Genetic variants affect diurnal glucose levels throughout the day.

Circadian rhythms not only coordinate the timing of wake and sleep but also regulate homeostasis within the body, including glucose metabolism. The genetic variants that contribute to the temporal control of glucose levels have not been previously examined. Using genome-wide data from ~420,000 individuals from the UK Biobank and replication in ~100,000 individuals from the Estonian Biobank, ~500,000 from FinnGen, ~160,000 from the VA Million Veteran Program, and ~52,000 from the MGB Biobank, we show that glucose levels are under diurnal genetic control. We discover a robust temporal association of glucose levels at the Melatonin receptor 1B (MTNR1B, rs10830963, P = 1×10-22) and a canonical circadian pacemaker gene Cryptochrome 2 (CRY2) loci (rs12419690, P = 1×10-16). Furthermore, we show that sleep modulates glucose levels, and the genetic variants have an independent role in diurnal glucose control. Finally, we show that these variants independently modulate risk of type 2 diabetes and that sleep medications including melatonin associate with type 2 diabetes. Our findings, together with earlier genetic and epidemiological evidence, show a clear connection between sleep and metabolism and highlight genetic variation at MTNR1B and CRY2 in the control of diurnal glucose levels.