Identification of myopia-associated WNT7B polymorphisms provides insights into the mechanism underlying the development of myopia

Miyake, Masahiro; Yamashiro, Kenji; Tabara, Yasuharu; Suda, K.; Morooka, Shigenori; Nakanishi, Hideo; Khor, Chiea‐Chuen; Chen, Peng; Fan, Qiao; Nakata, Isao; Akagi-Kurashige, Yumiko; Gotoh, Noriko; Tsujikawa, Akitaka; Meguro, Akira; Kusuhara, Sentaro; Polasek, Ozen; Hayward, Caroline; Wright, Alan F.; Campbell, Harry; Richardson, Andrea J.; Schäche, Maria; Takeuchi, Masaki; Mackey, David A.; Hewitt, Alex W.; Cuellar, Gabriel; Shi, Yi; Huang, Luling; Yang, Zhenglin; Leung, Kim Hung; Kao, Patrick Y. P.; Yap, Maurice; Yip, Shea Ping; Moriyama, Muka; Ohno‐Matsui, Kyoko; Mizuki, Nobuhisa; MacGregor, Stuart; Vitart, Véronique; Aung, Tin; Saw, Seang‐Mei; Tai, E. Shyong; Wong, Tien Yin; Cheng, Ching‐Yu; Baird, Paul N.; Yamada, Ryo; Matsuda, Fumihiko; Yoshimura, Nagahisa

doi:10.1038/ncomms7689

Cited by 70 publications

(60 citation statements)

References 65 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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“…The WNT7B gene has been reported to be expressed in the human cornea (28) and the mouse cornea (29).…”

Section: Biological Evidencementioning

confidence: 99%

“…WNT7B was upregulated in the human central cornea and is specific to the mature corneal epithelium (28) and was mainly expressed in the endothelial cell layer in the mouse cornea (29). Genevestigator (see Web…”

Section: Biological Evidencementioning

confidence: 99%

Genome-wide association study identifiesWNT7Bas a novel locus for central corneal thickness in Latinos

Gao¹,

Nannini²,

Corrao³

et al. 2016

Hum. Mol. Genet.

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The cornea is the outermost layer of the eye and is a vital component of focusing incoming light on the retina. Central corneal thickness (CCT) is now recognized to have a significant role in ocular health and is a risk factor for various ocular diseases, such as keratoconus and primary open angle glaucoma. Most previous genetic studies utilized European and Asian subjects to identify genetic loci associated with CCT. Minority populations, such as Latinos, may aid in identifying additional loci and improve our understanding of the genetic architecture of CCT. In this study, we conducted a genome-wide association study (GWAS) in Latinos, a traditionally understudied population in genetic research, to further identify loci contributing to CCT. Study participants were genotyped using either the Illumina OmniExpress BeadChip (~730K markers) or the Illumina Hispanic/SOL BeadChip (~2.5 million markers). All study participants were 40 years of age and older. We assessed the association between individual single nucleotide polymorphisms (SNPs) and CCT using linear regression, adjusting for age, gender, and principal components of genetic ancestry. To expand genomic coverage and to interrogate additional SNPs, we imputed SNPs from the 1000 Genomes Project reference panels. We identified a novel SNP, rs10453441 (P = 6.01E-09), in an intron of WNT7B that is associated with CCT. Furthermore, WNT7B is expressed in the human cornea. We also replicated 11 previously reported loci, including IBTK, RXRA-COL5A1, COL5A1, FOXO1, LRRK1, and ZNF469 (P < 1.25E-3). These findings provide further insight into the genetic architecture of CCT and illustrate that the use of minority groups in GWAS will help identify additional loci.3

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“…Recently, advances in genome technology have facilitated loci identification in genes associated with a variety of ocular disorders including myopia using strategies of exome sequencing or genome-wide association studies (GWASs) (Aldahmesh et al, 2013;Guo et al, 2015;Miyake et al, 2015). However, determining the genetic role of a specific gene/locus in the etiology of myopia is still difficult to achieve.…”

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confidence: 99%

Controversial opinion: evaluation of EGR1 and LAMA2 loci for high myopia in Chinese populations

Lin

Huang

Lü

et al. 2016

J. Zhejiang Univ. Sci. B

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Abstract:Functional studies have suggested the important role of early growth response 1 (EGR1) and Laminin α2-chain (LAMA2) in human eye development. Genetic studies have reported a significant association of the single nucleotide polymorphism (SNP) in the LAMA2 gene with myopia. This study aimed to evaluate the association of the tagging SNPs (tSNPs) in the EGR1 and LAMA2 genes with high myopia in two independent Han Chinese populations. Four tSNPs (rs11743810 in the EGR1 gene; rs2571575, rs9321170, and rs1889891 in the LAMA2 gene) were selected, according to the HapMap database (http://hapmap.ncbi.nlm.nih.gov), and were genotyped using the ligase detection reaction (LDR) approach for 167 Han Chinese nuclear families with extremely highly myopic offspring (<−10.0 diopters) and an independent group with 485 extremely highly myopic cases (<−10.0 diopters) and 499 controls. Direct sequencing was used to confirm the LDR results in twenty randomly selected subjects. Family-based association analysis was performed using the family-based association test (FBAT) software package (Version 1.5.5). Population-based association analysis was performed using the Chi-square test. The association analysis power was estimated using online software (http://design.cs.ucla.edu). The FBAT demonstrated that all four tSNPs tested did not show association with high myopia (P>0.05). Haplotype analysis of tSNPs in the LAMA2 genes also did not show a significant association (P>0.05). Meanwhile, population-based association analysis also showed no significant association results with high myopia (P>0.05). On the basis of our family-and population-based analyses for the Han Chinese population, we did not find positive association signals of the four SNPs in the LAMA2 and EGR1 genes with high myopia.

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Identification of myopia-associated WNT7B polymorphisms provides insights into the mechanism underlying the development of myopia

Cited by 70 publications

References 65 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

Genome-wide association study identifiesWNT7Bas a novel locus for central corneal thickness in Latinos

Controversial opinion: evaluation of EGR1 and LAMA2 loci for high myopia in Chinese populations

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