Meta-analysis of 542,934 subjects of European ancestry identifies new genes and mechanisms predisposing to refractive error and myopia

Abstract

Refractive errors, in particular myopia, are a leading cause of morbidity and disability worldwide and their prevalence is rising, largely due to cultural and environmental changes. Genetic investigation is a valuable tool to better understand the molecular mechanisms underlying abnormal eye development and impaired vision. We conducted a meta-analysis of genome-wide association studies involving 542,934 European participants and identified 336 novel genetic loci associated with refractive error that explain an additional 4.6% of spherical equivalent heritability, or an improvement by a third over the previous estimates. Collectively, all associated genetic variants explain 18.4% of heritability and improve the accuracy of myopia prediction (AUC=0.75). Our results suggest that refractive error is genetically heterogeneous, driven by genes participating in the development of every anatomical component of the eye. In addition, our analyses suggest that genetic factors controlling circadian rhythm and pigmentation are also involved in the development of myopia and refractive error. These results may make possible predicting refractive error and the development of personalized myopia prevention strategies in the future.

Visual Image Quality Impacts Circadian Rhythm-Related Gene Expression in Retina and in Choroid: A Potential Mechanism for Ametropias

“…73 Further, another recent meta-analysis of human genome-wide association studies of refractive errors, applying Gene Ontology, identified "Circadian Rhythm" and "Circadian Regulation of Gene Expression" as two of the enriched gene sets. 74 Besides clinical genetics, the results here and our prior findings on altered clock and circadian rhythm-related genes in myopia, 15,16,48 support the possibility that the circadian clock and melanopsin may provide the mechanistic link between environmental light exposures and refractive development. 13…”

Sleeping late is a risk factor for myopia development amongst school-aged children in China

“…Seasonal changes reported in myopia progression could also suggest an impact of seasonal variations of circadian rhythms on the development of myopia 46 . Evidence supporting a role of circadian rhythm in myopia development is further strengthened by the results from a recent metaanalysis of genome-wide association studies, where genetic factors regulating circadian rhythm are identified to also participate in the development of myopia and refractive error 15 . Finally, yet importantly, several ocular biometry parameters, such as intraocular pressure (IOP), choroidal thickness, and axial length, were found to exhibit diurnal rhythms in humans 47,48 .…”

Elevated Melatonin Levels Found in Young Myopic Adults Are Not Attributable to a Shift in Circadian Phase

“…Supportive of the hypotheses presented by Chakraborty et al, 23 recent work demonstrates that knockout of the circadian gene Bmal1 in the mouse retina or the circadian genes cycle and period in Drosophila melanogaster both result in myopic phenotypes, 24 and findings from a recent meta-analysis of genome-wide association studies suggest that genetic factors that control circadian rhythms are involved in human myopia development. 25 Circadian rhythms are biological processes that display an endogenous, entrainable oscillation of approximately 24 hours. In humans, these rhythms form a hierarchy of oscillators, orchestrated by a central pacemaker located in the suprachiasmatic nuclei (SCN), to synchronize our physiology and behaviors to the changing demands of the daynight cycle.…”

“…Supportive of the hypotheses presented by Chakraborty et al, 23 recent work demonstrates that knockout of the circadian gene Bmal1 in the mouse retina or the circadian genes cycle and period in Drosophila melanogaster both result in myopic phenotypes, 24 and findings from a recent meta-analysis of genome-wide association studies suggest that genetic factors that control circadian rhythms are involved in human myopia development. 25 …”