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OBJECTIVES: Sleep is a complex behavior regulated by genetic and environmental factors impacting disease outcomes. However, the effect of multidimensional sleep encompassing several sleep dimensions on common diseases, specifically mental health disorders, has yet to be fully elucidated. Using the Mass General Brigham Biobank, we examined the association of multidimensional sleep with disease outcomes and investigated whether sleep behaviors modulate genetic predisposition to unfavorable sleep on mental health diseases.METHODS: We generated a Polygenic Sleep Health Score using previously identified single nucleotide polymorphisms and constructed a Sleep Lifestyle Index based on self-reported questions and electronic health records; tested their association; performed phenome-wide association analyses between these indexes and clinical phenotypes; and analyzed their interaction on prevalent mental health diseases. A total of 15,884 participants were included in the analysis (mean age 54.4; 58.6% female).RESULTS: The Polygenic Sleep Health Score was associated with the Sleep Lifestyle Index (β=0.050, 95% CI=0.032, 0.068) and with 114 disease outcomes spanning 12 disease groups, including obesity, sleep, and substance use disease outcomes (p<3.3×10). The Sleep Lifestyle Index was associated with 458 disease outcomes spanning 17 groups, including sleep, mood, and anxiety disease outcomes (p<5.1×10). A total of 108 disease outcomes were associated with both indexes, spanning 12 disease groups. No interactions were found between the indexes on mental health diseases.CONCLUSIONS: Favorable sleep behaviors and genetic predisposition to healthy sleep may independently protect against disease, underscoring the impact of multidimensional sleep on population health and the need for prevention strategies focused on healthy sleep habits.