Dataset Information

Genome-wide scans of myopia in Pennsylvania Amish families reveal significant linkage to 12q15, 8q21.3 and 5p15.33.

ABSTRACT: Myopia is one of the most common ocular disorders in the world, yet the genetic etiology of the disease remains poorly understood. Specialized founder populations, such as the Pennsylvania Amish, provide the opportunity to utilize exclusive genomic architecture, like unique haplotypes, to better understand the genetic causes of myopia. We perform genetic linkage analysis on Pennsylvania Amish families that have a strong familial history of myopia to map any potential causal variants and genes for the disease. 293 individuals from 25 extended families were genotyped on the Illumina ExomePlus array and merged with previous microsatellite data. We coded myopia affection as a binary phenotype; myopia was defined as having a mean spherical equivalent (MSE) of less than or equal to -?1 D (diopters). Two-point and multipoint parametric linkage analyses were performed under an autosomal dominant model. When allowing for locus heterogeneity, we identified two novel genome-wide significantly linked variants at 12q15 (heterogeneity LOD, HLOD?=?3.77) in PTPRB and at 8q21.3 (HLOD?=?3.35) in CNGB3. We identified further three genome-wide significant variants within a single family. These three variants were located in exons of SLC6A18 at 5p15.33 (LODs ranged from 3.51 to 3.37). Multipoint analysis confirmed the significant signal at 5p15.33 with six genome-wide significant variants (LODs ranged from 3.6 to 3.3). Further suggestive evidence of linkage was observed in several other regions of the genome. All three novel linked regions contain strong candidate genes, especially CNGB3 on 8q21.3, which has been shown to affect photoreceptors and cause complete color blindness. Whole genome sequencing on these regions is planned to conclusively elucidate the causal variants.

SUBMITTER: Musolf AM

PROVIDER: S-EPMC6486401 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Genome-wide scans of myopia in Pennsylvania Amish families reveal significant linkage to 12q15, 8q21.3 and 5p15.33.

Musolf Anthony M AM Simpson Claire L CL Alexander Theresa A TA Portas Laura L Murgia Federico F Ciner Elise B EB Stambolian Dwight D Bailey-Wilson Joan E JE

Human genetics 20190302 4

Myopia is one of the most common ocular disorders in the world, yet the genetic etiology of the disease remains poorly understood. Specialized founder populations, such as the Pennsylvania Amish, provide the opportunity to utilize exclusive genomic architecture, like unique haplotypes, to better understand the genetic causes of myopia. We perform genetic linkage analysis on Pennsylvania Amish families that have a strong familial history of myopia to map any potential causal variants and genes fo ...[more]

PMID: 30826882

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Project description:Myopia is a common visual disorder caused by eye overgrowth, resulting in blurry vision. It affects one in four Americans, and its prevalence is increasing. The genetic mechanisms that underpin myopia are not completely understood. Here, we use genotype data and linkage analyses to identify high-risk genetic loci that are significantly linked to myopia.Individuals from 56 Caucasian families with a history of myopia were genotyped on an exome-based array, and the single nucleotide polymorphism (SNP) data were merged with microsatellite genotype data. Refractive error measures on the samples were converted into binary phenotypes consisting of affected, unaffected, or unknown myopia status. Parametric linkage analyses assuming an autosomal dominant model with 90% penetrance and 10% phenocopy rate were performed.Single variant two-point analyses yielded three significantly linked SNPs at 11p14.1 and 11p11.2; a further 45 SNPs at 11p were found to be suggestive. No other chromosome had any significant SNPs or more than seven suggestive linkages. Two of the significant SNPs were located in BBOX1-AS1 and one in the intergenic region between ORA47 and TRIM49B. Collapsed haplotype pattern two-point analysis and multipoint analyses also yielded multiple suggestively linked genes at 11p. Multipoint analysis also identified suggestive evidence of linkage on 20q13.We identified three genome-wide significant linked variants on 11p for myopia in Caucasians. Although the novel specific signals still need to be replicated, 11p is a promising region that has been identified by other linkage studies with a number of potentially interesting candidate genes. We hope that the identification of these regions on 11p as potential causal regions for myopia will lead to more focus on these regions and maybe possible replication of our specific linkage peaks in other studies. We further plan targeted sequencing on 11p for our most highly linked families to more clearly understand the source of the linkage in this region.

Dataset Information

Genome-wide scans of myopia in Pennsylvania Amish families reveal significant linkage to 12q15, 8q21.3 and 5p15.33.

Publications

Genome-wide scans of myopia in Pennsylvania Amish families reveal significant linkage to 12q15, 8q21.3 and 5p15.33.

Similar Datasets

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