Genetic epidemiologic studies on age-related maculopathy: a population-based approach

The western world is aging rapidly. In the Netherlands, the current mean life expectancy for men and women is 74.6 and 80.4 years, respectively, and those over 65 years of age comprise 13.6% of the total population. This proportion of elderly is expected to increase considerably within the coming years, and this will lead to higher frequencies of diseases. Age-related maculopathy (ARM) is one of those frequent geriatric diseases. It is an eye disease ultimately leading to blindness. The prevalence of the clinical end stages of this disorder range from 1 % in those aged 60 years of age to 10% in those aged 85 years and older. At least 60000 Dutch subjects are severely affected by these end stages, also called age-related macular degeneration (AMD). AMD has a great impact on visual function and the performance of daily tasks, in particular because there are still no means for long term restoration of vision. During the last decade there has been steadily increasing research activity investigating the disease etiology. It became better known that the pathogenesis was complex with a variety of risk factors involved. Family reports and twin studies pointed to a genetic background, and epidemiologic studies suggested environmental influences from vascular and dietmy factors, sunlight and smoking. However, findings were not unequivocal, and the evidence on most of these relations was insufficient and inconclusive. This called for more extensive research into the causes of ARM. This thesis aimed to answer the following questions: Pal'l I: What is the current genetic epidemiologic knowledge on ARM? Pari Jl: What is the incidence of AMD, what is the natural course of the disease, and what is the relation with visual impairment

Selecting likely causal risk factors from high-throughput experiments using multivariable Mendelian randomization

Modern high-throughput experiments provide a rich resource to investigate causal determinants of disease risk. Mendelian randomization (MR) is the use of genetic variants as instrumental variables to infer the causal effect of a specific risk factor on an outcome. Multivariable MR is an extension of the standard MR framework to consider multiple potential risk factors in a single model. However, current implementations of multivariable MR use standard linear regression and hence perform poorly with many risk factors. Here, we propose a two-sample multivariable MR approach based on Bayesian model averaging (MR-BMA) that scales to high-throughput experiments. In a realistic simulation study, we show that MR-BMA can detect true causal risk factors even when the candidate risk factors are highly correlated. We illustrate MR-BMA by analysing publicly-available summarized data on metabolites to prioritise likely causal biomarkers for age-related macular degeneration

Patient-reported utilities in bilateral visual impairment from amblyopia and age-related macular degeneration

Background: Utility of visual impairment caused by amblyopia is important for the cost-effectiveness of screening for amblyopia (lazy eye, prevalence 3-3.5 %). We previously measured decrease of utility in 35-year-old persons with unilateral persistent amblyopia. The current observational case-control study aimed to measure loss of utility in patients with amblyopia with recent decrease of vision in their better eye. As these patients are rare, the sample was supplemented by patients with bilateral age-related macular degeneration with similar decrease of vision. Methods: From our out-patient department, two groups of patients with recent deterioration to bilateral visual acuity less than Snellen 0.5 (bilateral visual impairment, BVI) were recruited, with either persistent amblyopia and age-related macular degeneration (AMB + AMD), or with bilateral age-related macular degeneration (BAMD). To measure utility, the time trade-off method and the standard gamble method were applied through interviews. Correlations were sought between utility values and visual acuity, age and Visual Function Questionnaire-25 scores. Results: Seventeen AMB + AMD patients (mean age 72.9 years), and 63 BAMD patients (mean age 79.6 years) were included in the study. Among AMB + AMD, 80 % were willing to trade lifetime in exchange for cure. The overall mean time trade-off utility was 0.925. Among BAMD, 75 % were willing to trade, utility was 0.917. Among AMB + AMD, 38 % accepted risk of death in exchange for cure, overall mean standard gamble utility was 0.999. Among BAMD, 49 % accepted risk of death, utility was 0.998. Utility was not related to visual acuity but it was to age (p = 0.02). Conclusion: Elderly patients with BVI, caused by persistent amblyopia and age-related macular degeneration (AMD) or by bilateral AMD, had an approximately 8 % loss of TTO utility. Notably, the 8 % loss in elderly with BVI differs little from the 3.7 % loss we found previously in 35-year-old persons with unilateral amblyopia with good vision in the other eye. The moderate impact of BVI in senescence could be explained by adaptation, comorbidity, avoidance of risk and a changed percept of cure

Myopia progression from wearing first glasses to adult age: The DREAM Study

Purpose: Data on myopia progression during its entire course are scarce. The aim of this study is to investigate myopia progression in Europeans as a function of age and degree of myopia from first prescription to final refractive error. Methods: The Drentse Refractive Error and Myopia Study assessed data from a branch of opticians in the Netherlands from 1985 onwards in a retrospective study. First pair of glasses prescribed was defined as a spherical equivalent of refraction (SER) ≤-0.5 D to ≥-3.0 D. Subjects with prescriptions at an interval of at least 1 year were included in the analysis. Results: A total of 2555 persons (57.3% female) met the inclusion criteria. Those with first prescription before the age of 10 years showed the strongest progression (-0.50 D; IQR: -0.75 to -0.19) and a significantly (p<0.001) more negative median final SER (-4.48 D; IQR: -5.37 to -3.42). All children who developed SER ≤-3 D at 10 years were highly myopic (SER ≤-6D) as adults, children who had SER between -1.5 D and -3 D at 10 years had 46.0% risk of high myopia, and children with SER between -0.5 D and -1.5 D had 32.6% risk of high myopia. Myopia progression diminished with age; all refractive categories stabilised after age 15 years except for SER ≤-5 D who progressed up to -0.25 D annually until age 21 years. Conclusion: Our trajectories of the natural course of myopia progression may serve as a guide for myopia management in European children. SER at 10 years is an important prognostic indicator and will help determine treatment intensity

The impact of computer use on myopia development in childhood

Environmental factors are important in the development of myopia. There is still limited evidence as to whether computer use is a risk factor. The aim of this study is to investigate the association between computer use and myopia in the context of other near work activities. Within the birth cohort study Generation R, we studied 5074 children born in Rotterdam between 2002 and 2006. Refractive error and axial length was measured at ages 6 and 9. Information on computer use and outdoor exposure was obtained at age 3, 6 and 9 years using a questionnaire, and reading time and reading distance were assessed at age 9 years. Myopia prevalence (spherical equivalent ≤–0.5 dioptre) was 11.5% at 9 years. Mean computer use was associated with myopia at age 9 (OR = 1.005, 95% CI = 1.001–1.009), as was reading time and reading distance (OR = 1.031; 95% CI = 1.007–1.055 (5–10 h/wk); OR = 1.113; 95% CI = 1.073–1.155 (>10 h/wk) and OR = 1.072; 95% CI = 1.048–1.097 respectively). The combined effect of near work (computer use, reading time and reading distance) showed an increased odds ratio for myopia at age 9 (OR = 1.072; 95% CI = 1.047–1.098), while outdoor exposure showed a decreased odds ratio (OR = 0.996; 95% CI = 0.994–0.999) and the interaction term was significant (P = 0.036). From our results, we can conclude that within our sample of children, increased computer use is associated with myopia development. The effect of combined near work was decreased by outdoor exposure. The risks of digital devices on myopia and the protection by outdoor exposure should become widely known. Public campaigns are warranted

Incidence of glaucomatous visual field loss after two decades of follow-up: the Rotterdam Study

To determine the incidence of glaucomatous visual field loss (GVFL) two decades after the start of the Rotterdam Study, and to compare known risk factors for open-angle glaucoma (OAG) between different clinical manifestations of OAG. Of 6806 participants aged 55 years and older from the population-based Rotterdam Study, 3939 underwent visual field testing at baseline and at least one follow-up round. The ophthalmic examinations included optic disc assessment and measurements of intraocular pressure (IOP), refractive error, diastolic blood pressure (DBP), and height and weight. The incidence rate of GVFL was calculated. Associations with the risk factors age, gender, baseline IOP, family history, myopia, DBP, and body-mass index [BMI] were assessed using Cox regression, with different clinical manifestations of OAG as outcome measure (glaucomatous optic neuropathy (GON), GVFL, GVFL and GON, GVFL without GON, and GON without GVFL). Median follow-up was 11.1 (IQR 6.8–17.2; range 5.0–20.3) years. The incidence rate of GVFL was 2.9 (95% confidence interval 2.4–3.4) per 1000 person years (140 cas

Growth in foetal life, infancy, and early childhood and the association with ocular biometry

Purpose: Ocular biometry varies within groups of emmetropic, hyperopic or myopic children. The aim of this study was to quantify the effect of foetal and infant growth on ocular biometry in early childhood, to determine the most important period for this association, and to examine genetic overlap with height and birth weight. Methods: 5931 children (50.1% girls) from a population-based prospective birth cohort study underwent intra-uterine and infant growth measurements at second and third trimester, and from birth to 72 months. An ophthalmic examination including axial length (mm) and corneal radius of curvature (mm) was performed at 6 years of age. The associations between prenatal and postnatal growth variables and axial length and corneal radius of curvature were assessed with conditional linear regression analyses. Weighted genetic risk scores for birth weight and height were calculated and causality was tested with Mendelian randomisation. Results: Weight and length from mid-pregnancy to 2 years of age were most important prognostic factors for axial length and corneal radius of curvature at age 4.9–9 years (mean 6.2 years S.D. 0.5). For height (Standard deviation score), the association with axial length and corneal radius of curvature was highest for the measurement at 12 months (β 0.171 p < 0.001 and 0.070 p < 0.001). The genetic height and birth weight risk scores were both significantly associated with ocular biometry. Conclusions: Larger neonates had longer axial length and greater corneal radius of curvature. Growth during pregnancy and 2 years postnatally is the most important period underlying this association and may be partly genetically determined by genes associated with height

The retinal microcirculation in migraine: The Rotterdam Study

Background: To explore the role of microvascular pathology in migraine, we investigated the association between migraine and retinal microvascular damage. Methods: We included 3270 participants (age ≥ 45 years, 63% women) from the population-based Rotterdam Study (2006–2009). Participants with migraine were identified using a validated questionnaire based on ICHD-II criteria (n = 562). Retinopathy signs were graded on fundus photographs. Retinal arteriolar and venular caliber were measured by semi-automatic assessment of fundus photographs. Associations of migraine with retinopathy and retinal microvascular calibers were examined using logistic and linear regression models, respectively, adjusting for age, sex, and cardiovascular risk factors. Results: Migraine was not associated with the presence of retinopathy (odds ratio (OR): 1.09, 95% confidence interval (CI) 0.62; 1.92). In the fully adjusted model, adjusting for the companion vessel, persons with migraine did not differ in retina

Thyroid function and age-related macular degeneration: A prospective population-based cohort study - the Rotterdam Study

Background: In animal models, lack of thyroid hormone is associated with cone photoreceptor preservation, while administration of high doses of active thyroid hormone leads to deterioration. The association between thyroid function and age-related macular degeneration (AMD) has not been investigated in the general population. Methods: Participants of age ≥55 years from the Rotterdam Study with thyroid-stimulating hormone (TSH) and/or free thyroxine (FT4) measurements and AMD assessment were included. We conducted age- and sex-adjusted Cox proportional hazards models to explore the association of TSH or FT4 with AMD, in the full range and in those with TSH (0.4-4.0 mIU/L) and/or FT4 in normal range (11-25 pmol/L). Cox proportional hazards models were performed for the association of TSH or FT4 with retinal pigment alterations (RPA), as an early marker of retinal changes. Multivariable models additionally included cardiovascular risk factors and thyroid peroxidase antibodies positivity. We also performed stratification by age and sex. A bidirectional look-up in genome-wide association study (GWAS) data for thyroid parameters and AMD was performed. Single nucleotide polymorphisms (SNPs) that are significantly associated with both phenotypes were identified. Results: We included 5,573 participants with a median follow-up of 6.9 years (interquartile range 4.4-10.8 years). During follow-up 805 people developed AMD. TSH levels were not associated with increased risk of AMD. Within normal range of FT4, participants in the highest FT4 quintile had a 1.34-fold increased risk of developing AMD, compared to individuals in the middle group (95% confidence interval [CI] 1.07-1.66). Higher FT4 values in the full range were associated with a higher risk of AMD (hazard ratio 1.04, CI, 1.01-1.06 per 1 pmol/L increase). Higher FT4 levels were similarly associated with a higher risk of RPA. Restricting analyses to euthyroid individuals, additional multivariable models, and stratification did not change estimates. We found a SNP (rs943080) in the VEGF-A gene, associated with AMD, to be significant in the TSH GWAS (P = 1.2 x 10-4). Adding this SNP to multivariable models did not change estimates. Conclusions: Higher FT4 values are associated with increased risk of AMD - even in euthyroid individuals - and increased risk of RPA. Our data suggest an important role of thyroid hormone in pathways leading to AMD