PubMed · 4896640
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G K Von Noorden. 1969. Strabismus.. https://doi.org/10.1001/archopht.1969.00990020395019
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OBJECTIVE: To identify genetic variants associated with amblyopia in African (AFR) and Admixed American (AMR) ancestry groups, expanding on previous studies conducted in European ancestry. DESIGN: Retrospective ancestry-stratified genome-wide association study (GWAS) and gene-level rare variant association study (RVAS). PARTICIPANTS: Participants in the All of Us Research Program from AFR and AMR ancestry groups who had whole-genome sequencing available. Cases and controls were distinguished based on the presence of International Classification of Diseases 9/10/SNOMED diagnosis codes for amblyopia in electronic health records. This yielded ancestry-stratified subsets of 269 cases and 71 585 controls of AMR ancestry and 366 cases and 79 460 controls of AFR ancestry. METHODS: Stratified logistic regression models were adjusted for age, biological sex, and the top 10 principal components of genomic ancestry. GWAS was limited to common variants (minor allele frequency ≥1%), and RVAS was limited to rare variants with coding sequence-altering effects (minor allele frequency >1%, exonic only, excluding synonymous variants) aggregated at the gene level using the SKAT algorithm. Downstream analyses of the significant variants were performed using KEGG and GO pathway analysis and STRING database queries for protein-protein interactions and gene-gene interactions. MAIN OUTCOME MEASURES: Single-nucleotide polymorphisms were determined to have genome-wide significance if P < 5e-8 in the GWAS, and genes were determined to have significant association with amblyopia in the RVAS if P < 8.0 × 10-4. RESULTS: In the AMR GWAS, 245 unique single-nucleotide polymorphisms mapping to 97 distinct loci were identified, notably within neurodevelopmental and axonal guidance genes, including ROBO1, SEMA4B, PTPRD, NRXN1, and CAMK2D. The AFR GWAS identified 11 significant variants corresponding to 6 loci mapping primarily to long noncoding RNAs and pseudogenes. The AMR RVAS identified 15 genes, including axonal transport genes (KIF1B and KIF7) and growth factor signaling genes (EGF, ERBIN, and AKAP17A). The AFR RVAS identified a single gene, DLG2, which encodes the postsynaptic protein PSD-93, which promotes the closure of the sensitive period of neuroplasticity for vision in early childhood. CONCLUSIONS: Genetic risk architectures for amblyopia differ across ancestries but fundamentally converge on neurodevelopmental signaling, cortical synapse assembly, and sensitive period plasticity rather than ocular structural dynamics. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.
We assessed refractive errors in 19 monkeys (Macaca nemestrina) raised with experimentally produced strabismus or unilateral defocus. These procedures resulted in hyperopic anisometropia in 10 monkeys. All 10 of the hyperopic animals were amblyopic; the amblyopic eye was always the more hyperopic eye. The degree of anisometropia was correlated with the degree of amblyopia. Hyperopic anisometropia did not develop in non-amblyopic animals. There was an association between early onset of visual abnormality and later development of hyperopic anisometropia. Since the refractive changes were correlated with changes in axial length and vitreous chamber depth, we suggest that amblyopia may cause alterations in eye growth and late-onset hyperopia.
Although the spatial vision deficits of human strabismic amblyopes have been well documented, surprisingly little is known about the mechanisms underlying their visual performance. In an effort to reveal the structure underlying the spatial vision deficits associated with strabismic amblyopia, we measured the performance of monkeys (Macaca nemestrina) with experimental strabismus in a contrast detection task with oblique masks. The masks were two adjacent identical oblique sine-wave gratings modulated in space by a Gaussian envelope. The target stimulus was a vertically oriented Gabor patch that appeared superimposed on the center of either the left or the right mask. The animals were trained by operant methods to indicate the location of the target. We measured detection thresholds in each eye independently for a large number of test and mask spatial frequencies. For each test spatial frequency, detection thresholds were elevated in the presence of the mask. The threshold evaluations showed a peak for a particular spatial frequency that was typically similar to the test spatial frequency. This pattern of results is consistent with the idea that the tests are detected by a discrete number of channels tuned to a narrow range of spatial frequencies. The data from the deviated eyes did not appear qualitatively different from those of the fellow eyes, and could be accounted by the same number of channels in both eyes. Quantitative estimates of the channels' characteristics revealed that the channels derived from the deviated eyes' data were similar to those yielded by the fellow eyes, but showed a reduction in their sensitivity to contrast.