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

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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.

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Acknowledgements

The authors thank all study participants and their families. This work was funded in part by the National Eye Institute Grant R01 EY020483 and the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health.

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Authors and Affiliations

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

    Anthony M. Musolf, Claire L. Simpson, Theresa A. Alexander, Laura Portas, Federico Murgia & Joan E. Bailey-Wilson

  2. Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN, USA

    Claire L. Simpson

  3. Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN, USA

    Claire L. Simpson

  4. The Pennsylvania College of Optometry at Salus University, Elkins Park, PA, USA

    Elise B. Ciner

  5. Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA, USA

    Dwight Stambolian

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  1. Anthony M. Musolf
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Musolf, A.M., Simpson, C.L., Alexander, T.A. et al. Genome-wide scans of myopia in Pennsylvania Amish families reveal significant linkage to 12q15, 8q21.3 and 5p15.33. Hum Genet 138, 339–354 (2019). https://doi.org/10.1007/s00439-019-01991-0

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