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Anthony Musolf, Claire L. Simpson, Laura Portas, Federico Murgia, Qing Li, Elise B. Ciner, Dwight Stambolian, Joan E Bailey-Wilson; Myopia in Amish Families Linked to Five Chromosomes. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1824. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Myopia is a complex ocular disorder that affects about 25% of Americans. However, the genetic underpinnings of myopia are still not well understood. This study uses Amish families with a history of myopia to find genetic linkage between myopia and genetic variants. As the Amish are a founder population with lower near work exposure than the general population, families with multiple affected family members have a higher chance of containing highly penetrant variants of large effect.
We analyzed exome enriched array genotypes for 349 patients from 43 extended Amish families. The phenotype was myopia affectation; individuals were coded as either affected, unaffected, or unknown. Two discrete types of two-point parametric linkage analysis were performed: variant-based and gene-based. Variant-based analysis tested for linkage between the phenotype and individual SNPs while gene-based analysis tested for linkage using haplotypes of rare variants located within a gene. We assumed an autosomal dominant model with a disease allele frequency of 1% and a 90% penetrance for carriers and 10% phenocopy rate.
Both the variant-based and gene-based tests identified loci that were genome-wide significant or highly suggestive in the individual families. Each linkage was unique to a family and many of the linkages were present along long linked haplotypes (as expected in family data). It is likely that these linkage regions are carrying variants of high effect on disease risk. Our most interesting linked haplotypes were present at 1p36.22-32.2, 12q14.2-21.1, 3p14.1-q13.13, 4p14-q12 and 5p15.33. The signal at 5p was the highest (LOD = 3.3) and was genome-wide significant (which is very rare for a single family). All of these regions contain good candidate genes, such as GUCA1C (3q13), which is known to be expressed in retinal photoreceptors. Two regions have shown linkage in other studies: MYP14 and MYP3 at 1p36 and 12q21. All of the linked haplotypes contained rare variant(s).
We have identified several linked regions to myopia in Amish extended families. Each family contained different linked regions and the high LOD scores within the different families suggest the possibility of highly penetrant, large risk effect genes. The linked regions have quality candidate genes and targeted sequencing is planned on the linked haplotypes to elucidate the causal variant(s).
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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