Genetic Variants on Chromosome 1q41 Influence Ocular Axial Length and High Myopia

Fan, Qiao; Barathi, Veluchamy A; Cheng, Ching‐Yu; Zhou, Xin; Meguro, Akira; Nakata, Isao; Khor, Chiea‐Chuen; Goh, Liang Kee; Li, Yi-Ju; Lim, W.S.; Ho, Candice; Hawthorne, Felicia; Zheng, Yingfeng; Chua, Daniel; Inoko, Hidetoshi; Yamashiro, Kenji; Ohno‐Matsui, Kyoko; Matsuo, Keitaro; Matsuda, Fumihiko; Vithana, Eranga N.; Seielstad, Mark; Mizuki, Nobuhisa; Beuerman, Roger W.; Tai, E. Shyong; Yoshimura, Nagahisa; Aung, Tin; Young, Terri L.; Wong, Tien Yin; Teo, Yik Ying; Saw, Seang Mei

doi:10.1371/journal.pgen.1002753

Cited by 96 publications

(77 citation statements)

References 71 publications

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“…36 Genome-wide association studies identified single-nucleotide polymorphisms in several genes, such as GRIA4, KCNQ5, RDH5, LAMA2, BMP2, SIX6, PRSS56, GJD2, RASGRF1, ZC3H11B, and WNT7B, as risk factors for refractive error including myopia. [6][7][8] Although some of these genes (SIX6, PRSS56, and WNT7B) function in eye development, 7,8 it remains unclear how such sequence variants shape phenotypic variation. Phenotyping studies by using genetically engineered mice with different genetic backgrounds in conjunction with sequence analyses will provide useful information on the association between genomic and phenotypic variations.…”

Section: Discussionmentioning

confidence: 99%

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Severe ocular phenotypes in Rbp4-deficient mice in the C57BL/6 genetic background

Shen

Shi

Suzuki

et al. 2016

Laboratory Investigation

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Retinol-binding protein 4 (RBP4) is a specific carrier for retinol in the blood. In hepatocytes, newly synthesized RBP4 associates with retinol and transthyretin and is secreted into the blood. The ternary transthyretin-RBP4-retinol complex transports retinol in the circulation and delivers it to target tissues. Rbp4-deficient mice in a mixed genetic background (129xC57BL/6J) have decreased sensitivity to light in the b-wave amplitude on electroretinogram. Sensitivity progressively improves and approaches that of wild-type mice at 24 weeks of age. In the present study, we produced Rbp4-deficient mice in the C57BL/6 genetic background. These mice displayed more severe phenotypes. They had decreased a-and b-wave amplitudes on electroretinograms. In accordance with these abnormalities, we found structural changes in these mice, such as loss of the peripheral choroid and photoreceptor layer in the peripheral retinas. In the central retinas, the distance between the inner limiting membrane and the outer plexiform layer was much shorter with fewer ganglion cells and fewer synapses in the inner plexiform layer. Furthermore, ocular developmental defects of retinal depigmentation, optic disc abnormality, and persistent hyaloid artery were also observed. All these abnormalities had not recovered even at 40 weeks of age. Our Rbp4-deficient mice accumulated retinol in the liver but it was undetectable in the serum, indicating an inverse relation between serum and liver retinol levels. Our results suggest that RBP4 is critical for the mobilization of retinol from hepatic storage pools, and that such mobilization is necessary for ocular development and visual function.

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Section: Discussionmentioning

confidence: 99%

“…2 In humans, genome-wide association studies revealed new susceptibility loci for eye diseases, such as refractive error including myopia. [6][7][8] Over 450 inbred strains of mice have been described, 9 providing a wealth of different genotypes and phenotypes for studying human diseases.…”

Section: Introductionmentioning

confidence: 99%

Severe ocular phenotypes in Rbp4-deficient mice in the C57BL/6 genetic background

Shen

Shi

Suzuki

et al. 2016

Laboratory Investigation

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“…Twin studies and population-based epidemiological investigations show that genetic factors significantly contribute to the development of myopia (6,14,15), particularly HM (5). Genomewide association studies (GWAS) and subsequent metaanalyses have identified dozens of loci and genes that are associated with general myopia or HM (16,17). Of note, the identified genetic contributions of the dozens of loci and genes to myopia are very limited.…”

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confidence: 99%

Trio-based exome sequencing arrests de novo mutations in early-onset high myopia

Jin

Huang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The etiology of the highly myopic condition has been unclear for decades. We investigated the genetic contributions to early-onset high myopia (EOHM), which is defined as having a refraction of less than or equal to −6 diopters before the age of 6, when children are less likely to be exposed to high educational pressures. Trios (two nonmyopic parents and one child) were examined to uncover pathogenic mutations using whole-exome sequencing. We identified parent-transmitted biallelic mutations or de novo mutations in asyet-unknown or reported genes in 16 probands. Interestingly, an increased rate of de novo mutations was identified in the EOHM patients. Among the newly identified candidate genes, a BSG mutation was identified in one EOHM proband. Expanded screening of 1,040 patients found an additional four mutations in the same gene. Then, we generated Bsg mutant mice to further elucidate the functional impact of this gene and observed typical myopic phenotypes, including an elongated axial length. Using a trio-based exonic screening study in EOHM, we deciphered a prominent role for de novo mutations in EOHM patients without myopic parents. The discovery of a disease gene, BSG, provides insights into myopic development and its etiology, which expands our current understanding of high myopia and might be useful for future treatment and prevention.early-onset high myopia | de novo mutations | BSG | rare inherited mutations

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“…A number of researchers have therefore used this proxy or 'endophenotype' for use in genetic association studies of myopia as a quantitative trait. The first of these, published in 2012, examined 4944 individuals of East and South East Asian ancestry (46).…”

Section: Genome-wide Association Studies and Myopia Endophenotypesmentioning

confidence: 99%

GWAS in myopia: insights into disease and implications for the clinic

Williams

Hammond

2016

Expert Review of Ophthalmology

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 IntroductionMyopia is already the commonest eye condition and its prevalence is increasing across the world (1-4). Although myopia is strongly associated with a number of environmental factors, the most important risk factor in determining whether an individual develops the trait is having a family history of myopia, suggesting a genetic predisposition. The heritability of a trait is an estimate of how much phenotypic variation in a population is due to genetic factors. The heritability of refractive error, using spherical equivalent as a quantitative trait, has been determined in a number of family and, more credibly, twin studies [ Figure 1].These indicate the heritability of myopia is high at around 70% (5-15). Myopia is a complex trait influenced by a complicated interplay of genetic and environmental factors. As with many complex traits there is a distribution of refractive error in the population, meaning the risk of ordinary or "simple" myopia developing is not determined by a classic Mendelian single gene mode of inheritance; there are likely many genes, each contributing a small effect to overall myopia risk. This may not be true for very high, familial or syndromeassociated forms of myopia, where a rare dominantly inherited mutation may be important in an individual family, but not important in the overall population risk. Up until the era of genome-wide association studies (GWAS), identification of disease-associated genes relied on family studies (using linkage analysis) or candidate gene studies. In myopia, these were singularly unsuccessful and prior 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 Genome-wide association studies (GWAS)Genome-wide association studies (GWAS) are approaches that allow a vast array of markers scattered across an individual's DNA or genome to be rapidly tested for association with a disease or trait. These 'markers' are variations in the base pair of nucleotides at specific points along the genome, commonly known as SNPs (single-nucleotide polymorphisms), and give an indication of what nearby genes may be associated with the trait.In order for this analysis technique to be possible, all of the base pairs, namely adenine (A), guanine (G), thymine (T) or cytosine (C), forming the human DNA code had to be sequenced (ie. read and mapped). The human genome project, completed in 2003, was a major international scientific collaboration that identified all of the base pairs and genes that make up the human genome, approximately 20,500 genes in total (16, 17). This has enabled researchers to have access to a detailed resource on the structure, function and organization of the co...

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Genetic Variants on Chromosome 1q41 Influence Ocular Axial Length and High Myopia

Cited by 96 publications

References 71 publications

Severe ocular phenotypes in Rbp4-deficient mice in the C57BL/6 genetic background

Severe ocular phenotypes in Rbp4-deficient mice in the C57BL/6 genetic background

Trio-based exome sequencing arrests de novo mutations in early-onset high myopia

GWAS in myopia: insights into disease and implications for the clinic

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