Genome-wide gene by environment study of time spent in daylight and chronotype identifies emerging genetic architecture underlying light sensitivity

Light is the primary stimulus for synchronizing the circadian clock in humans. There are very large interindividual differences in the sensitivity of the circadian clock to light. Little is currently known about the genetic basis for these interindividual differences. We performed a genome-wide gene-by-environment interaction study (GWIS) in 280,897 individuals from the UK Biobank cohort to identify genetic variants that moderate the effect of daytime light exposure on chronotype (individual time of day preference), acting as light sensitivity variants for the impact of daylight on the circadian system. We identified a genome-wide significant SNP mapped to the ARL14EP gene (rs3847634; p < 5x10-8), where additional minor alleles were found to enhance the morningness effect of daytime light exposure ({beta}GxE = -.03, SE = 0.005) and were associated with increased gene ARL14EP expression in brain and retinal tissues. Gene-property analysis showed light sensitivity loci were enriched for genes in the G protein-coupled glutamate receptor signaling pathway and in Per2+ hypothalamic neurons. Linkage disequilibrium score regression identified significant genetic correlations of the light sensitivity GWIS with chronotype and sleep duration, such that greater light sensitivity was associated with later chronotype, greater insomnia symptoms and shorter sleep duration. Greater light sensitivity was also genetically correlated with greater risk for PTSD. This study is the first to assess light as an important exposure in the genomics of chronotype and is a critical first step in uncovering the genetic architecture of human circadian light sensitivity and its links to sleep and mental health.