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    ABSTRACT: IMPORTANCE To date, relatively few genes responsible for a fraction of heritability have been identified by means of large genetic association studies of refractive error. OBJECTIVE To explore the genetic mechanisms that lead to refractive error in the general population. DESIGN, SETTING, AND PARTICIPANTS Genome-wide association studies were carried out in 2 British population-based independent cohorts (N = 5928 participants) to identify genes moderately associated with refractive error. MAIN OUTCOMES AND MEASURES Enrichment analyses were used to identify sets of genes overrepresented in both cohorts. Enriched groups of genes were compared between both participating cohorts as a further measure against random noise. RESULTS Groups of genes enriched at highly significant statistical levels were remarkably consistent in both cohorts. In particular, these results indicated that plasma membrane (P = 7.64 × 10-30), cell-cell adhesion (P = 2.42 × 10-18), synaptic transmission (P = 2.70 × 10-14), calcium ion binding (P = 3.55 × 10-15), and cation channel activity (P = 2.77 × 10-14) were significantly overrepresented in relation to refractive error. CONCLUSIONS AND RELEVANCE These findings provide evidence that development of refractive error in the general population is related to the intensity of photosignal transduced from the retina, which may have implications for future interventions to minimize this disorder. Pathways connected to the procession of the nerve impulse are major mechanisms involved in the development of refractive error in populations of European origin.
    Jama Ophthalmology 11/2013;
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    ABSTRACT: To determine whether corneal hysteresis and central corneal thickness are independent risk factors for glaucoma. This was a cross-sectional population based cohort study. Associations were tested between corneal hysteresis, measured in 1754 population-based subjects from the TwinsUK cohort, and glaucoma-related endophenotypes, including intraocular pressure (IOP), vertical cup to disc ratio, optic disc area and optic disc cup area. Corneal hysteresis, IOP and Central Corneal Thickness (CCT) were measured using the Ocular Response Analyser (ORA-Reichert(®) Buffalo, NY). Optic disc photographs were analysed using the Stereo DX program. Multivariable linear regression analysis was performed using STATA software. Data was available on 1645 individuals. Multiple regression analysis showed corneal hysteresis to be significantly negatively associated with age (beta coefficient = -0.03, p <0.00005) and IOP (beta coefficient = -0.06, p< 0.00005). Corneal hysteresis was also found to be associated with CCT (beta coefficient =0.02, p<0.0005). There was no significant association between corneal hysteresis and optic disc area (p=0.6), cup area (p=0.77), vertical cup to disc ratio (p=0.51), or spherical equivalent (p=0.08). CCT was also found to be significantly associated with IOP (beta coefficient =3.3, p<0.0005) and corneal hysteresis (beta coefficient = 9.4, p<0.0005), but not with age (p=0.59 or spherical equivalent (p=0.16). In this large cohort of healthy British twins, we found no relationship between corneal hysteresis or CCT and quantitative measures of optic disc cupping, suggesting that corneal hysteresis and CCT are not independent risk factors for glaucoma.
    American Journal of Ophthalmology 11/2013;
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    ABSTRACT: The association between various measures of sun exposure and melanoma risk is quite complex to dissect as many case-control studies of melanoma included different subtypes of melanomas which are likely to be biologically different, so interpretation of the data is difficult. Screening bias in countries with high levels of sun exposure is also an issue. Now that progress is being made in the genetic subclassification of melanoma tumours, it is apparent that melanomas have different somatic changes according to body sites/histological subtypes and that UV exposure may be relevant for some but not all types of melanomas. Melanoma behaviour also points to non-sun-related risk factors, and complex gene-environment interactions are likely. As UV exposure is the only environmental factor ever linked to melanoma, it is still prudent to avoid excessive sun exposure and sunburn especially in poor tanners. However, the impact of strict sun avoidance, which should not be recommended, may take years to be apparent as vitamin D deficiency is a now a common health issue in Caucasian populations, with a significant impact on health in general.
    Current Oncology Reports 10/2013;
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    ABSTRACT: Rheumatic diseases encompass a wide range of conditions of poorly characterized etiopathology, many having both genetic and environmental susceptibility factors. Epigenetic studies are providing new insights into disease pathogenesis. Recent rheumatology literature related to DNA methylation studies-both epigenome-wide and candidate gene-are discussed, as well as methodological issues. A PubMed search for articles published until April 2013 was conducted using the following keywords: ("methylation" OR "epigenetics") AND ("rheumatoid arthritis" OR "lupus" OR "autoimmune disease" OR "osteoporosis" OR "osteoarthritis" OR "musculoskeletal disorder") and EWAS. The reference lists of identified articles were searched for further articles. Several genome-wide methylation studies have been reported recently, mostly in autoimmune rheumatic diseases. Overall, these studies have identified methylation signatures in disease, clustering of subgroups as well as new and known epigenetic associations. Methodological issues, small sample sizes and reduced coverage of methylation assays render many results preliminary. There have been a number of epigenetic advances in rheumatic diseases recently. The new technologies and emerging field of epigenome-wide association will provide novel perspectives in disease etiology, diagnosis, classification, and therapy.
    Seminars in arthritis and rheumatism 10/2013;
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    ABSTRACT: Eye diseases represent a significant source of health impairment in humans. Twin studies offer an excellent model to dissect the genetic basis of human diseases. In this review, we discuss the potential advantages of using twin-based studies in investigating the genetics of eye diseases - from heritability estimation to identifying underlying genetic and epigenetic changes. We also discuss some of the notable findings of twin studies exploring the genetics of eye diseases. Finally we suggest other novel approaches that can be utilised to tap the potential of twin studies to provide a more complete understanding of genetic factors underlying ocular diseases.
    Clinical and Experimental Ophthalmology 09/2013;
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    ABSTRACT: Cognitive performance is known to change over age 45, especially processing speed. Studies to date indicate that change in performance with ageing is largely environmentally mediated, with little contribution from genetics. We estimated the heritability of a longitudinal battery of computerised cognitive tests including speed measures, using a classical twin design. 324 (127 MZ, 197 DZ) female twins, aged 43-73 at baseline testing, were followed-up after 10 years, using seven measures of the Cambridge Automated Neuropsychological Test battery, four of which were measures of response latency (speed). Results were analysed using univariate and bivariate structural equation modelling. Heritability of longitudinal change was found in 5 of the 7 tests, ranging from 21 to 41 %. The genetic aetiology was remarkably stable. The first principle component of change was strongly associated with age (p < 0.001) and heritable at 47 % (27-62 %). While estimates for heritability increased in all measures over time compared to baseline, these increases were statistically non-significant. This computerised battery showed significant heritability of age-related change in cognition. Focus on this form of change may aid the search for genetic pathways involved in normal and pre-morbid cognitive ageing.
    Behavior Genetics 08/2013;
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    ABSTRACT: Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects. We performed a two-stage meta-analysis on more than 78 000 participants. In stage 1, we synthesised data from eight GWAS whereas data from 10 centres were used for 'in silico' or 'de novo' replication. Besides the main analysis, a stratified by sex analysis was performed to detect possible sex-specific signals. Meta-analysis was performed using inverse-variance fixed effects models. A random effects approach was also used. We accumulated 11 277 cases of radiographic and symptomatic hip OA. We prioritised eight single nucleotide polymorphism (SNPs) for follow-up in the discovery stage (4349 OA cases); five from the combined analysis, two male specific and one female specific. One locus, at 20q13, represented by rs6094710 (minor allele frequency (MAF) 4%) near the NCOA3 (nuclear receptor coactivator 3) gene, reached genome-wide significance level with p=7.9×10(-9) and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p=5.6×10(-8)) and follow-up studies (p=7.3×10(-4)). We showed that this gene is expressed in articular cartilage and its expression was significantly reduced in OA-affected cartilage. Moreover, two loci remained suggestive associated; rs5009270 at 7q31 (MAF 30%, p=9.9×10(-7), OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2×10(-6), OR=1.27 in male specific analysis). Novel genetic loci for hip OA were found in this meta-analysis of GWAS.
    Annals of the rheumatic diseases 08/2013;
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    ABSTRACT: Summary A lot has been written about the opportunities of the Internet for medicine, and lately, also for disease research specifically. Although it remains to be seen how significant and sustainable a change this will result in, some recent developments are highly relevant for the area of genetic research. User-friendly, low-threshold web-based tools do not only provide information to patients and other users, but they also supply user-generated data that can be utilized by both medical practice and medical research. Many of these developments have been below the radar of mainstream academic research so far. Issues related to data quality and standardization, as well as data protection and privacy, still need to be addressed. Dismissing these platforms as fads of a tiny privileged minority risks missing the opportunity to have our say in these debates.
    Genetics Research 08/2013;
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    ABSTRACT: Supplementation with carotenoids is proposed to protect against age-related macular degeneration. There is, however, considerable variability in retinal macular pigment response, which may be due to underlying genetic variation. The purpose of this study was to determine whether genetic factors, which have been previously associated with cross-sectional macular pigment levels in the retina or serum lutein, also influence response to supplementation. To this end we conducted an association study in 310 subjects from the TwinsUK cohort between variants in 8 candidate genes and serum lutein and retinal macular pigment optical density (MPOD) levels before and after supplementation. Four variants were associated with MPOD response to supplementation (p<0.05): rs11057841 (SCARB1), rs4926339 (RPE65), rs1929841 (ABCA1) and rs174534 (FADS1). We also confirmed previous associations between rs6564851 near BMCO1 (p<0.001) and rs11057841 within SCARB1 (p=0.01) and baseline measures of serum lutein; while the latter was also associated with MPOD response, none of the BMCO1 variants were. Finally, there was evidence for association between variants near RPE65 and ELOVL2 and changes in lutein concentration after supplementation. This study is the first to show association between genetic variants and response to carotenoids supplementation. Our findings suggest an important link between MP response and the biological processes of carotenoids transport and fatty acid metabolism.
    Experimental Eye Research 07/2013;
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    ABSTRACT: Cobalamin (Cbl) is an essential B vitamin involved in the normal functioning of the nervous system, the formation of key components of blood, DNA synthesis and methylation, and energy production. Physiological levels of Cbl vary greatly within populations, although the basis for this variability remains largely unknown. We conducted a twin study to characterise the basis of variation in plasma Cbl levels and to test whether common genetic polymorphisms in genes known to cause defects in inborn errors of Cbl metabolism and transport are also associated with mean plasma Cbl levels in the general population. The present results showed that plasma levels of Cbl were heritable, with genetic and phenotypic variance increasing with age, and levels significantly correlated with age, BMI, exercise, alcohol consumption, smoking status, social class and folate levels, which collectively accounted for up to 15 % of Cbl variation. Of eight genes responsible for the defects of the Cbl metabolic pathway (cblA-G and mut), MMAA, MMACHC, MTRR and MUT harboured polymorphisms that showed evidence of association with Cbl levels. Characterisation of the heritable component of variation in Cbl levels can facilitate the early diagnosis and prognosis of Cbl insufficiency/deficiency in individuals at a higher risk of associated diseases.
    The British journal of nutrition 04/2013;
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