Associations of a multidimensional polygenic sleep health score and a sleep lifestyle index on health outcomes and their interaction in a clinical biobank

Sleep is a complex behavior regulated by genetic and environmental factors, and is known to influence health outcomes. However, the effect of multidimensional sleep encompassing several sleep dimensions on diseases has yet to be fully elucidated. Using the Mass General Brigham Biobank, we aimed to examine the association of multidimensional sleep with health outcomes and investigate whether sleep behaviors modulate genetic predisposition to unfavorable sleep on mental health outcomes. First, we generated a Polygenic Sleep Health Score using previously identified single nucleotide polymorphisms for sleep health and constructed a Sleep Lifestyle Index using data from self-reported sleep questions and electronic health records; second, we performed phenome-wide association analyses between these indexes and clinical phenotypes; and third, we analyzed the interaction between the indexes on prevalent mental health outcomes. Fifteen thousand eight hundred and eighty-four participants were included in the analysis (mean age 54.4; 58.6% female). 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<3.3×10−5). The Sleep Lifestyle Index was associated with 458 disease outcomes spanning 17 groups, including sleep, mood, and anxiety disease outcomes (p<5.1×10−5). No interactions were found between the indexes on prevalent mental health outcomes. These findings suggest that favorable sleep behaviors and genetic predisposition to healthy sleep may independently be protective of disease outcomes. This work provides novel insights into the role of multidimensional sleep on population health and highlights the need to develop prevention strategies focused on healthy sleep habits. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement VP was funded by Comision Sectorial de Investigacion Cientifica (CSIC, UdelaR, Uruguay), Programa de Desarollo de las Ciencias Basicas (PEDECIBA, MEC-UdelaR, Uruguay) and Comision Academica de Posgrados (CAP, UdelaR, Uruguay). VG was funded by the Professor David Matthews Non-Clinical Fellowship (ref: SCA/01/NCF/22) and the UK Medical Research Council (MC\_UU\_00019/2). HSD is supported by the National Institutes of Health (grant number R00HL153795). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The present study protocol was approved by the MGB Institutional Review Board (#2018P002276). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data are available from the Mass General Brigham Human Research Office/Institutional Review Board at Mass General Brigham (contact located at https://www.partners.org/Medical-Research/Support-Offices/Human-Research-Committee-IRB/Default.aspx) for researchers who meet the criteria for access to confidential data.