Jenny Mountain

Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus

Central corneal thickness (CCT) is associated with eye conditions including keratoconus and glaucoma. We performed a meta-analysis on >20,000 individuals in European and Asian populations that identified 16 new loci associated with CCT at genome-wide significance (P < 5 × 10−8). We further showed that 2 CCT-associated loci, FOXO1 and FNDC3B, conferred relatively large risks for keratoconus in 2 cohorts with 874 cases and 6,085 controls (rs2721051 near FOXO1 had odds ratio (OR) = 1.62, 95% confidence interval (CI) = 1.4–1.88, P = 2.7 × 10−10, and rs4894535 in FNDC3B had OR = 1.47, 95% CI = 1.29–1.68, P = 4.9 × 10−9). FNDC3B was also associated with primary open-angle glaucoma (P = 5.6 × 10−4; tested in 3 cohorts with 2,979 cases and 7,399 controls). Further analyses implicate the collagen and extracellular matrix pathways in the regulation of CCT.

Maternal vitamin D status during pregnancy and bone mass in offspring at 20 years of age: a prospective cohort study.

It is uncertain whether the vitamin D status of pregnant women influences bone mass of their children. Cohort studies have yielded conflicting results; none have examined offspring at skeletal maturity. This longitudinal, prospective study investigated the association between maternal vitamin D status and peak bone mass of offspring in 341 mother and offspring pairs in the Western Australian Pregnancy Cohort (Raine) Study. Maternal serum samples collected at 18 weeks gestation were assayed for 25‐hydroxyvitamin D (25OHD). Outcomes were total body bone mineral content (BMC) and bone mineral density (BMD) measured by dual‐energy X‐ray absorptiometry in offspring at 20 years of age. The mean (± SD) maternal serum 25OHD concentration was 57.2 ± 19.2 nmol/L; 132 women (38.7%) were vitamin D‐deficient (25OHD <50 nmol/L). After adjustment for season of sample collection, maternal factors, and offspring factors (sex, birth weight, and age, height, lean mass, and fat mass at 20 years), maternal 25OHD concentration was positively associated with total body BMC and BMD in offspring, with a mean difference of 19.2 (95% confidence interval [CI], 5.6–32.7) g for BMC and 4.6 (95% CI, 0.1–9.1) mg/cm2 for BMD per 10.0 nmol/L of maternal 25OHD. Maternal vitamin D deficiency was associated with 2.7% lower total body BMC (mean ± SE) (2846 ± 20 versus 2924 ± 16 g, p = 0.004) and 1.7% lower total body BMD (1053 ± 7 versus 1071 ± 5 mg/cm2, p = 0.043) in the offspring. We conclude that vitamin D deficiency in pregnant women is associated with lower peak bone mass in their children. This may increase fracture risk in the offspring in later life.

Vitamin D in Fetal Development: Findings From a Birth Cohort Study

Birth cohort studies provide an invaluable resource for studies of the influence of the fetal environment on health in later life. It is uncertain to what extent maternal vitamin D status influences fetal development. Using an unselected community-based cohort of 901 mother-offspring pairs (the Western Australian Pregnancy Cohort [Raine] Study), we examined the relationship between maternal vitamin D deficiency at 18 weeks’ pregnancy and long-term health outcomes of offspring who were born in Perth, Western Australia (32° South), in 1989–1991. Vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D] <50 nmol/L) was present in 36% (323 of 901) of the pregnant women. After adjusting for relevant covariates, maternal vitamin D deficiency during pregnancy was associated with impaired lung development in 6-year-old offspring, neurocognitive difficulties at age 10, increased risk of eating disorders in adolescence, and lower peak bone mass at 20 years. In summary, vitamin D may have an important, multifaceted role in the development of fetal lungs, brain, and bone. Experimental animal studies support an active contribution of vitamin D to organ development. Randomized controlled trials of vitamin D supplementation in pregnant women with long-term follow-up of offspring are urgently required to examine whether the correction of vitamin D deficiency in pregnant women is beneficial for their offspring and to determine the optimal level of maternal serum 25(OH)D for fetal development.

Myopia is associated with lower Vitamin D status in young adults.

PURPOSE To investigate the association between serum vitamin D levels and myopia in young adults. METHODS A total of 946 individuals participating in the 20-year follow-up of the Western Australian Pregnancy Cohort (Raine) Study were included in this study. Ethnicity, parental myopia, and education status were ascertained by self-reported questionnaire. A comprehensive ophthalmic examination was performed, including postcycloplegic autorefraction and conjunctival UV autofluorescence photography. Serum 25-hydroxyvitamin D₃ (25(OH)D₃) concentrations were determined using mass spectrometry. The association between serum 25(OH)D₃ concentrations and prevalent myopia was determined using multivariable logistic regression. Myopia was defined as mean spherical equivalent ≤ -0.5 diopters. RESULTS Of the 946 participants, 221 (23.4%) had myopia (n = 725 nonmyopic). Myopic subjects had lower serum 25(OH)D₃ concentrations compared to nonmyopic participants (median 67.6 vs. 72.5 nmol, P = 0.003). In univariable analysis, lower serum 25(OH)D₃ concentration was associated with higher risk of having myopia (odds ratio [OR] for <50 vs. ≥50 nmol/L: 2.63; confidence interval [95% CI] 1.71-4.05; P < 0.001). This association persisted after adjustment for potential confounders, including age, sex, ethnicity, parental myopia, education status, and ocular sun-exposure biomarker score (adjusted OR 2.07; 95% CI 1.29-3.32; P = 0.002). CONCLUSIONS Myopic participants had significantly lower 25(OH)D₃ concentrations. The prevalence of myopia was significantly higher in individuals with vitamin D deficiency compared to the individuals with sufficient levels. Longitudinal studies are warranted to investigate whether higher serum 25(OH)D₃ concentration is protective against myopia or whether it is acting as a proxy for some other biologically effective consequence of sun exposure.

Birth of a cohort - the first 20 years of the Raine study

n Th se I the beginning there was an idea ... and funding. e project might never have started if not for a rendipitous meeting between an accountant for the Raine Medical Research Foundation and a young obstetrician. The Foundation had been established 30 years earlier by the bequest of Mary Raine (Box 1), a successful businesswoman who left her property empire to the University of Western Australia (UWA) for medical research. The accountant mentioned that the Foundation had decided to award a large sum of money to one big, visionary project, and the very next day the grant application was underway. The obstetrician’s big idea, the Western Australian Pregnancy Cohort, had two objectives: to investigate the hypothesis that complications of pregnancy might be prevented by frequent ultrasound scans, and to develop a long-term cohort to study the role that early life events have on later health. From 1989 to 1991, 2900 pregnant women were randomly assigned to either routine obstetric ultrasound or multiple scans.1 Extensive data were collected during pregnancy and the children were assessed at birth and at ages 1, 2, 3, 5, 8, 10, 14, 17, 18 and 20 years (Box 2). Questionnaire data, physical measurements and biological samples were collected looking at growth, cardiovascular, respiratory, immunological, musculoskeletal, nutritional, psychiatric, neurocognitive and ophthalmic health. The current dataset contains more than 85 000 measures on each participant, as well as 2.5 million genetic variants, with an exponential increase in publication output over time. Selected findings are summarised in Box 3.

Identification of a dietary pattern prospectively associated with bone mass in Australian young adults

BACKGROUND Relatively little is known about the relations between dietary patterns and bone health in adolescence, which is a period of substantial bone mass accrual. OBJECTIVES We derived dietary patterns that were hypothesized to be related to bone health on the basis of their protein, calcium, and potassium contents and investigated their prospective associations with bone mineral density (BMD), bone area, and bone mineral content (BMC) in a cohort of young adults. DESIGN The study included 1024 young adults born to mothers who were participating in the Western Australian Pregnancy Cohort (Raine) Study. Dietary information was obtained from food-frequency questionnaires at 14 and 17 y of age. Dietary patterns were characterized according to protein, calcium, and potassium intakes with the use of reduced-rank regression. BMD, bone area, and BMC were estimated with the use of a total body dual-energy X-ray absorptiometry scan at 20 y of age. RESULTS We identified 2 major dietary patterns. The first pattern was positively correlated with intakes of protein, calcium, and potassium and had high factor loadings for low-fat dairy products, whole grains, and vegetables. The second pattern was positively correlated with protein intake but negatively correlated with intakes of calcium and potassium and had high factor loadings for meat, poultry, fish, and eggs. After adjustment for anthropometric, sociodemographic, and lifestyle factors, a higher z score for the first pattern at 14 y of age was positively associated with BMD and BMC at 20 y of age [differences: 8.6 mg/cm(2) (95% CI: 3.0, 14.1 mg/cm(2)) and 21.9 g (95% CI: 6.5, 37.3 g), respectively, per SD increase in z score]. The z score for this same pattern at 17 y of age was not associated with bone outcomes at 20 y of age. The second pattern at 14 or 17 y of age was not associated with BMD, BMC, or bone area. CONCLUSIONS A dietary pattern characterized by high intakes of protein, calcium, and potassium in midadolescence was associated with higher BMD and BMC at 20 y of age. Our results indicate that high consumption of low-fat dairy products, whole grains, and vegetables in adolescence are associated with beneficial effects on bone development.

Genetic variants near PDGFRA are associated with corneal curvature in Australians

PURPOSE Irregularity in the corneal curvature (CC) is highly associated with various eye disorders such as keratoconus and myopia. The sample had limited power to find genomewide significant (5 × 10(-8)) hits but good power for replication. Thus, an attempt was made to test whether alleles in the FRAP1 and PDGFRA genes, recently found to be associated with CC in Asian populations, also influence CC in Australians of North European ancestry. Results of initial genomewide association studies (GWAS) for CC in Australians were also reported. METHODS Two population-based cohorts of 1788 Australian twins and their families, as well as 1013 individuals from a birth cohort from Western Australia, were genotyped using genomewide arrays. Following separate individual analysis and quality control, the results from each cohort underwent meta-analysis. RESULTS Meta-analysis revealed significant replication of association between rs2114039 and corneal curvature (P = 0.0045). The SNP rs2114039 near PDGFRA has been previously implicated in Asians. No SNP at the FRAP1 locus was found to be associated in our Australian samples. No SNP surpassed the genomewide significance threshold of 5 × 10(-8). The SNP with strongest association was rs2444240 (P = 3.658 × 10(-7)), which is 31 kb upstream to the TRIM29 gene. CONCLUSIONS A significant role of the PDGFRA gene in determining corneal curvature in the Australian population was confirmed in this study, also highlighting the putative association of the TRIM29 locus with CC.

Longitudinal Trajectories of Television Watching Across Childhood and Adolescence Predict Bone Mass at Age 20 Years in the Raine Study.

Sedentary behaviors such as watching television (TV) are associated with increased risk of cardiometabolic disease. The effects of TV watching during key developmental stages on skeletal health are uncertain. Hours of TV watching/week were recorded by parental or self‐report at 5, 8, 10, 14, 17, and 20 years of age in 1181 members (48% female) of a pregnancy cohort (the Raine Study). Participants were classified into one of three TV‐watching trajectories (using latent class analysis): low (consistently <14 h/week; 20.3%), high (consistently ≥14 h/week; 44.4%), or increasing (increased from <14 to ≥14 h/week during adolescence; 35.3%). General linear models tested associations between TV trajectory and bone mineral content (BMC) measured at age 20 years using dual‐energy X‐ray absorptiometry. After adjustment for height, body mass, physical activity, calcium intake, serum 25‐hydroxyvitamin D levels, alcohol, and smoking (all at age 20 years), males in the low TV‐watching trajectory had greater BMC for whole body (mean ± SEM, 3338 ± 59 g versus 3111 ± 31 g), legs (612 ± 12 g versus 569 ± 6 g), and arms (234 ± 5 g versus 214 ± 3 g) than those in the high TV‐watching trajectory. Differences between low and high TV‐watching trajectories were similar for females. BMC in the increasing TV‐watching trajectory also differed for both sexes, for example males in the increasing TV‐watching trajectory had greater whole‐body BMC (3252 ± 38 g) than males in the high TV‐watching trajectory (3111 ± 31 g) but less arm BMC (218 ± 3 g) than those in the low TV‐watching trajectory (234 ± 5 g). In this community‐based cohort, consistently high TV watching during childhood and adolescence independently predicted reduced peak bone mass at age 20 years. Because attainment of optimal peak bone mass is protective against osteoporosis in later life, reducing sedentary time in children may have long‐term skeletal benefits.

Raine eye health study: design, methodology and baseline prevalence of ophthalmic disease in a birth-cohort study of young adults.

ABSTRACT Purpose: The Raine Eye Health Study (REHS) was conceived to determine the prevalence of and risk factors for eye disease in young adults, and to characterize ocular biometric parameters in a young adult cohort. This article summarizes the rationale and study design of REHS and outlines the baseline prevalence of ophthalmic disease in this population. Methods: The Western Australian Pregnancy Cohort (Raine) Study originated as a randomized-controlled trial of 2900 women recruited from the state’s largest maternity hospital. Their offspring (N = 2868) have been followed at birth, ages 1, 2, 3, 5, 8, 10, 14, 17 and 20 years of age in a prospective cohort study. DNA has been collected from participants for genome-wide association studies. At the 20-year follow-up participants completed a comprehensive eye assessment that included visual acuity, orthoptic assessment and cycloplegic autorefraction, as well as several ocular biometric variables and multiple ophthalmic photographs of the anterior and posterior segments. Results: A total of 1344 participants (51.3% male) were assessed over a 24-month period. For the majority of examined participants (85.5%) both parents were Caucasian, 63.3% had completed school year 12 or equivalent, 5.5% had myopia (spherical equivalent ≤−3 diopters) and 15 participants (1.2%) had unilateral or bilateral pterygia. Keratoconus, cataract, keratitis and uveitis were rare. Conclusion: The REHS design and methodology allow comparison with other population-based studies of eye disease. The study established the prevalence of eye disorders in a large sample of predominantly Caucasian young Australian adults.

Parental pre-pregnancy BMI is a dominant early-life risk factor influencing BMI of offspring in adulthood.

We examined parental and early‐life variables in order to identify risk factors for adulthood overweight and obesity in offspring. We report here on the longitudinal prevalence of overweight and obesity in Australian children born between 1989 and 1991 and followed from birth to age 22.