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Genetic variants on chromosome 1q41 influence ocular axial length and high myopia.

Fan Q, Barathi VA, Cheng CY, Zhou X, Meguro A, Nakata I, Khor CC, Goh LK, Li YJ, Lim W, Ho CE, Hawthorne F, Zheng Y, Chua D, Inoko H, Yamashiro K, Ohno-Matsui K, Matsuo K, Matsuda F, Vithana E, Seielstad M, Mizuki N, Beuerman RW, Tai ES, Yoshimura N, Aung T, Young TL, Wong TY, Teo YY, Saw SM - PLoS Genet. (2012)

Bottom Line: We identified a genetic locus on chromosome 1q41 harboring the zinc-finger 11B pseudogene ZC3H11B showing genome-wide significant association with AL variation (rs4373767, β = -0.16 mm per minor allele, P(meta) =2.69 × 10(-10)).In an experimental myopia mouse model, we observed significant alterations to gene and protein expression in the retina and sclera of the unilateral induced myopic eyes for the murine genes ZC3H11A, SLC30A10, and LYPLAL1.This supports the likely role of genetic variants at chromosome 1q41 in influencing AL variation and high myopia.

View Article: PubMed Central - PubMed

Affiliation: Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.

ABSTRACT
As one of the leading causes of visual impairment and blindness, myopia poses a significant public health burden in Asia. The primary determinant of myopia is an elongated ocular axial length (AL). Here we report a meta-analysis of three genome-wide association studies on AL conducted in 1,860 Chinese adults, 929 Chinese children, and 2,155 Malay adults. We identified a genetic locus on chromosome 1q41 harboring the zinc-finger 11B pseudogene ZC3H11B showing genome-wide significant association with AL variation (rs4373767, β = -0.16 mm per minor allele, P(meta) =2.69 × 10(-10)). The minor C allele of rs4373767 was also observed to significantly associate with decreased susceptibility to high myopia (per-allele odds ratio (OR) =0.75, 95% CI: 0.68-0.84, P(meta) =4.38 × 10(-7)) in 1,118 highly myopic cases and 5,433 controls. ZC3H11B and two neighboring genes SLC30A10 and LYPLAL1 were expressed in the human neural retina, retinal pigment epithelium, and sclera. In an experimental myopia mouse model, we observed significant alterations to gene and protein expression in the retina and sclera of the unilateral induced myopic eyes for the murine genes ZC3H11A, SLC30A10, and LYPLAL1. This supports the likely role of genetic variants at chromosome 1q41 in influencing AL variation and high myopia.

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The chromosome 1q41 region and its association with axial length in the Asian cohorts.A) Regional plots for AL from the meta-analysis of three Asian GWAS cohorts: SCES, SCORM and SiMES. The association signals in a 1 megabase (Mb) region at chromosome 1q41 from 217,400 kb to 218,400 kb around the top SNP rs4373767 (red diamond) are plotted. The degree of pair-wise LD between the rs4373767 and any genotyped SNPs in this region is indicated by red shading, measured by r2. Superimposed on the plots are gene locations and recombination rates in HapMap Chinese and Japanese populations (blue lines). B) LD plot showing pair-wise r2 for all the SNPs genotyped in HapMap database residing between rs4428898 and rs7544369, inclusively, at chromosome 1q41. The four identified top SNPs are in red rectangles. The LD plot is generated by Haploview using SNPs (MAF>1%) genotyped on Han Chinese and Japanese samples in the HapMap database. All coordinates are in Build hg18.
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pgen-1002753-g002: The chromosome 1q41 region and its association with axial length in the Asian cohorts.A) Regional plots for AL from the meta-analysis of three Asian GWAS cohorts: SCES, SCORM and SiMES. The association signals in a 1 megabase (Mb) region at chromosome 1q41 from 217,400 kb to 218,400 kb around the top SNP rs4373767 (red diamond) are plotted. The degree of pair-wise LD between the rs4373767 and any genotyped SNPs in this region is indicated by red shading, measured by r2. Superimposed on the plots are gene locations and recombination rates in HapMap Chinese and Japanese populations (blue lines). B) LD plot showing pair-wise r2 for all the SNPs genotyped in HapMap database residing between rs4428898 and rs7544369, inclusively, at chromosome 1q41. The four identified top SNPs are in red rectangles. The LD plot is generated by Haploview using SNPs (MAF>1%) genotyped on Han Chinese and Japanese samples in the HapMap database. All coordinates are in Build hg18.

Mentions: This associated interval spans approximately 70 kb in the extended linkage disequilibrium (LD) block within an intergenic region on chromosome 1q41 (pairwise r2>0.5 with the most significant SNP rs4373767, Figure 2A). Zinc finger family CCCH-type 11B pseudogene ZC3H11B (RefSeq NG_007367.2) is embedded between the associated top SNPs rs4373767 and rs10779363 (Figure 2B). The most significant SNP rs4373767 is located 223 kb downstream from SLC30A10 (RefSeq NM_018713.2), which is a member of solute carrier family 30, and 354 kb downstream of LYPLAL1 (RefSeq NM_138794.3), encoding a lysophospholipase-like protein.


Genetic variants on chromosome 1q41 influence ocular axial length and high myopia.

Fan Q, Barathi VA, Cheng CY, Zhou X, Meguro A, Nakata I, Khor CC, Goh LK, Li YJ, Lim W, Ho CE, Hawthorne F, Zheng Y, Chua D, Inoko H, Yamashiro K, Ohno-Matsui K, Matsuo K, Matsuda F, Vithana E, Seielstad M, Mizuki N, Beuerman RW, Tai ES, Yoshimura N, Aung T, Young TL, Wong TY, Teo YY, Saw SM - PLoS Genet. (2012)

The chromosome 1q41 region and its association with axial length in the Asian cohorts.A) Regional plots for AL from the meta-analysis of three Asian GWAS cohorts: SCES, SCORM and SiMES. The association signals in a 1 megabase (Mb) region at chromosome 1q41 from 217,400 kb to 218,400 kb around the top SNP rs4373767 (red diamond) are plotted. The degree of pair-wise LD between the rs4373767 and any genotyped SNPs in this region is indicated by red shading, measured by r2. Superimposed on the plots are gene locations and recombination rates in HapMap Chinese and Japanese populations (blue lines). B) LD plot showing pair-wise r2 for all the SNPs genotyped in HapMap database residing between rs4428898 and rs7544369, inclusively, at chromosome 1q41. The four identified top SNPs are in red rectangles. The LD plot is generated by Haploview using SNPs (MAF>1%) genotyped on Han Chinese and Japanese samples in the HapMap database. All coordinates are in Build hg18.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3369958&req=5

pgen-1002753-g002: The chromosome 1q41 region and its association with axial length in the Asian cohorts.A) Regional plots for AL from the meta-analysis of three Asian GWAS cohorts: SCES, SCORM and SiMES. The association signals in a 1 megabase (Mb) region at chromosome 1q41 from 217,400 kb to 218,400 kb around the top SNP rs4373767 (red diamond) are plotted. The degree of pair-wise LD between the rs4373767 and any genotyped SNPs in this region is indicated by red shading, measured by r2. Superimposed on the plots are gene locations and recombination rates in HapMap Chinese and Japanese populations (blue lines). B) LD plot showing pair-wise r2 for all the SNPs genotyped in HapMap database residing between rs4428898 and rs7544369, inclusively, at chromosome 1q41. The four identified top SNPs are in red rectangles. The LD plot is generated by Haploview using SNPs (MAF>1%) genotyped on Han Chinese and Japanese samples in the HapMap database. All coordinates are in Build hg18.
Mentions: This associated interval spans approximately 70 kb in the extended linkage disequilibrium (LD) block within an intergenic region on chromosome 1q41 (pairwise r2>0.5 with the most significant SNP rs4373767, Figure 2A). Zinc finger family CCCH-type 11B pseudogene ZC3H11B (RefSeq NG_007367.2) is embedded between the associated top SNPs rs4373767 and rs10779363 (Figure 2B). The most significant SNP rs4373767 is located 223 kb downstream from SLC30A10 (RefSeq NM_018713.2), which is a member of solute carrier family 30, and 354 kb downstream of LYPLAL1 (RefSeq NM_138794.3), encoding a lysophospholipase-like protein.

Bottom Line: We identified a genetic locus on chromosome 1q41 harboring the zinc-finger 11B pseudogene ZC3H11B showing genome-wide significant association with AL variation (rs4373767, β = -0.16 mm per minor allele, P(meta) =2.69 × 10(-10)).In an experimental myopia mouse model, we observed significant alterations to gene and protein expression in the retina and sclera of the unilateral induced myopic eyes for the murine genes ZC3H11A, SLC30A10, and LYPLAL1.This supports the likely role of genetic variants at chromosome 1q41 in influencing AL variation and high myopia.

View Article: PubMed Central - PubMed

Affiliation: Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.

ABSTRACT
As one of the leading causes of visual impairment and blindness, myopia poses a significant public health burden in Asia. The primary determinant of myopia is an elongated ocular axial length (AL). Here we report a meta-analysis of three genome-wide association studies on AL conducted in 1,860 Chinese adults, 929 Chinese children, and 2,155 Malay adults. We identified a genetic locus on chromosome 1q41 harboring the zinc-finger 11B pseudogene ZC3H11B showing genome-wide significant association with AL variation (rs4373767, β = -0.16 mm per minor allele, P(meta) =2.69 × 10(-10)). The minor C allele of rs4373767 was also observed to significantly associate with decreased susceptibility to high myopia (per-allele odds ratio (OR) =0.75, 95% CI: 0.68-0.84, P(meta) =4.38 × 10(-7)) in 1,118 highly myopic cases and 5,433 controls. ZC3H11B and two neighboring genes SLC30A10 and LYPLAL1 were expressed in the human neural retina, retinal pigment epithelium, and sclera. In an experimental myopia mouse model, we observed significant alterations to gene and protein expression in the retina and sclera of the unilateral induced myopic eyes for the murine genes ZC3H11A, SLC30A10, and LYPLAL1. This supports the likely role of genetic variants at chromosome 1q41 in influencing AL variation and high myopia.

Show MeSH
Related in: MedlinePlus