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Erratum: Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia (Nature Genetics (2013) 45 (314-318))

1] Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands. [2] Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. [3].
Nature Genetics (Impact Factor: 29.65). 02/2013; 45(6). DOI: 10.1038/ng.2554
Source: PubMed

ABSTRACT Refractive error is the most common eye disorder worldwide and is a prominent cause of blindness. Myopia affects over 30% of Western populations and up to 80% of Asians. The CREAM consortium conducted genome-wide meta-analyses, including 37,382 individuals from 27 studies of European ancestry and 8,376 from 5 Asian cohorts. We identified 16 new loci for refractive error in individuals of European ancestry, of which 8 were shared with Asians. Combined analysis identified 8 additional associated loci. The new loci include candidate genes with functions in neurotransmission (GRIA4), ion transport (KCNQ5), retinoic acid metabolism (RDH5), extracellular matrix remodeling (LAMA2 and BMP2) and eye development (SIX6 and PRSS56). We also confirmed previously reported associations with GJD2 and RASGRF1. Risk score analysis using associated SNPs showed a tenfold increased risk of myopia for individuals carrying the highest genetic load. Our results, based on a large meta-analysis across independent multiancestry studies, considerably advance understanding of the mechanisms involved in refractive error and myopia.

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Available from: Virginie Johanna Maria Verhoeven, Sep 02, 2015
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    • "The use of a dichotomous phenotype definition for our GWAS meta-analysis of astigmatism contrasts with the quantitative trait approach used in previous GWAS metaanalyses by the CREAM consortium for refractive error and axial eye length (Verhoeven et al. 2013b; Cheng et al. 2013). It has been shown that binary trait GWAS metaanalysis results are sensitive to unequal numbers of cases and controls in individual cohorts, especially when the sample size is small (Willer et al. 2010). "
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    ABSTRACT: To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged <25 years (4 cohorts, N = 5,640); and all independent individuals from the above three samples combined with a sample of Chinese subjects aged <25 years (N = 45,931). Participants were classified as cases with refractive astigmatism if the average cylinder power in their two eyes was at least 1.00 diopter and as controls otherwise. Genome-wide association analysis was carried out for each cohort separately using logistic regression. Meta-analysis was conducted using a fixed effects model. In the older European group the most strongly associated marker was downstream of the neurexin-1 (NRXN1) gene (rs1401327, P = 3.92E-8). No other region reached genome-wide significance, and association signals were lower for the younger European group and Asian group. In the meta-analysis of all cohorts, no marker reached genome-wide significance: The most strongly associated regions were, NRXN1 (rs1401327, P = 2.93E-07), TOX (rs7823467, P = 3.47E-07) and LINC00340 (rs12212674, P = 1.49E-06). For 34 markers identified in prior GWAS for spherical equivalent refractive error, the beta coefficients for genotype versus spherical equivalent, and genotype versus refractive astigmatism, were highly correlated (r = -0.59, P = 2.10E-04). This work revealed no consistent or strong genetic signals for refractive astigmatism; however, the TOX gene region previously identified in GWAS for spherical equivalent refractive error was the second most strongly associated region. Analysis of additional markers provided evidence supporting widespread genetic co-susceptibility for spherical and astigmatic refractive errors.
    Human Genetics 11/2014; 134(2). DOI:10.1007/s00439-014-1500-y · 4.52 Impact Factor
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    • "The strongest association was observed for the T allele of rs8027411, a variant located 78 kb upstream of the RASGRF1 coding region, overlapping with the RASGRF1 transcription initiation site. This association of the RASGRF1 gene with myopia was confirmed in a genome-wide meta-analysis that included 27 studies (Verhoeven et al., 2013). Given the combined ocular and hippocampal phenotype of RASGRF1-deficient mice and the association of rs8027411 with human refractive error, we hypothesized that genetic variation of RASGRF1 may be associated with interindividual variability of learning and memory in healthy humans. "
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    ABSTRACT: The guanine nucleotide exchange factor RASGRF1 is an important regulator of intracellular signaling and neural plasticity in the brain. RASGRF1-deficient mice exhibit a complex phenotype with learning deficits and ocular abnormalities. Also in humans, a genome-wide association study has identified the single nucleotide polymorphism (SNP) rs8027411 in the putative transcription regulatory region of RASGRF1 as a risk variant of myopia. Here we aimed to assess whether, in line with the RASGRF1 knockout mouse phenotype, rs8027411 might also be associated with human memory function. We performed computer-based neuropsychological learning experiments in two independent cohorts of young, healthy participants. Tests included the Verbal Learning and Memory Test (VLMT) and the logical memory section of the Wechsler Memory Scale (WMS). Two sub-cohorts additionally participated in functional magnetic resonance imaging (fMRI) studies of hippocampus function. 119 participants performed a novelty encoding task that had previously been shown to engage the hippocampus, and 63 subjects participated in a reward-related memory encoding study. RASGRF1 rs8027411 genotype was indeed associated with memory performance in an allele dosage-dependent manner, with carriers of the T allele (i.e., the myopia risk allele) showing better memory performance in the early encoding phase of the VLMT and in the recall phase of the WMS logical memory section. In fMRI, T allele carriers exhibited increased hippocampal activation during presentation of novel images and during encoding of pictures associated with monetary reward. Taken together, our results provide evidence for a role of the RASGRF1 gene locus in hippocampus-dependent memory and, along with the previous association with myopia, point toward pleitropic effects of RASGRF1 genetic variations on complex neural function in humans.
    Frontiers in Human Neuroscience 04/2014; 8:260. DOI:10.3389/fnhum.2014.00260 · 2.90 Impact Factor
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    • "Recently, Verhoeven et al. reported a comprehensive Genome-wide meta-analysis of multi-ancestry cohorts identified multiple new susceptibility loci for refractive error and myopia [20]. According their findings, rs524952 in 15q14 (P = 1.44 × 10-15) and rs4778879 (P = 4.25 × 10-11) in 15q25 showed genome-wide significant association with myopia. "
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    ABSTRACT: Refractive errors and high myopia are the most common ocular disorders, and both of them are leading causes of blindness in the world. Recently, genetic association studies in European and Japanese population identified that common genetic variations located in 15q14 and 15q25 were associated with high myopia. To validate whether the same variations conferred risk to high myopia in the Han Chinese population, we genotyped 1,461 individuals (940 controls and 521 cases samples) recruited of Han Chinese origin.Result: We found rs8027411 in 15q25 (P = 0.012 after correction, OR = 0.78) was significantly associated with high myopia but rs634990 in 15q14 (P = 0.54 after correction), OR = 0.88) was not. Our findings supported that 15q25 is a susceptibility locus for high myopia, and gene RASGRF1 was possible to play a role in the pathology of high myopia.
    BMC Genetics 04/2014; 15(1):51. DOI:10.1186/1471-2156-15-51 · 2.36 Impact Factor
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