Clinical characteristics indexing genetic differences in bipolar disorder – a systematic review

Bipolar disorder is a heterogenous condition with a varied clinical presentation. While progress has been made in identifying genetic variants associated with bipolar disorder, most common genetic variants have not yet been identified. More detailed phenotyping (beyond diagnosis) may increase the chance of finding genetic variants. Our aim therefore was to identify clinical characteristics that index genetic differences in bipolar disorder. We performed a systematic review of all genome-wide molecular genetic, family, and twin studies investigating familial/genetic influences on the clinical characteristics of bipolar disorder. We performed an electronic database search of PubMed and PsycInfo until October 2022. We reviewed title/abstracts of 2693 unique records and full texts of 391 reports, identifying 445 relevant analyses from 142 different reports. These reports described 199 analyses from family studies, 183 analyses from molecular genetic studies and 63 analyses from other types of studies. We summarized the overall evidence per phenotype considering study quality, power, and number of studies. We found moderate to strong evidence for a positive association of age at onset, subtype (bipolar I versus bipolar II), psychotic symptoms and manic symptoms with familial/genetic risk of bipolar disorder. Sex was not associated with overall genetic risk but could indicate qualitative genetic differences. Assessment of genetically relevant clinical characteristics of patients with bipolar disorder can be used to increase the phenotypic and genetic homogeneity of the sample in future genetic studies, which may yield more power, increase specificity, and improve understanding of the genetic architecture of bipolar disorder.