👤 Corey Tesdahl

Despite significant evidence of a genetic contribution to strabismus, precise genetic mechanisms have not been identified. There are distinct population differences in the prevalence of strabismus and its subtypes. This study aimed to explore the genetic contributions to strabismus in different ancestral groups. Case-control. The Genome-wide association study of common variants (minor allele frequency >1%) and rare variant association study at the gene level for strabismus. Individual single nucleotide polymorphisms (SNPs) significantly associated with strabismus and genes with significant burden of rare variants in strabismus. Genome-wide association study identified one locus with 3 significant SNPs (rs2247113, rs2667037, and rs2715926) in intron 1 of Genetic associations with strabismus differed between ancestry groups, although genes in similar pathways, such as synaptic signaling and structural muscle proteins, were found in multiple groups. This highlights the importance of including diverse populations in studies of genetic associations and suggests that multiple pathways may lead to strabismus in different population groups. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. Show less

Amblyopia is characterized by decreased visual acuity due to abnormal visual experience during development. It affects approximately 3% of the population and is associated with abnormal development of the visual cortex. Despite treatment, many patients have residual visual acuity deficits. This study aimed to explore the genetic contributions to amblyopia. Case-control. The All of Us Research Program includes genotypic and phenotypic data from a diverse population of adults (age ≥ 18 years) across the United States. A total of 764 subjects with amblyopia (based on International Classification of Diseases and Systematized Nomenclature of Medicine codes) and 122 305 controls with no record of amblyopia and with whole genome sequencing data were compared. Only participants of European genetic ancestry were included because of small numbers of affected participants in other ancestral groups. Genome-wide association study (GWAS) of common variants (minor allele frequency > 1%) and rare variant association study (RVAS) at the gene level for amblyopia of participants in the All of Us Research Program. Individual single nucleotide polymorphisms (SNPs) significantly associated with amblyopia and genes with significant burden of rare variants in amblyopia. The GWAS revealed 4 loci that approached statistical significance defined as P < 5e-8: rs56105618, rs1349660, rs7958343, and rs138693522. Each of the variants is an expression quantitative trait locus (eQTL) for a gene expressed in the brain or related to neural development. This RVAS revealed 15 genes with a statistically significant (P < 5e-05) different burden of variants: DCP1B, OR12D2, PCDHA4, ALKBH8, NMUR2, OR52P1P, NEU1, CACNB2, PSMA7, LRR1, ZNF831, FSIP2, ZNF654, CES5A, and MPV17, several of which have known roles in neurodevelopment. The identification of genes linked to amblyopia with roles in neurodevelopment suggests that the neurodevelopmental changes in amblyopia are not only secondary to abnormal visual experience but also may result from the interaction of primary neurodevelopmental deficits with abnormal experience. This potentially explains why some children develop amblyopia and others do not with the same ocular risk factors, may explain differences in treatment outcomes, and suggests new avenues for amblyopia treatment. Proprietary or commercial disclosure may be found after the references. Show less