LAUSR

Background In Bipolar Disorder (BD), some endophenotypes such as the occurrence of psychotic symptoms or suicide attempts, the level of psychosocial functioning, disorder subphenotypes like type I/II disorder and comorbidities like alcohol or drug abuse are highly familial. We explored whether polygenic risk scores for bipolar disorder (BD-PRS) or schizophrenia (SZ-PRS) can predict these phenotypes in a sample of German and Austrian patients diagnosed with BD according to DSM-IV-criteria. Methods The present study included 326 BD patients belonging to the German KFO/PsyCourse cohort (www.kfo241.de; www.PsyCourse.de). The study protocol was approved by the local ethics committees and is in accordance with the 1964 Declaration of Helsinki. Sociodemographic and clinical information on patients was assessed using a comprehensive inventory for phenotype characterization. Association of BD- and SZ-PRS with target variables was tested via logistic regression analyses at several inclusion p-value thresholds (0.00000005 to 1). Polygenic risk scores were calculated using imputed, quality-controlled genome-wide patient genotypes (Illumina Infinium PsychArray) and summary statistics of two large case-control genome-wide association studies (Hou et al., 2016; PGC-Schizophrenia-Working-Group, 2014). Results were corrected for age, sex, recruitment center, duration of illness and population stratification. Results A higher SZ polygenic burden was significantly associated with lifetime use of illicit drugs at several p-value thresholds (strongest association at threshold 0.0001, R2 change 2.7%, p-value=0.005). Only with one threshold a slightly positive association of SZ-PRS with alcohol abuse was observed (0.0000001, R2change 3.1%, p=0.026). Patients diagnosed with bipolar I disorder had higher SZ-PRS compared to patients with bipolar II disorder at several thresholds (strongest association at 0.05 threshold, R2 change= 2.4%, p=0.020, OR=1,6). We found no significant association of SZ-PRS with other target variables. Higher BD-PRS were significantly associated with higher levels of psychosocial functioning in our patient sample (measured by Global-Assessment-of-Functioning-scores, strongest effect at threshold 0.001, R2 change= 2.6%, p=0.014,), but not with any other target variable. Discussion Our results suggest that a higher polygenic SZ burden plays a bigger role for lifetime occurrence of substance abuse in BD patients than the polygenic BD burden. Also, there may be a stronger genetic overlap between schizophrenia and BD I disorder subtype than between schizophrenia and BD II disorder subtype. Interestingly, a higher polygenic BD burden may even have positive effects on overall psychosocial functioning in BD patients.