Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus

: Identifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and identify alleles under present-day selection. Using data in 785,604 individuals of European ancestry, we identified 43 genomic loci associated with either number of children ever born (NEB) or childlessness. These loci span diverse aspects of reproductive biology, including puberty timing, age at first birth, sex hormone regulation, endometriosis and age at menopause. Missense variants in ARHGAP27 were associated with higher NEB but shorter reproductive lifespan, suggesting a trade-off at this locus between reproductive ageing and intensity. Other genes implicated by coding variants include PIK3IP1, ZFP82 and LRP4, and our results suggest a new role for the melanocortin 1 receptor (MC1R) in reproductive biology. As NEB is one component of evolutionary fitness, our identified associations indicate loci under present-day natural selection. Integration with data from historical selection scans highlighted an allele in the FADS1/2 gene locus that has been under selection for thousands of years and remains so today. Collectively, our findings demonstrate that a broad range of biological mechanisms contribute to reproductive success

Genome-wide analysis identifies 12 loci influencing human reproductive behavior.

The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits

Genetic variants linked to myopic macular degeneration in persons with high myopia: CREAM Consortium

Purpose To evaluate the roles of known myopia-associated genetic variants for development of myopic macular degeneration (MMD) in individuals with high myopia (HM), using case-control studies from the Consortium of Refractive Error and Myopia (CREAM). Methods A candidate gene approach tested 50 myopia-associated loci for association with HM and MMD, using meta-analyses of case-control studies comprising subjects of European and Asian ancestry aged 30 to 80 years from 10 studies. Fifty loci with the strongest associations with myopia were chosen from a previous published GWAS study. Highly myopic (spherical equivalent [SE] -5.0 diopters [D]) cases with MMD (N = 348), and two sets of controls were enrolled: (1) the first set included 16,275 emmetropes (SE -0.5 D); and (2) second set included 898 highly myopic subjects (SE -5.0 D) without MMD. MMD was classified based on the International photographic classification for pathologic myopia (META-PM). Results In the first analysis, comprising highly myopic cases with MMD (N = 348) versus emmetropic controls without MMD (N = 16,275), two SNPs were significantly associated with high myopia in adults with HM and MMD: (1) rs10824518 (P = 6.20E-07) in KCNMA1, which is highly expressed in human retinal and scleral tissues; and (2) rs524952 (P = 2.32E-16) near GJD2. In the second analysis, comprising highly myopic cases with MMD (N = 348) versus highly myopic controls without MMD (N = 898), none of the SNPs studied reached Bonferroni-corrected significance. Conclusions Of the 50 myopia-associated loci, we did not find any variant specifically associated with MMD, but the KCNMA1 and GJD2 loci were significantly associated with HM in highly myopic subjects with MMD, compared to emmetropes

The impact of modest prematurity on visual function at age 6 years - Findings from a population-based study

Objective: To determine the effects of modest low birth weight and prematurity on visual function of children predominantly aged 6 years. Methods: Children with a birth weight of 1500 to 2499 g were considered exposed to a modest low birth weight (n = 82) and were compared with children with a birth weight of 2500 g or more (n = 1386). Exposure to modest prematurity, 32 to 36 weeks' gestation (n = 115), was similarly analyzed and compared with birth at term, 37 or more weeks' gestation (n = 1446). Logarithm of the minimum angle of resolution visual acuity was measured in both eyes. Cycloplegic autorefraction (cyclopentolate), cover testing, and dilated fundus examinations were performed. Results: A modest low birth weight increased the risk of amblyopia (relative risk [RR], 5.1; 95% confidence interval [CI], 2.2-12.0), strabismus (RR, 3.7; 95% CI, 1.5-9.1), and anisometropia (RR, 3.7; 95% CI, 1.2-11.1), together with an increased risk of uncorrected visual acuity in the lowest quartile (RR, 1.7; 95% CI, 1.3-2.2). Modest prematurity increased the risk of amblyopia (RR, 4.5; 95% CI, 1.9-10.6), strabismus (RR, 2.6; 95% CI, 1.1-6.0), and uncorrected visual acuity in the lowest quartile (RR, 1.5; 95% CI, 1.1-2.0). Conclusion: Modest degrees of low birth weight and prematurity may be associated with increased ophthalmic morbidity at age 6 years

Use of visual acuity to screen for significant refractive errors in adolescents

Objective: To detect significant refractive error in a population-based random cluster sample of 12-year-old schoolchildren by using sensitivity and specificity of uncorrected visual acuity (VA). Methods: The Sydney Myopia Study randomly selected 21 secondary schools stratified by socioeconomic status. All year 7 students (mean age, 12.7 years) were invited to participate. We tested VA monocularly, unaided at 2.44 m, using a retroilluminated logMAR chart. Cycloplegic autorefraction (induced with instillation of cyclopentolate hydrochloride, 1%) was used to define clinically significant refractive error as a spherical equivalent of -1.00 diopters (D) or less for myopia; at least + 2.00 D for hyperopia; and -1.00 D or less cylinder power for astigmatism. Results: Data for both eyes were pooled for a total of 4497 observations. The sensitivity and specificity for all clinically significant refractive errors at the best VA cutoff level of 53 letters (6/6-2) were 72.2% and 93.3%, respectively. Myopia had the highest sensitivity and specificity of any of the refractive errors for detection using VA (97.8% and 97.1%, respectively, for a 45-letter VA cutoff [6/9.5]). The best VA cutoffs for hyperopia and astigmatism were 57 (6/ 6+2) and 55 (6/6) letters, respectively, with sensitivities of 69.2% and 77.4%, respectively, and specificities of 58.1% and 75.4%, respectively. Conclusions: In this adolescent group, a VA cutoff of 6/9.5 or less detects myopic refractive error reliably. However, there is no reliable VA cutoff for clinically significant hyperopia or astigmatism. Improved VA screening methods are required to improve detection of these conditions. Even so, with the methods described herein, the prevalence of uncorrected VA may provide a reasonably accurate estimate of the prevalence of myopia

Astigmatism in 12 year old Australian children: Comparisons with a 6 year old population

PURPOSE. To study the distributions of refractive (RA), corneal (CA), and internal astigmatism (IA) in 12-year-old Australian children and to explore differences from previous findings in 6-year-old children. METHODS. Eligible year 7 students (2353/3144 [75.3%], median age, 12 years) from a random cluster sample of 21 high schools in Sydney, Australia, were examined by keratometry, cycloplegic autorefraction, and review of questionnaire data. RESULTS. Prevalence rates of RA, CA, and IA ≥1.0 D in right eyes were 6.7% (95% confidence interval [CI], 5.0-8.4), 26.6% (CI, 22.1-31.1), and 26.5% (CI, 22.9-30.0), respectively. RA was predominantly with-the-rule (WTR; 40.4%, CI, 32.6 to 48.2) and against-the-rule (ATR; 43.6%, CI, 35.7-51.5), CA was WTR (88.8%, CI, 86.3-91.3), and IA was ATR (90.2%, CI, 87.8-92.6). The girls had significantly greater CA and IA prevalence, with greater ATR astigmatism and lower oblique IA than did the boys. The European white-Australian children had lower CA prevalence than did the East Asian-Australian children and higher IA prevalence than did the South Asian-Australian children. Ethnic differences in RA prevalence were not significant, when adjusted for confounders. RA was more frequently ATR in European white than in other ethnic groups. Compensation between CA and IA reduced the magnitude of RA. Comparison with the data on 6-year-old children revealed minimal differences for all astigmatic components. CONCLUSIONS. There was a relatively low prevalence of RA, due to compensation between CA and IA. The minimal differences in all components of astigmatism between the two age cohorts suggest that astigmatism is stable between ages 6 and 12 years, although this conclusion needs to be confirmed in longitudinal studies

Astigmatism and its components in 6-year-old children

PURPOSE. The purpose of the present study was to report the prevalence of refractive (RA), corneal (CA), and internal astigmatism (IA) in a population of 6-year-old children; examine their variation with gender, ethnicity, and refraction; and examine th

Astigmatism and its components in 6-year-old children

Purpose: The purpose of the present study was to report the prevalence of refractive (RA), corneal (CA), and internal astigmatism (IA) in a population of 6-year-old children; examine their variation with gender, ethnicity, and refraction; and examine the effects of gender, ethnicity, and spherical equivalent refraction on the relationship between CA and RA in this population. Methods: The Sydney Myopia Study is a population-based survey of refraction and eye health in 6-year-old children. A random cluster design was used to recruit children from schools across Sydney, Australia, during 2003 to 2004. Data collection used a detailed questionnaire and comprehensive eye examination. Keratometric and cycloplegic autorefraction data from right eyes were analyzed. Results: Of 2238 eligible children, 1765 (78.9%; 50.7% boys) had parental consent to participate. Overall prevalence of RA (1.0 diopter [D]) was 4.8% (95% confidence interval [CI] 3.8%–6.1%), CA (1.0 D) 27.7% (CI 23.8%–32.3%), and IA (1.0 D) 21.1% (CI 19.0%–23.5%). The RA axis was fairly evenly distributed, with predominance of oblique axis (39.1%; CI 35.9%–42.6%). CA axis was mainly with the rule (75.1%; CI 72.6%–77.8%), while IA axis was mainly against the rule (76.7%; CI 74.2%–79.3%). After adjustment for multiple variables, girls had significant, marginally greater mean CA and IA than boys. East Asian and South Asian children had significantly greater prevalence and mean RA and CA than European Caucasian children. There were no significant ethnic differences of mean IA. Compared to reference (spherical equivalent [SEq] 1.01–1.50 D), mean RA and CA increased significantly with more hyperopic and more myopic refractions. Mean IA was significantly greater only for hyperopic refractions (SEq > 2.00 D). Conclusions: The prevalence of astigmatism found in this population of 6-year-old children was relatively low, and showed significant variation with ethnicity. The data suggest that emmetropization for RA occurs by a compensatory process between CA and IA.10 page(s

Outdoor activity reduces the prevalence of myopia in children

Objective: To assess the relationship of near, midworking distance, and outdoor activities with prevalence of myopia in school-aged children. Design: Cross-sectional study of 2 age samples from 51 Sydney schools, selected using a random cluster design. Participants: One thousand seven hundred sixty-five 6-year-olds (year 1) and 2367 12-year-olds (year 7) participated in the Sydney Myopia Study from 2003 to 2005. Methods: Children had a comprehensive eye examination, including cycloplegic refraction. Parents and children completed detailed questionnaires on activity. Main Outcome Measures: Myopia prevalence and mean spherical equivalent (SE) in relation to patterns of near, midworking distance, and outdoor activities. Myopia was defined as SE refraction ≤-0.5 diopters (D). Results: Higher levels of outdoor activity (sport and leisure activities) were associated with more hyperopic refractions and lower myopia prevalence in the 12-year-old students. Students who combined high levels of near work with low levels of outdoor activity had the least hyperopic mean refraction (+0.27 D; 95% confidence interval [CI],0.02-0.52), whereas students who combined low levels of near work with high levels of outdoor activity had the most hyperopic mean refraction (+0.56 D; 95% CI,0.38-0.75). Significant protective associations with increased outdoor activity were seen for the lowest (P=0.04) and middle (P=0.02) tertiles of near-work activity. The lowest odds ratios for myopia, after adjusting for confounders, were found in groups reporting the highest levels of outdoor activity. There were no associations between indoor sport and myopia. No consistent associations between refraction and measures of activity were seen in the 6-year-old sample. Conclusion: Higher levels of total time spent outdoors, rather than sport per se, were associated with less myopia and a more hyperopic mean refraction, after adjusting for near work, parental myopia, and ethnicity

Prevalence of Heterophoria and Associations with Refractive Error, Heterotropia and Ethnicity in Australian School Children

Aims: To establish the prevalence of heterophoria and its association with refractive error and ethnicity in a population-based study of Australian schoolchildren. Methods: The Sydney Myopia Study is a stratified, random cluster (school-based) sample of 4093 students (examined: 2003e2005). Two samples aged 6 (n=1692) and 12 years (n=2289) without heterotropia were included. Prevalent heterophoria was assessed using cover un-cover and prism bar alternate cover testing at 33 cm and 6 m distance fixation. Cycloplegic autorefraction (1% cyclopentolate) was performed. Significant refractive error was defined as ≤-0.50SE and ≥+2.00SE. Results: Exophoria was highly prevalent at near fixation (age 6: 58.3%, age 12: 52.2%). Orthophoria predominated at distance fixation (age 6: 85.4%, age 12: 90.9%). Hyperopia was associated with esophoria at near (age 6: OR 1.7, 95% CI 1.1 to 2.8, age 12: OR 2.9, CI 1.1 to 2.8) and distance fixation (age 6: OR 9.7, CI 3.5 to 26, age 12: 9.6 OR, CI 4.2 to 22). Myopia was associated with exophoria at near (OR 2.1, CI 1.5 to 2.7) and distance fixation (OR 3.1, CI 2.1 to 4.4) for 12-year-old children only. Exophoria was more frequent in children of East Asian than European Caucasian origins, even after adjusting for refraction; at near (age 6: OR 1.4, CI 1.0 to 2.0, age 12: OR 1.4, CI 1.0 to 1.9) and distance (age 12: OR 1.7, CI 1.1 to 2.7). Conclusion: Contrary to other studies, exophoria, not orthophoria, was predominant for near. Exophoria was more prevalent in children of East Asian origin. Longitudinal studies are needed to establish if incident heterotropia is preceded by heterophoria