Supplementary Material for: Circadian and sleep-related polygenic scores in relation to lithium treatment response in bipolar disorder

Introduction
Circadian rhythms are reflected through sleep-wake patterns and chronotype. Patients with bipolar disorder (BD) frequently exhibit disrupted sleep patterns, and a tendency for evening chronotype. Also, genetic risk factors for BD partially overlap with those influencing sleep traits. Lithium (Li), the first-line therapy for BD, stabilizes circadian rhythms and promotes morningness in responders. This study aimed to evaluate whether the polygenic burden of sleep-related traits is associated with Li response in BD patients.
Methods
A total of 114 European-ancestry BD patients were categorized as Li responders (N=79) or non-responders (N=35), based on the reduction of 50% of the episodes. Polygenic scores (PGS) for chronotype, daytime dozing, ease of getting up, insomnia, morningness, napping, sleep duration, and snoring were calculated using PRS-CS. Associations between each PGS and Li response were tested using logistic regression models. Comparisons were made between the extreme quartiles of each PGS.
Results
The polygenic score for ease of getting up was significantly associated with Li response, explaining 9.989% of the variance based on Nagelkerke’s pseudo-R² (FDR-adjusted p-value= 0.046). Additionally, individuals with a higher genetic predisposition for ease of getting up had increased odds of a good response (FDR-adjusted p-value= 0.039; OR= 5.143; 95% CI= 1.537–17.209).
Conclusion
The study suggests that a higher genetic predisposition for ease of getting up in the morning may increase the likelihood of responding to Li treatment in BD patients. Our study aligns with previous evidence, highlighting the importance of sleep and chronotype patterns in response to Li in BD patients.