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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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Related in: MedlinePlus

Manhattan plot of -log10(P) for the association on axial length from the meta-analysis in the combined cohorts of SCES, SCORM, and SiMES.The red horizontal line denotes genome-wide significance (P = 5×10−8).
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pgen-1002753-g001: Manhattan plot of -log10(P) for the association on axial length from the meta-analysis in the combined cohorts of SCES, SCORM, and SiMES.The red horizontal line denotes genome-wide significance (P = 5×10−8).

Mentions: A cluster of four SNPs on chromosome 1q41 (rs4373767, rs10779363, rs7544369 and rs4428898) attained genome-wide significance on meta-analysis for AL, adjusting for age, gender, height and education level (Figure 1). Analyses conducted without adjustment for height or education level yielded the same pattern of results. The most significant SNP rs4373767 (Pmeta = 2.69×10−10) explained 0.98% of AL variance in SCES, 0.86% in SCORM and 0.73% in SiMES, and each copy of the minor allele (cytosine) decreased AL by 0.16 mm on average (Table 2). These top associated SNPs at chromosome 1q41 remained significant after adjustment for genomic control (Pmeta≤1.85×10−8). Table 2 also lists three genetic loci at chromosome 2p13.1 (SEMA4F), 2p21 (SPTBN1) and 5q11.1 (PARP8) exhibiting suggestive evidence of association with AL that were seen in at least one SNP with P-values<1×10−5.


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)

Manhattan plot of -log10(P) for the association on axial length from the meta-analysis in the combined cohorts of SCES, SCORM, and SiMES.The red horizontal line denotes genome-wide significance (P = 5×10−8).
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1002753-g001: Manhattan plot of -log10(P) for the association on axial length from the meta-analysis in the combined cohorts of SCES, SCORM, and SiMES.The red horizontal line denotes genome-wide significance (P = 5×10−8).
Mentions: A cluster of four SNPs on chromosome 1q41 (rs4373767, rs10779363, rs7544369 and rs4428898) attained genome-wide significance on meta-analysis for AL, adjusting for age, gender, height and education level (Figure 1). Analyses conducted without adjustment for height or education level yielded the same pattern of results. The most significant SNP rs4373767 (Pmeta = 2.69×10−10) explained 0.98% of AL variance in SCES, 0.86% in SCORM and 0.73% in SiMES, and each copy of the minor allele (cytosine) decreased AL by 0.16 mm on average (Table 2). These top associated SNPs at chromosome 1q41 remained significant after adjustment for genomic control (Pmeta≤1.85×10−8). Table 2 also lists three genetic loci at chromosome 2p13.1 (SEMA4F), 2p21 (SPTBN1) and 5q11.1 (PARP8) exhibiting suggestive evidence of association with AL that were seen in at least one SNP with P-values<1×10−5.

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