (MEDAL).

BACKGROUND: Web-based time-use diaries for schoolchildren are limited, and existing studies focus mostly on capturing physical activities and sedentary behaviors but less comprehensively on dietary behaviors. OBJECTIVE: This study aims to describe the development of My E-Diary for Activities and Lifestyle (MEDAL)-a self-administered, web-based time-use application to assess diet and movement behavior-and to evaluate its usability in schoolchildren in Singapore. METHODS: MEDAL was developed through formative research and an iterative user-centric design approach involving small groups of schoolchildren (ranging from n=5 to n=15, aged 7-13 years). To test the usability, children aged 10-11 years were recruited from 2 primary schools in Singapore to complete MEDAL for 2 weekdays and 2 weekend days and complete a 10-item usability questionnaire. RESULTS: The development process revealed that younger children (aged <9 years) were less able to complete MEDAL independently. Of the 204 participants (118/204, 57.8% boys, and 31/201, 15.4% overweight) in the usability study, 57.8% (118/204) completed 3 to 4 days of recording, whereas the rest recorded for 2 days or less. The median time taken to complete MEDAL was 14.2 minutes per day. The majority of participants agreed that instructions were clear (193/203, 95.1%), that MEDAL was easy to use (173/203, 85.2%), that they liked the application (172/202, 85.1%), and that they preferred recording their activities on the web than on paper (167/202, 82.7%). Among all the factors evaluated, recording for 4 days was the least satisfactory component reported. Compared with boys, girls reported better recall ability and agreed that the time spent on completing 1-day entry was appropriate. CONCLUSIONS: MEDAL appears to be a feasible application to capture diet and movement behaviors in children aged 10-12 years, particularly in the Asian context. Some gender differences in usability performance were observed, but the majority of the participants had a positive experience using MEDAL. The validation of the data collected through the application is in progress.

Genome-Wide Association Study in Asians Identifies Novel Loci for High Myopia and Highlights a Nervous System Role in Its Pathogenesis.

PURPOSE: To identify novel susceptibility loci for high myopia. DESIGN: Genome-wide association study (GWAS) followed by replication and meta-analysis. PARTICIPANTS: A total of 14 096 samples from East and Southeast Asian populations (2549 patients with high myopia and 11 547 healthy controls). METHODS: We performed a GWAS in 3269 Japanese individuals (1668 with high myopia and 1601 control participants), followed by replication analysis in a total of 10 827 additional samples (881 with high myopia and 9946 control participants) from Japan, Singapore, and Taiwan. To confirm the biological role of the identified loci in the pathogenesis of high myopia, we performed functional annotation and Gene Ontology (GO) analyses. MAIN OUTCOME MEASURES: We evaluated the association of single nucleotide polymorphisms with high myopia and GO terms enriched among genes identified in the current study. RESULTS: We identified 9 loci with genome-wide significance (P < 5.0 × 10-8). Three loci were previously reported myopia-related loci (ZC3H11B on 1q41, GJD2 on 15q14, and RASGRF1 on 15q25.1), and the other 6 were novel (HIVEP3 on 1p34.2, NFASC/CNTN2 on 1q32.1, CNTN4/CNTN6 on 3p26.3, FRMD4B on 3p14.1, LINC02418 on 12q24.33, and AKAP13 on 15q25.3). The GO analysis revealed a significant role of the nervous system related to synaptic signaling, neuronal development, and Ras/Rho signaling in the pathogenesis of high myopia. CONCLUSIONS: The current study identified 6 novel loci associated with high myopia and demonstrated an important role of the nervous system in the disease pathogenesis. Our findings give new insight into the genetic factors underlying myopia, including high myopia, by connecting previous findings and allowing for a clarified interpretation of the cause and pathophysiologic features of myopia at the molecular level.

Mendelian randomization analysis does not support causal associations of birth weight with hypertension risk and blood pressure in adulthood.

Epidemiology studies suggested that low birthweight was associated with a higher risk of hypertension in later life. However, little is known about the causality of such associations. In our study, we evaluated the causal association of low birthweight with adulthood hypertension following a standard analytic protocol using the study-level data of 183,433 participants from 60 studies (CHARGE-BIG consortium), as well as that with blood pressure using publicly available summary-level genome-wide association data from EGG consortium of 153,781 participants, ICBP consortium and UK Biobank cohort together of 757,601 participants. We used seven SNPs as the instrumental variable in the study-level analysis and 47 SNPs in the summary-level analysis. In the study-level analyses, decreased birthweight was associated with a higher risk of hypertension in adults (the odds ratio per 1 standard deviation (SD) lower birthweight, 1.22; 95% CI 1.16 to 1.28), while no association was found between genetically instrumented birthweight and hypertension risk (instrumental odds ratio for causal effect per 1 SD lower birthweight, 0.97; 95% CI 0.68 to 1.41). Such results were consistent with that from the summary-level analyses, where the genetically determined low birthweight was not associated with blood pressure measurements either. One SD lower genetically determined birthweight was not associated with systolic blood pressure (ß = - 0.76, 95% CI - 2.45 to 1.08 mmHg), 0.06 mmHg lower diastolic blood pressure (ß = - 0.06, 95% CI - 0.93 to 0.87 mmHg), or pulse pressure (ß = - 0.65, 95% CI - 1.38 to 0.69 mmHg, all p > 0.05). Our findings suggest that the inverse association of birthweight with hypertension risk from observational studies was not supported by large Mendelian randomization analyses.

A review on the epidemiology of myopia in school children worldwide.

BACKGROUND: Due to high prevalence myopia has gained importance in epidemiological studies. Children with early onset are at particular risk of complications associated with myopia, as progression over time might result in high myopia and myopic macular degeneration. Both genetic and environmental factors play a role in the increasing prevalence of myopia. The aim of this study is to review the current literature on epidemiology and risk factors for myopia in school children (aged 6-19 years) around the world. MAIN BODY: PubMed and Medline were searched for the following keywords: prevalence, incidence, myopia, refractive error, risk factors, children and visual impairment. English language articles published between Jan 2013 and Mar 2019 were included in the study. Studies were critically reviewed for study methodology and robustness of data. Eighty studies were included in this literature review. Myopia prevalence remains higher in Asia (60%) compared with Europe (40%) using cycloplegic refraction examinations. Studies reporting on non-cycloplegic measurements show exceptionally high myopia prevalence rates in school children in East Asia (73%), and high rates in North America (42%). Low prevalence under 10% was described in African and South American children. In recent studies, risk factors for myopia in schoolchildren included low outdoor time and near work, dim light exposure, the use of LED lamps for homework, low sleeping hours, reading distance less than 25 cm and living in an urban environment. CONCLUSION: Low levels of outdoor activity and near work are well-established risk factors for myopia; this review provides evidence on additional environmental risk factors. New epidemiological studies should be carried out on implementation of public health strategies to tackle and avoid myopia. As the myopia prevalence rates in non-cycloplegic studies are overestimated, we recommend considering only cycloplegic measurements.

The association between digital screen time and myopia: A systematic review.

PURPOSE: Digital screen time has been cited as a potential modifiable environmental risk factor that can increase myopia risk. However, associations between screen time and myopia have not been consistently reported. Although myopia prevalence increased before the massive use of digital devices in some countries, with the rise being influenced by education, there may be an added recent effect of screen time. The aim of this systematic review is to determine the association between screen time and the risk of developing (1) prevalent or incident myopia, or (2) the risk of myopia progression in children. Published manuscripts were identified in PubMed, ScienceDirect and the Cochrane Library, and citation lists were reviewed. RECENT FINDINGS: Fifteen studies were included (nine cross-sectional and six cohort studies) with a total of 49 789 children aged between 3 and 19 years old. Seven studies found an association between screen time and myopia. The results showed mixed evidence with the more recent studies exposing a trend of association between hours spent by children using screens and myopia. Meta-analysis using a random-effects model was performed in five studies (n = 20 889) that reported odds ratio (OR). The I2 statistics was used to assess heterogeneity. A pooled OR of 1.02 (95% CI: 0.96-1.08; p = 0.48) suggests that screen time is not associated with prevalent and incident myopia in this group of five studies. SUMMARY: The results for screen time and myopia are mixed. Further studies with objective screen time measurements are necessary to assess evidence of an association between screen time and myopia.

Genome-wide association study of Parkinson's disease in East Asians.

Genome-wide association studies (GWAS) on Parkinson's disease (PD) have mostly been done in Europeans and Japanese. No study has been done in Han Chinese, which make up nearly a fifth of the world population. We conducted the first Han Chinese GWAS analysing a total of 22,729 subjects (5,125 PD cases and 17,604 controls) from Singapore, Hong Kong, Malaysia, Korea, mainland China and Taiwan. We performed imputation, merging and logistic regression analyses of 2,402,394 SNPs passing quality control filters in 779 PD cases, 13,227 controls, adjusted for the first three principal components. 90 SNPs with association P < 10-4 were validated in 9 additional sample collections and the results were combined using fixed-effects inverse-variance meta-analysis. We observed strong associations reaching genome-wide significance at SNCA, LRRK2 and MCCC1, confirming their important roles in both European and Asian PD. We also identified significant (P < 0.05) associations at 5 loci (DLG2, SIPA1L2, STK39, VPS13C and RIT2), and observed the same direction of associations at 9 other loci including BST1 and PARK16. Allelic heterogeneity was observed at LRRK2 while European risk SNPs at 6 other loci including MAPT and GBA-SYT11 were non-polymorphic or very rare in our cohort. Overall, we replicate associations at SNCA, LRRK2, MCCC1 and 14 other European PD loci but did not identify Asian-specific loci with large effects (OR > 1.45) on PD risk. Our results also demonstrate some differences in the genetic contribution to PD between Europeans and Asians. Further pan-ethnic meta-analysis with European GWAS cohorts may unravel new PD loci.

Sex-specific longitudinal associations of screen viewing time in children at 2-3 years with adiposity at 3-5 years.

OBJECTIVES: Screen-viewing in late childhood has been associated with adiposity and blood pressure (BP), but evidence is lacking at younger ages. To investigate the prospective associations of total and device-specific screen-viewing at age 2-3 years with BMI, sum of skinfold thicknesses and BP among Singaporean children at age 3-5 years. METHODS: As part of the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort, mothers/caregivers reported the time per day their 2 and 3-year-old children watched/used television, handheld devices and computers. Average screen-viewing time (total, television and handheld-devices) at ages 2 and 3 years was used in the analyses. Height; weight; triceps, biceps and subscapular skinfold thicknesses; and systolic and diastolic BP were measured at ages 3, 4 and 5. Associations of screen-viewing with BMI, sum of skinfold thicknesses and BP in 956 children were investigated using repeated-measures linear regression models. Analyses were further stratified by sex as we found significant interaction. RESULTS: Among boys and girls combined, screen-viewing was positively associated with sum of skinfold thicknesses, but not with BMI or BP. Sex-specific analyses showed significant associations with both BMI and sum of skinfold thicknesses in boys, but not in girls. Screen-viewing was not associated with BP in boys or girls. The increases in mean (95% CI) BMI per hour increase in daily total, television and handheld-devices screen-viewing among boys were 0.12 (0.03, 0.21), 0.18 (0.06, 0.30) and 0.11 (-0.07, 0.29) kg/m2, respectively. The corresponding increases in mean sum of skinfold thicknesses were 0.68 (0.29, 1.07), 0.79 (0.26, 1.32) and 1.18 (0.38, 1.99) mm. CONCLUSIONS: Greater screen-viewing at age 2-3 years was associated with later adiposity at 3-5 years in boys, but not in girls. In light of the increasing use of screen devices and cardiometabolic risk in young children, these findings may have important public health implications.

Population genomics in South East Asia captures unexpectedly high carrier frequency for treatable inherited disorders.

PURPOSE: Genomic studies have demonstrated the necessity of ethnicity-specific population data to ascertain variant pathogenicity for disease diagnosis and treatment. This study examined the carrier prevalence of treatable inherited disorders (TIDs), where early diagnosis of at-risk offspring can significantly improve clinical outcomes. METHODS: Existing exome/ genome sequencing data of 831 Singaporeans were aggregated and examined for disease causing variants in 104 genes associated with 80 TIDs. RESULTS: Among the 831 Singaporean participants, genomic variant filtering and analysis identified 1 in 18 individuals (6%) to be carriers amongst one of 13 TIDs. Citrin deficiency and Wilson disease had the highest carrier frequency of 1 in 41, and 1 in 103 individuals, respectively. The pathogenic variants associated with citrin deficiency were 24 times more prevalent in our local cohorts when compared to Western cohorts. CONCLUSION: This study demonstrates the value of a population specific genomic database to determine true disease prevalence and has enabled the discovery of carrier frequencies of treatable genetic conditions specific to South East Asian populations, which are currently underestimated in existing data sources. This study framework can be adapted to other population groups and expanded to multiple genetic conditions to inform health policies directing precision medicine.

Prevalence, Characteristics, and Risk Factors of Moderate or High Hyperopia among Multiethnic Children 6 to 72 Months of Age: A Pooled Analysis of Individual Participant Data.

PURPOSE: To describe the prevalence, ocular characteristics, and associated risk factors of moderate to high hyperopia in early childhood. DESIGN: Pooled analysis of individual participant data from population-based studies. PARTICIPANTS: Six- to 72-month-old multiethnic children who participated in 4 population-based studies of pediatric eye diseases. METHODS: The pooled studies conducted comparable parental interviews and ocular examinations including cycloplegic autorefraction. Presence of hyperopia was defined based on cycloplegic refractive error in the worse eye. Multivariate analyses were performed to evaluate the association of potential risk factors with hyperopia risk. MAIN OUTCOME MEASURES: Prevalence and odds ratios of moderate to high hyperopia (≥4.0 diopters [D]). RESULTS: Cycloplegic refraction was completed in 15 051 children 6 to 72 months of age. Among these children, the overall prevalence of moderate to high hyperopia (≥4.0 D) in the worse eye was 3.2% (95% confidence interval, 2.9%-3.5%), accounting for 15.6% of all hyperopia (≥2.0 D). Among children with moderate to high hyperopia, both eyes were affected in 64.4%, 28.9% showed spherical anisometropia of 1.0 D or more, and 19.5% showed astigmatism of 1.5 D or more. Among 36- to 72-month-old children with moderate to high hyperopia, 17.6% wore glasses. Prevalence of moderate to high hyperopia was slightly less in 12- to 23-month-old children and was relatively stable in children 24 months of age and older. Non-Hispanic and Hispanic white race and ethnicity, family history of strabismus, maternal smoking during pregnancy, and being a participant in the United States studies were associated with a higher risk of moderate to high hyperopia (P < 0.05). CONCLUSIONS: By assembling similarly designed studies, our consortium provided robust estimates of the prevalence of moderate to high hyperopia in the general population and showed that in 6- to 72-month-old children, moderate to high hyperopia is not uncommon and its prevalence does not decrease with age. Risk factors for moderate to high hyperopia differ from those for low to moderate hyperopia (2.0-<4.0 D) in preschool children, with family history of strabismus and maternal smoking during pregnancy more strongly associated with moderate to high hyperopia than low to moderate hyperopia.

Behavioral Heterogeneity in Relation with Brain Functional Networks in Young Children.

This study aimed to identify distinct behavioral profiles in a population-based sample of 654 4-year-old children and characterize their relationships with brain functional networks using resting-state functional magnetic resonance imaging data. Young children showed 7 behavioral profiles, including a super healthy behavioral profile with the lowest scores across all Child Behavior CheckList (CBCL) subscales (G1) and other 6 behavioral profiles, respectively with pronounced withdrawal (G2), somatic complaints (G3), anxiety and withdrawal (G4), somatic complaints and withdrawal (G5), the mixture of emotion, withdrawal, and aggression (G6), and attention (G7) problems. Compared with children in G1, children with withdrawal shared abnormal functional connectivities among the sensorimotor networks. Children in emotionally relevant problems shared the common pattern among the attentional and frontal networks. Nevertheless, children in sole withdrawal problems showed a unique pattern of connectivity alterations among the sensorimotor, cerebellar, and salience networks. Children with somatic complaints showed abnormal functional connectivities between the attentional and subcortical networks, and between the language and posterior default mode networks. This study provides novel evidence on the existence of behavioral heterogeneity in early childhood and its associations with specific functional networks that are clinically relevant phenotypes for mental illness and are apparent from early childhood.

HOXA9 is a novel myopia risk gene.

PURPOSE: A recent meta-analysis revealed PAX6 as a risk gene for myopia. There is a link between PAX6 and HOXA9. Furthermore, HOXA9 has been reported to activate TGF-ß that is a risk factor for myopia. We speculate HOXA9 may participate in myopia development. METHODS: The Singapore GUSTO birth cohort provides data on children's cycloplegic refraction measured at age of 3 years and their methylation profile based on the umbilical cord DNA. The HOXA9 expression levels were measured in the eyes of mono-ocular form deprivation myopia in mice. The plasmid with the mouse HOXA9 cDNA was constructed and then transfected to mouse primary retinal pigment epithelial (RPE) cells. The expression levels of myopia-related genes and cell proliferation were measured in the HOXA9-overexpressed RPE cells. RESULTS: A total of 519 children had data on methylation profile and cycloplegic refraction. The mean spherical equivalent refraction (SE) was 0.90D. Among 8 SE outliers (worse than -2D), 7 children had HOXA9 hypomethylation. The HOXA9 levels in the retina of myopic eyes was 2.65-fold (p = 0.029; paired t-test) higher than the uncovered fellow eyes. When HOXA9 was over-expressed in the RPE cells, TGF-ß, MMP2, FGF2 and IGF1R expression levels were dose-dependently increased by HOXA9. However, over-expression of HOXA9 had no significant influence on IGF1 or HGF expression. In addition, HOXA9 also increased RPE proliferation. CONCLUSION: Based on the human, animal and cellular data, the transcription factor HOXA9 may promote the expression of pro-myopia genes and RPE proliferation, which eventually contribute to myopia development.

An Update of Eye Shape and Myopia.

Myopia is one of the most prevalent eye diseases, and its advanced form, high myopia, is a leading cause of subsequent pathologic myopia, which in turn results in an increased risk of retinal diseases. The prevalence of myopia and high myopia is 28.3% and 4.0% of the global population, respectively, and these numbers are estimated to increase to 49.8% for myopia 9.8% for high myopia by 2050, thus making myopia a severe global socioeconomic problem. The eye shape has been receiving increasing attention as a possible biomarker for myopia. Among several modalities, magnetic resonance imaging (MRI) is currently considered to be the best to measure the 3-dimensional eye shape, and one study using MRI revealed that myopic eyes became much larger in all 3 dimensions, but more so in length (0.35 mm/D) than in height (0.19 mm/D) or in width (0.10 mm/D), which fitted in global and axial elongation models. Another recent study reported that emmetropic retinas were oblate but oblateness decreased with myopia progression. According to a study to evaluate eye shapes in high myopia, although all emmetropic eyes had a blunt shape, almost half of the high myopic eyes had a pointed shape. Multiple lines of evidence suggest that abnormal eye shape changes can cause not only simple myopia but also various ocular complications through biomechanical stretching. In this review, we highlight recent findings on eye shape changes in myopic eyes and abnormal eye shapes in pathologic myopia.

Establishment of the nasal microbiota in the first 18 months of life: Correlation with early-onset rhinitis and wheezing.

BACKGROUND: Dynamic establishment of the nasal microbiota in early life influences local mucosal immune responses and susceptibility to childhood respiratory disorders. OBJECTIVE: The aim of this case-control study was to monitor, evaluate, and compare development of the nasal microbiota of infants with rhinitis and wheeze in the first 18 months of life with those of healthy control subjects. METHODS: Anterior nasal swabs of 122 subjects belonging to the Growing Up in Singapore Towards Healthy Outcomes (GUSTO) birth cohort were collected longitudinally over 7 time points in the first 18 months of life. Nasal microbiota signatures were analyzed by using 16S rRNA multiplexed pair-end sequencing from 3 clinical groups: (1) patients with rhinitis alone (n = 28), (2) patients with rhinitis with concomitant wheeze (n = 34), and (3) healthy control subjects (n = 60). RESULTS: Maturation of the nasal microbiome followed distinctive patterns in infants from both rhinitis groups compared with control subjects. Bacterial diversity increased over the period of 18 months of life in control infants, whereas infants with rhinitis showed a decreasing trend (P < .05). An increase in abundance of the Oxalobacteraceae family (Proteobacteria phylum) and Aerococcaceae family (Firmicutes phylum) was associated with rhinitis and concomitant wheeze (adjusted P < .01), whereas the Corynebacteriaceae family (Actinobacteria phylum) and early colonization with the Staphylococcaceae family (Firmicutes phylum; 3 weeks until 9 months) were associated with control subjects (adjusted P < .05). The only difference between the rhinitis and control groups was a reduced abundance of the Corynebacteriaceae family (adjusted P < .05). Determinants of nasal microbiota succession included sex, mode of delivery, presence of siblings, and infant care attendance. CONCLUSION: Our results support the hypothesis that the nasal microbiome is involved in development of early-onset rhinitis and wheeze in infants.

Association between maternal mid-gestation vitamin D status and neonatal abdominal adiposity.

OBJECTIVES: Lower vitamin D status has been associated with adiposity in children through adults. However, the evidence of the impact of maternal vitamin-D status during pregnancy on offspring's adiposity is mixed. The objective of this study was to examine the associations between maternal vitamin-D [25(OH)D] status at mid-gestation and neonatal abdominal adipose tissue (AAT) compartments, particularly the deep subcutaneous adipose tissue linked with metabolic risk. METHODS: Participants (N = 292) were Asian mother-neonate pairs from the mother-offspring cohort, Growing Up in Singapore Towards healthy Outcomes. Neonates born at ≥34 weeks gestation with birth weight ≥2000 g had magnetic resonance imaging (MRI) within 2-weeks post-delivery. Maternal plasma glucose using an oral glucose tolerance test and 25(OH)D concentrations were measured. 25(OH)D status was categorized into inadequate (≤75.0 nmol/L) and sufficient (>75.0 nmol/L) groups. Neonatal AAT was classified into superficial (sSAT), deep subcutaneous (dSAT), and internal (IAT) adipose tissue compartments. RESULTS: Inverse linear correlations were observed between maternal 25(OH)D and both sSAT (r = -0.190, P = 0.001) and dSAT (r = -0.206, P < 0.001). Each 1 nmol/L increase in 25(OH)D was significantly associated with reductions in sSAT (ß = -0.14 (95% CI: -0.24, -0.04) ml, P = 0.006) and dSAT (ß = -0.04 (-0.06, -0.01) ml, P = 0.006). Compared to neonates of mothers with 25(OH)D sufficiency, neonates with maternal 25(OH)D inadequacy had higher sSAT (7.3 (2.1, 12.4) ml, P = 0.006), and dSAT (2.0 (0.6, 3.4) ml, P = 0.005) volumes, despite similar birth weight. In the subset of mothers without gestational diabetes, neonatal dSAT was also greater (1.7 (0.3, 3.1) ml, P = 0.019) in neonates with maternal 25(OH)-inadequacy. The associations with sSAT and dSAT persisted even after accounting for maternal glycemia (fasting and 2-h plasma glucose). CONCLUSIONS: Neonates of Asian mothers with mid-gestation 25(OH)D inadequacy have a higher abdominal subcutaneous adipose tissue volume, especially dSAT (which is metabolically similar to visceral adipose tissue in adults), even after accounting for maternal glucose levels in pregnancy.

Correction: Population genomics in South East Asia captures unexpectedly high carrier frequency for treatable inherited disorders.

At the time of publication the author Jyn Ling Kuan did not have a master's degree; this has now been amended to BSc. This has now been corrected in the PDF and HTML versions of the article.

A genome-wide association study of corneal astigmatism: The CREAM Consortium.

Purpose: To identify genes and genetic markers associated with corneal astigmatism. Methods: A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as having >0.75 diopters of corneal astigmatism. Subsequent gene-based and gene-set analyses of the meta-analyzed results of European ancestry cohorts were performed using VEGAS2 and MAGMA software. Additionally, estimates of single nucleotide polymorphism (SNP)-based heritability for corneal and refractive astigmatism and the spherical equivalent were calculated for Europeans using LD score regression. Results: The meta-analysis of all cohorts identified a genome-wide significant locus near the platelet-derived growth factor receptor alpha (PDGFRA) gene: top SNP: rs7673984, odds ratio=1.12 (95% CI:1.08-1.16), p=5.55×10-9. No other genome-wide significant loci were identified in the combined analysis or European/Asian ancestry-specific analyses. Gene-based analysis identified three novel candidate genes for corneal astigmatism in Europeans-claudin-7 (CLDN7), acid phosphatase 2, lysosomal (ACP2), and TNF alpha-induced protein 8 like 3 (TNFAIP8L3). Conclusions: In addition to replicating a previously identified genome-wide significant locus for corneal astigmatism near the PDGFRA gene, gene-based analysis identified three novel candidate genes, CLDN7, ACP2, and TNFAIP8L3, that warrant further investigation to understand their role in the pathogenesis of corneal astigmatism. The much lower number of genetic variants and genes demonstrating an association with corneal astigmatism compared to published spherical equivalent GWAS analyses suggest a greater influence of rare genetic variants, non-additive genetic effects, or environmental factors in the development of astigmatism.