Sex-Specific Associations of Late Chronotype and Genetic Risk With Incident Metabolic Syndrome Running Title: Sex Differences of Late Chronotype and Genetic Risk of Metabolic Syndrome

Abstract We attempted to evaluate the association between late chronotype and incidental metabolic syndrome differently by sex and menopausal status. Late chronotype was defined as habitual bedtime after midnight while polygenic risk score (PRS) was constructed to assess genetic susceptibility of MetS. By analyzed 35,156 adults (11,885 men and 23,271 women) from the Taiwan Biobank who were free of MetS at baseline and followed for a mean of 4.5 years, we had identified the prevalence of self-reported late chronotype was comparable between men and women. Despite younger age, men with a late chronotype had a higher incidence of MetS than those with an early chronotype (20.6% vs. 18.2%, P = 0.031). A smaller but significant increase was observed in women (15.8% vs. 15.2%, P = 0.011), with a more pronounced association in postmenopausal women (22.4% vs. 20.4%, P < 0.001). Late chronotype and MetS PRS independently increased MetS risk in both sexes. After adjustment for lifestyle factors, late chronotype was associated with higher MetS risk across all PRS tertiles in men, whereas in women the association was evident only in the highest PRS tertile. We conclude that late chronotype is associated with an increased risk of incident MetS, with associations differing according to sex and menopausal status.