September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Strong Evidence for Myopia Linkage on Chromosomes 1, 3, and 15 in Pennsylvania Amish Families
Author Affiliations & Notes
  • Anthony M Musolf
    National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland, United States
  • Claire L Simpson
    National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland, United States
  • Federico Murgia
    Institute of Population Genetics, Sassari, Italy
  • Laura Portas
    Institute of Population Genetics, Sassari, Italy
  • Qing Li
    National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland, United States
  • Dwight Stambolian
    Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Joan E Bailey-Wilson
    National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland, United States
  • Footnotes
    Commercial Relationships   Anthony Musolf, None; Claire Simpson, None; Federico Murgia, None; Laura Portas, None; Qing Li, None; Dwight Stambolian, None; Joan Bailey-Wilson, None
  • Footnotes
    Support  5-R01-EY-020483-05
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 2495. doi:
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      Anthony M Musolf, Claire L Simpson, Federico Murgia, Laura Portas, Qing Li, Dwight Stambolian, Joan E Bailey-Wilson; Strong Evidence for Myopia Linkage on Chromosomes 1, 3, and 15 in Pennsylvania Amish Families. Invest. Ophthalmol. Vis. Sci. 2016;57(12):2495.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : We have previously reported on linkage analysis of extended Pennsylvania Amish families, finding suggestive evidence of linkage to 5qter. Exome array analysis was performed to attempt to refine this signal and find other evidence of linkage elsewhere in the genome.

Methods : Illumina Exome Array genotyping was performed in 65 extended Old Order Amish families recruited to the Myopia Family Study. Prior genome-wide microsatellite data was merged with exome-focused SNP data from an array. Myopia was defined as used previously as a mean spherical equivalent (MSE) of -1D or worse and both two-point (MCLink) and multi-point (SimWalk2) parametric linkage analyses were performed, using a disease allele (D) frequency of 0.0133 and penetrance model of 0.9/0.9/0.0 for DD/Dd/dd genotypes.

Results : Low coverage of the prior linkage region on 5qter resulted in no further refinement of this signal. However, we saw suggestive evidence of replication of known myopia loci including MYP9 (4q12, max HLOD=2.61), MYP17 (7p15, max HLOD 2.83), MYP18 (14q21, max HLOD=2.05), and the GWAS loci 15q14 (max HLOD=2.4). Examination of individual family LOD scores found several additional regions of interest. The strongest LOD scores came from a 7.8 Mb region of 15q in Family 3012; 14 SNPs ranged from 1.8 – 2.3. The most promising candidate gene in the region is HERC2, which is expressed in the retina. Another strong signal of linkage (LOD score = 2.01) was observed in Family 3041, in a variant in the ZPLD1 (zona pellucida-like domain containing 1) gene on chromosome 3. The last interesting linkage peak is located in a 23.6 Mb region on 1q in Family 3022. Though the region is only suggestive (LOD scores ranging from 1.5 – 1.8), two excellent candidate genes are located here. CRB1 is known to localize to the inner segment of mammalian photoreceptors. USH2A is thought to be involved in retinal development and known to be linked to Usher syndrome. Both variants in USH2A had LOD scores of 1.46 and were exonic. Ten other families showed suggestive linkage peaks across the genome.

Conclusions : We have identified at least three strong candidate regions for myopia in Old Order Amish families. Two of these regions have genes that are known to be associated with eye disease. Targeted sequencing of these regions will be needed to find the variants responsible for these linkage peaks.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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