0042 Gene-by-Sleep Duration Interaction for Glycemic Traits in Over 480,000 Individuals

Abstract Introduction Both short and long sleep duration have been associated with poor glycemic control and an increased risk of developing type 2 diabetes mellitus. Although sleep duration extremes may differentially modify the effects of genetic risk factors for type 2 diabetes, this has not been systematically investigated. Methods We conducted genome-wide gene by sleep duration meta-analyses, separately assessing interactions of short and long sleep, for fasting glucose, fasting insulin, and hemoglobin A1c in up to 4893, 09 individuals without diabetes from seven different population groups. Both 2 degree of freedom (df) joint tests of main and interaction effects, and 1df interaction tests were employed. Results In total, 16 loci were identified to interact with sleep duration — six with short sleep and ten with long sleep. Of these, four loci were identified through cross-population meta-analysis, twelve were specific to a population group, and eleven showed significant sex-dependent effects. Eleven loci (VRK2, PCDH7, TFAP2A, CAP2, PAPPA, ZCCHC2, MYH9, SGIP1, JAKMIP3, RRAS2, MAPT) have not been reported in previous glycemic trait genome-wide association studies. Interaction loci identify divergent biological mechanisms for short and long sleep duration influencing glycemic control, such as copper regulation for long sleep and diacylglycerol pathways for short sleep. The identified gene targets suggest potential therapeutic approaches for type 2 diabetes, including strategies involving JIP1–JNK interaction disruption, pericyte health, NMDA receptor activity, anti-inflammatory and leptin-enhancing dietary supplements, and serpins. Conclusion These findings suggest that short and long sleep duration influence glycemic regulation through distinct biological pathways, providing novel insights for precision approaches to diabetes prevention and management. Support (if any) NHLBI R01HL118305 and R01HL156991