Novel quantitative pigmentation phenotyping enhances genetic association, epistasis, and prediction of human eye colour.

Success of genetic association and the prediction of phenotypic traits from DNA are known to depend on the accuracy of phenotype characterization, amongst other parameters. To overcome limitations in the characterization of human iris pigmentation, we introduce a fully automated approach that specifies the areal proportions proposed to represent differing pigmentation types, such as pheomelanin, eumelanin, and non-pigmented areas within the iris. We demonstrate the utility of this approach using high-resolution digital eye imagery and genotype data from 12 selected SNPs from over 3000 European samples of seven populations that are part of the EUREYE study. In comparison to previous quantification approaches, (1) we achieved an overall improvement in eye colour phenotyping, which provides a better separation of manually defined eye colour categories. (2) Single nucleotide polymorphisms (SNPs) known to be involved in human eye colour variation showed stronger associations with our approach. (3) We found new and confirmed previously noted SNP-SNP interactions. (4) We increased SNP-based prediction accuracy of quantitative eye colour. Our findings exemplify that precise quantification using the perceived biological basis of pigmentation leads to enhanced genetic association and prediction of eye colour. We expect our approach to deliver new pigmentation genes when applied to genome-wide association testing.

Complement factor H genetic variant and age-related macular degeneration: effect size, modifiers and relationship to disease subtype.

BACKGROUND: Variation in the complement factor H gene (CFH) is associated with risk of late age-related macular degeneration (AMD). Previous studies have been case-control studies in populations of European ancestry with little differentiation in AMD subtype, and insufficient power to confirm or refute effect modification by smoking. METHODS: To precisely quantify the association of the single nucleotide polymorphism (SNP rs1061170, 'Y402H') with risk of AMD among studies with differing study designs, participant ancestry and AMD grade and to investigate effect modification by smoking, we report two unpublished genetic association studies (n = 2759) combined with data from 24 published studies (26 studies, 26,494 individuals, including 14,174 cases of AMD) of European ancestry, 10 of which provided individual-level data used to test gene-smoking interaction; and 16 published studies from non-European ancestry. RESULTS: In individuals of European ancestry, there was a significant association between Y402H and late-AMD with a per-allele odds ratio (OR) of 2.27 [95% confidence interval (CI) 2.10-2.45; P = 1.1 x 10(-161)]. There was no evidence of effect modification by smoking (P = 0.75). The frequency of Y402H varied by ancestral origin and the association with AMD in non-Europeans was less clear, limited by paucity of studies. CONCLUSION: The Y402H variant confers a 2-fold higher risk of late-AMD per copy in individuals of European descent. This was stable to stratification by study design and AMD classification and not modified by smoking. The lack of association in non-Europeans requires further verification. These findings are of direct relevance for disease prediction. New research is needed to ascertain if differences in circulating levels, expression or activity of factor H protein explain the genetic association.

DNA-based eye colour prediction across Europe with the IrisPlex system.

The ability to predict Externally Visible Characteristics (EVCs) from DNA, also referred to as Forensic DNA Phenotyping (FDP), is an exciting new chapter in forensic genetics holding great promise for tracing unknown individuals who are unidentifiable via standard forensic short tandem repeat (STR) profiling. For the purpose of DNA-based eye colour prediction, we previously developed the IrisPlex system consisting of a multiplex genotyping assay and a prediction model based on genotype and phenotype data from 3804 Dutch Europeans. Recently, we performed a forensic developmental validation study of the highly sensitive IrisPlex assay, which currently represents the only validated tool available for DNA-based prediction of eye colour in forensic applications. In the present study, we validate the IrisPlex prediction model by extending our initially described model towards genotype and phenotype data from multiple European populations. We performed IrisPlex analysis on 3840 individuals from seven sites across Europe as part of the European Eye (EUREYE) study for which DNA and high-resolution eye images were available. The accuracy rate of correctly predicting an individual's eye colour as being blue or brown, above the empirically established probability threshold of 0.7, was on average 94% across all seven European populations, ranging from 91% to 98%, despite the large variation in eye colour frequencies between the populations. The overall prediction accuracies expressed by the area under the receiver characteristic operating curves (AUC) were 0.96 for blue and 0.96 for brown eyes, which is considerably higher than those established before. The IrisPlex prediction model parameters generated from this multi-population European dataset, and thus its prediction capabilities, were highly comparable to those previously established. Therefore, the increased information regarding eye colour phenotype and genotype distributions across Europe, and the system's ability to provide eye colour predictions across Europe accurately, both highlight additional evidence for the utility of the IrisPlex system in forensic casework.

Evidence of association of APOE with age-related macular degeneration: a pooled analysis of 15 studies.

Age-related macular degeneration (AMD) is the most common cause of incurable visual impairment in high-income countries. Previous studies report inconsistent associations between AMD and apolipoprotein E (APOE), a lipid transport protein involved in low-density cholesterol modulation. Potential interaction between APOE and sex, and smoking status has been reported. We present a pooled analysis (n = 21,160) demonstrating associations between late AMD and APOε4 (odds ratio [OR] = 0.72 per haplotype; confidence interval [CI]: 0.65-0.74; P = 4.41×10(-11) ) and APOε2 (OR = 1.83 for homozygote carriers; CI: 1.04-3.23; P = 0.04), following adjustment for age group and sex within each study and smoking status. No evidence of interaction between APOE and sex or smoking was found. Ever smokers had significant increased risk relative to never smokers for both neovascular (OR = 1.54; CI: 1.38-1.72; P = 2.8×10(-15) ) and atrophic (OR = 1.38; CI: 1.18-1.61; P = 3.37×10(-5) ) AMD but not early AMD (OR = 0.94; CI: 0.86-1.03; P = 0.16), implicating smoking as a major contributing factor to disease progression from early signs to the visually disabling late forms. Extended haplotype analysis incorporating rs405509 did not identify additional risks beyond ε2 and ε4 haplotypes. Our expanded analysis substantially improves our understanding of the association between the APOE locus and AMD. It further provides evidence supporting the role of cholesterol modulation, and low-density cholesterol specifically, in AMD disease etiology.

Variations in apolipoprotein E frequency with age in a pooled analysis of a large group of older people.

Variation in the apolipoprotein E gene (APOE) has been reported to be associated with longevity in humans. The authors assessed the allelic distribution of APOE isoforms ε2, ε3, and ε4 among 10,623 participants from 15 case-control and cohort studies of age-related macular degeneration (AMD) in populations of European ancestry (study dates ranged from 1990 to 2009). The authors included only the 10,623 control subjects from these studies who were classified as having no evidence of AMD, since variation within the APOE gene has previously been associated with AMD. In an analysis stratified by study center, gender, and smoking status, there was a decreasing frequency of the APOE ε4 isoform with increasing age (χ(2) for trend = 14.9 (1 df); P = 0.0001), with a concomitant increase in the ε3 isoform (χ(2) for trend = 11.3 (1 df); P = 0.001). The association with age was strongest in ε4 homozygotes; the frequency of ε4 homozygosity decreased from 2.7% for participants aged 60 years or less to 0.8% for those over age 85 years, while the proportion of participants with the ε3/ε4 genotype decreased from 26.8% to 17.5% across the same age range. Gender had no significant effect on the isoform frequencies. This study provides strong support for an association of the APOE gene with human longevity.

Visual impairment and quality of life in the older European population, the EUREYE study.

PURPOSE: To determine the prevalence of visual impairment (VI) in populations 65 year or older from six European countries and describe the association with vision-related quality of life. VI was defined according to WHO as best corrected visual acuity <6/18/log MAR >0,48 (World Health Organization (1992): International Statistical Classification of Diseases and Related Health Problems, 10th revised ed. Vol 1. Geneva). METHODS: 4166 participants in The European Eye study, 65 years and older selected randomly from the general census in the participating centres, were interviewed for vision-related quality of life and underwent an eye exam including distance visual acuity, refraction and fundus photography. RESULTS: The prevalence of VI rose with increasing age and more so in women. There was a pattern of a higher prevalence of VI in the Mediterranean countries compared to Northern European countries with the exception of Tallinn (Estonia) which had higher VI prevalence rates than the other north European centres. The prevalence of low vision was 3% or less in all centres. Blindness prevalence varied from 2% to less than half a per cent. Vision-related quality of life was strongly associated with visual acuity and the presence of bilateral age-related macular degeneration. CONCLUSION: The prevalence of visual impairment in the examined ageing European populations shows a definite increasing trend from north to south.

Implantation of scleral-fixated posterior chamber intraocular lenses in adults.

PURPOSE: To report the results of transscleral fixation of posterior chamber intraocular lenses in adults. METHODS: We carried out a retrospective analysis of 91 eyes of 81 patients who underwent implantation of posterior chamber lenses with transscleral sutures between 1997 and 2006. The mean age of the patients was 62 years (range 19-94 years). Sixty-eight eyes (74.7%) were aphakic at the time of surgery. In 10 patients (11.0%) an intracapsular cataract extraction and in six patients (6.6%) a pars plana lensectomy was performed prior to the fixation of the posterior chamber intraocular lens. In seven eyes (7.7%) a previously implanted IOL was removed. The mean follow-up was 36 months (range 6-116 months). RESULTS: The mean preoperative best corrected visual acuity (BCVA) was 0.37 (range counting fingers to 1.0), which improved to 0.5 (range light perception to 1.0) postoperatively. At the end of follow-up, BCVA was unchanged or improved in 81 eyes (89.0%), reduced by 2 Snellen lines in four eyes (4.4%), and between finger counting and light perception in four eyes (4.4%). The most serious complication was suprachoroidal haemorrhage, which occurred in two eyes. Retinal detachment occurred in three eyes, all of which successfully reattached after surgery. Suture erosion or spontaneous dislocation caused by suture degradation or breakage was not seen. CONCLUSIONS: Secondary implantation of posterior chamber intraocular lenses with transscleral fixation is a reasonably safe procedure in adults, with relatively few serious complications. Even in patients with longterm follow-up, suture breakage was not seen.

Refraction, axial length and age-related maculopathy.

PURPOSE: To study the relationship between age-related maculopathy (ARM)/age-related macular degeneration (AMD) and phakic refraction and between ARM/AMD and axial length. METHODS: The study was a point prevalence study that included 663 randomly selected persons aged over 65 years. We measured axial length and refraction. Fundus images were graded for ARM according to a modified Wisconsin Age-related Maculopathy Grading System standard. Data from both eyes were available from most participants. We analysed the results for both individual eyes and pairs. RESULTS: The mean axial length was 23.22 mm for right eyes and 23.21 mm for left eyes. Women had a 0.57-mm shorter mean axial length than men. The mean refraction was +1.0 dioptres (D) for right eyes and +0.9 D for left eyes. At 70 years of age women were more hypermetropic than men by 0.66 D. There was no significant difference in refraction or axial length among the groups with different ARM stages. CONCLUSION: We found no statistically significant relationship between axial length/refraction and AMD/ARM. There was a statistically significant sex difference in axial length and refraction, where women had shorter axial lengths and were more hypermetropic than men.

Refraction, axial length and age-related maculopathy.

PURPOSE: To study the relationship between age-related maculopathy (ARM)/age-related macular degeneration (AMD) and phakic refraction and between ARM/AMD and axial length. METHODS: The study was a point prevalence study that included 663 randomly selected persons aged over 65 years. We measured axial length and refraction. Fundus images were graded for ARM according to a modified Wisconsin Age-related Maculopathy Grading System standard. Data from both eyes were available from most participants. We analysed the results for both individual eyes and pairs. RESULTS: The mean axial length was 23.22 mm for right eyes and 23.21 mm for left eyes. Women had a 0.57-mm shorter mean axial length than men. The mean refraction was +1.0 dioptres (D) for right eyes and +0.9 D for left eyes. At 70 years of age women were more hypermetropic than men by 0.66 D. There was no significant difference in refraction or axial length among the groups with different ARM stages. CONCLUSION: We found no statistically significant relationship between axial length/refraction and AMD/ARM. There was a statistically significant sex difference in axial length and refraction, where women had shorter axial lengths and were more hypermetropic than men.

[Optic neuritis--diagnosis, treatment and follow up]. / Optikusnevritt--diagnose, behandling og oppfølging.

A national group of neurologists and ophthalmologists have evaluated guidelines and recommendations for diagnosis, treatment and follow up of optic neuritis based on clinical experience and a review of relevant literature. Optic neuritis is a common, well characterised condition that appears as an isolated syndrome or as a manifestation of multiple sclerosis. Several other diseases must be considered for a differential diagnosis. Corticosteroid treatment of optic neuritis has been investigated in a number of trials, which show that corticosteroid treatment speeds up the recovery of vision without affecting the final visual outcome. The diagnostic procedure and the treatment options have changed over the last few years. Some aspects of investigation, treatment and follow up are still controversial.

[Age-related macular degeneration]. / Aldersrelatert maculadegenerasjon.

Age-related macula degeneration is the most common cause of visual disability in the industrialised world. The disease can be diagnosed as a maculopathy in 10-20% of the population over the age of 65. About 25% of these will have degeneration with reduced vision. Today, only a small proportion of patients with the aggressive wet form of the disease can be offered any therapy in the form of laser or photodynamic laser treatment. Worldwide epidemiological investigations designed to define contributing factors have so far not been conclusive, but the use of antioxidants and trace metals may be a useful prophylactic measure. Research into antiangiogenic therapy may also result in useful tools for ophthalmologists caring for this group of patients.