Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error

160,420 participants in discovery, 95,505 in replication

European and Asian ancestry adult cohorts

Genome-wide association meta-analysis with independent replication, plus expression experiments and in silico functional annotation. Graded C for this archive's purposes because GWAS establishes genetic architecture and biological mechanism, not the causal effect of any educational input. Included for the mechanism it implicates, which is directly relevant to the outdoor-time trials.

Established independent genetic signals for refractive error rose from 37 to 161. Genetic correlation between Europeans and Asians exceeded 0.78 - the genetic architecture of myopia is largely shared across the populations with wildly different myopia prevalence, so the East Asian myopia epidemic is an environmental shift acting on a common genetic substrate, not a different genetic disease. Functional analysis implicates retinal cell physiology and light processing as the prominent mechanisms, supporting a light-dependent retina-to-sclera signalling cascade, with contributions from all neurosensory retinal cell types, retinal pigment epithelium, vascular endothelium and extracellular matrix. Thirty-one loci sit in or near small-RNA regions.

Not applicable as confound - this is the genetic-architecture evidence itself. Its relevance to the topic is that the heritable pathway and the modifiable environmental lever are the same pathway: light hitting the retina. That is why an environmental intervention (outdoor light) works on a highly heritable trait without contradicting the heritability estimate.