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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.

Original publication

DOI

10.1007/s00439-019-01991-0

Type

Journal article

Journal

Human genetics

Publication Date

04/2019

Volume

138

Pages

339 - 354

Addresses

Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, 333 Cassell Dr, Suite 1200, Baltimore, MD, 21224, USA.

Keywords

Chromosomes, Human, Pair 5, Chromosomes, Human, Pair 8, Chromosomes, Human, Pair 12, Humans, Myopia, Genetic Predisposition to Disease, Family, Gene Frequency, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Child, Child, Preschool, Pennsylvania, Female, Male, Genome-Wide Association Study, Genetic Linkage, Amish