Visual acuity significantly impacts quality of life, with deficits in childhood linked to reading difficulties and poor educational outcomes. While adult studies show a positive association between myopia and higher educational attainment (EA), the genetic factors and developmental trajectory remain unclear. This study aimed to understand the genetic contributions to childhood visual acuity and its relationship with cognitive skills and education. The researchers hypothesized that genetic factors influencing EA would positively associate with childhood visual acuity, while those increasing myopia risk would show a negative association. This contrasting pattern would suggest gene-environment correlation, where genetic predispositions to higher EA lead to environmental exposures (e.g., increased near work) that negatively impact vision later in life. The study used the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort to examine these associations, conducting a GWAS to identify specific genetic loci influencing visual acuity and employing polygenic scores (PGS) to investigate associations with cognitive measures, neurodevelopmental conditions, and visual phenotypes. This multifaceted approach aimed to provide a more comprehensive understanding of the complex relationship between genes, environment, and visual acuity throughout development.

Previous research has explored the association between visual acuity and neurodevelopmental conditions like ADHD and ASD, yielding mixed results. The magnocellular theory of dyslexia proposes a link between visual and auditory sensitivity and reading skills. Studies on the relationship between visual acuity and reading have shown inconsistent findings, with some showing no association after adjusting for confounding factors, while others demonstrated reduced visual acuity in children with reading difficulties. Several GWAS have investigated refractive error and myopia, identifying numerous loci, primarily in adult cohorts. However, these studies show differing effects across age groups, suggesting gene-environment interactions. Mendelian randomization studies indicate that higher EA is a causal risk factor for myopia in adults, contrasting with the potential positive association observed in childhood. This discrepancy highlights the need to investigate the developmental trajectory of these relationships and the potential role of gene-environment correlation.

The study utilized data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK population-based longitudinal cohort. Visual acuity was assessed in 6807 children (mean age 11.8 years) using a logMAR chart, with the best-corrected visual acuity from both eyes used for analysis. Cognitive measures included reading skill, communication skills, listening comprehension, short-term memory, total IQ, verbal IQ, performance IQ, and GCSE scores. Socioeconomic status (SES) was assessed using maternal education. A GWAS was performed on 5571 children with available genotype data. Genotype quality control included filtering for European ancestry and imputation using the HRC 1.1 reference panel. SNP-heritability (h²) and genetic correlations were estimated using GCTA-GREML. A linear mixed model (LMM) in BOLT-LMM was used for association testing in the GWAS. Replication analysis was conducted for SNPs previously associated with refractive error or myopia. Post-GWAS analyses involved FUMA and FINDOR for gene-based and gene set enrichment analyses. Finally, polygenic scores (PGS) for neurodevelopmental disorders, EA, and visual function were tested for associations with visual acuity using PRSice. Statistical analyses included linear regression, partial correlation, ANOVA, and LD score regression.

Better visual acuity was positively associated with higher cognitive performance, including GCSE scores (p<3.0x10^-7), even after adjusting for confounding factors like sex, reading skill, IQ, and SES (r=0.05, p=0.001). Children with reading difficulties had significantly reduced visual acuity compared to controls (p<0.0001). The GWAS identified 12 SNPs at the NPLOC4 locus on chromosome 17 reaching genome-wide significance (p=2.1x10^-8), with each copy of the major allele associated with better visual acuity. Gene-based analysis confirmed NPLOC4's association. Replication analysis highlighted loci in NPLOC4 and PDE6G, both implicated in previous vision GWAS. Significant positive genetic correlations were observed between visual acuity and cognitive measures like listening comprehension, short-term memory, and GCSE scores. EA PGS showed a robust positive association with visual acuity (p=0.0001), while myopia PGS showed a negative association, supporting the hypothesized gene-environment correlation. No associations were found between PGS for neurodevelopmental disorders and visual acuity.

This study provides strong evidence for the positive association between childhood visual acuity and cognitive development, particularly language-related skills, aligning with the magnocellular theory of dyslexia. The identified association with the NPLOC4 locus, replicated from previous adult studies, contributes to the understanding of the genetic architecture of visual acuity. The finding of a positive association between EA PGS and visual acuity in children, contrasting with the negative association found in adults, supports the proposed gene-environment correlation model. Genetic predisposition to higher EA might lead to increased near-work activities, ultimately increasing myopia risk. These findings highlight the complex interaction between genetic predisposition, environmental exposures, and visual development. While the findings indicate the importance of good visual acuity for positive developmental outcomes, further longitudinal studies are necessary to confirm these relationships and examine the causal relationships more precisely.

This study confirms the positive association between childhood visual acuity and cognitive development, particularly reading skills. The GWAS identified the NPLOC4 locus as significantly associated with visual acuity, replicating findings from adult studies. The positive association between EA PGS and childhood visual acuity, in contrast to the negative association observed in adults, suggests a gene-environment correlation where the initial positive effect is offset by increased near-work exposure. Future research should focus on longitudinal studies to track these associations over time and utilize more refined visual phenotypes to clarify the complex interplay between genetics, environment, and visual development.

The use of maternal education as a proxy for SES might not fully capture all relevant aspects of socioeconomic environment. The cross-sectional nature of the visual acuity and education assessments limits the ability to determine causal relationships. The single time point assessment of visual acuity prevents distinguishing between corrected and uncorrected refractive error. Future studies should incorporate longitudinal designs, diverse SES measures, and more detailed visual phenotype assessments.