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Ryan Wang, Baojian Fan, P. Ferdina Marie Sharmila, N. Soumittra, S. Sripriya, D. s. Friedman, L. Vijaya, Jonathan L Haines, Ronnie J George, Janey L Wiggs; Linkage and association analyses identify a vCDR locus on chromosome 14q32 in consanguineous pedigrees from South India. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3794.
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© ARVO (1962-2015); The Authors (2016-present)
Optic nerve parameters, such as vertical cup-to-disc ratio (vCDR) are highly heritable quantitative traits that can also contribute to glaucoma disease risk. Identification of genetic variants influencing these traits can help define the molecular architecture of glaucoma. While genome-wide association studies can reveal loci of interest, they often require large sample sizes. Genetic mapping using consanguineous pedigrees are useful for the identification of gene loci contributing to quantitative traits with additive effects. Family-based analyses are also protected from the effects of population stratification, another confounding factor in association studies. The purpose of this study is to identify loci and variants associated with vCDR using linkage and association analyses of genome-wide genotype data from consanguineous pedigrees from South India.
vCDR was measured using the Heidelberg Retina Tomograph III (HRT III ) in 240 members of 16 consanguineous families recruited from South India. Genotyping was performed using the Illumina HumanOmni2.5 SNP arrays. Genome-wide linkage analysis was performed using variance components analysis in MERLIN (v1.1.2). Family-based association analysis was performed using the likelihood-ratio test in MERLIN.
A significant linkage signal for vCDR was identified on 14q32.12, with a LOD score of 3.62. This locus contains 10 genes: C14orf109, CHGA, GOLGA5, ITPK1, ITPK1-AS1, LGMN, MOAP1, RIN3, SLC24A4 and UBR7. MOAP1, coding for modulator of apoptosis 1, a protein impacting apoptosis and also with expression in retinal ganglion cells, was selected for further study. Sanger sequencing of the entire coding region identified two missense variants, Val197Met and Val200Ile in family members. Family-based association studies did not find evidence of association with vCDR (P > 0.05) for these two variants. No other variants were identified in MOAP1 coding sequence.
Our results suggest that MOAP1 missense variants are not likely to be responsible for the vCDR linkage signal on chromosome 14. Future studies include the evaluation of MOAP1 regulatory regions and also investigation of other genes in the chromosome 14 region that may contribute to vCDR. Additionally, investigating association between genetic variants in genes located in the vCDR locus and primary open angle glaucoma (POAG) will also be of interest.
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