Caucasian Families Exhibit Significant Linkage of Myopia to Chromosome 11p

Abstract

PurposeMyopia 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.MethodsIndividuals 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.ResultsSingle 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.ConclusionsWe 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.

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

“…The linked variant and gene do not have any prior evidence of involvement in causation of myopia or eye disease in general. However other protein tyrosine phosphatase receptors have been associated or linked with myopia including PTPRR, PTPRF, and PTPRJ (Haw thorne et al 2013;Musolf et al 2017). Both PTPRR and PTPRF have been put forth as possible candidate genes for the MYP3 locus at 12q21-24.…”

“…On the genetic side, population-based genome-wide association studies (GWAS) have identified multiple risk loci for a negative refractive error (Fan et al 2016;Kiefer et al 2013;Miyake et al 2015;Simpson et al 2014;Simpson et al 2013;Stambolian et al 2013;Verhoeven et al 2012;Verhoeven et al 2013), although the vast majority of these associations are to common variants with small to moderate effect. Family-based linkage studies have identified several linked regions that appear to harbor risk loci as well (Ciner et al 2009;Guo et al 2015;Musolf et al 2017;Stambolian et al 2004;Wojciechowski et al 2006;Zhou et al 2015). although the actual causal variant(s) at the linked and/or associated loci mostly remain unknown.…”

Linear mixed models for association analysis of quantitative traits with next‐generation sequencing data

“…To evaluate the performance of the ‐test and LRT statistics in a more realistic setting, we exploit exome chip genotypes and a quantitative trait, refractive error measured in Diopters, from Amish families that are part of the Myopia Family Study (Wojciechowski, Bailey‐Wilson, et al, ; Wojciechowski, Stambolian, et al, ). After sample quality checks using a thorough and rigorous data cleaning pipeline, which included checks for chromosomal aberrations, gender, Hardy–Weinberg equilibrium, relatedness, duplicates, and genotype quality, 300 genotyped and phenotyped individuals were available for analysis (see Wojciechowski, Bailey‐Wilson, et al, , for details of quality control on phenotype data; Musolf et al, , , for details of exome chip genotype data quality control processes). To completely specify the pedigree structures, we included nongenotyped or nonphenotyped individuals who shared the same family with phenotyped and genotyped family members.…”

“…The LMMs and FLMMs are an extension of traditional variance component models (Amos, ; Lange, ). We evaluate the performance of the LMMs and FLMMs via extensive simulations and illustrate their application by analyzing a complex trait, refractive error, with exome chip genotyping of Amish pedigrees (Musolf et al, , ; Wojciechowski, Bailey‐Wilson, & Stambolian, ; Wojciechowski, Stambolian et al, ).…”

Potential Mutations in Chinese Pathologic Myopic Patients and Contributions to Phenotype

“…However, previous data provided strong evidence that genetic factors also play a key role. Twin studies and genetic linkage analysis studies revealed a handful of potential loci for myopia-related genes [8, 9]. Recently, genome-wide association studies (GWAS) with large sample sizes identified more than 100 single nucleotide polymorphisms (SNPs) that influence myopia.…”