Use of polygenic risk scores in bipolar disorder sub-phenotypes: a systematic review

Bipolar disorder (BD) is a highly heritable disease, with genetic influences explaining 60–85% of the risk. Clinical presentation is heterogeneous, often co-occurring with other mental illnesses and medical conditions. To better understand its pathophysiology, BD has been conceptualized in multiple sub-phenotypes with diverse clinical characteristics and courses of illness. Although BD type I (BDI) and type II (BDII) are the most widely recognized sub-phenotypes, others such as BD with psychosis, suicidality, and early onset, can also be encompassed within this term. There is evidence to suggest that BD sub-phenotypes might be partly genetically determined. Hence, polygenic risk scores (PRSs) for various diseases and traits have been tested for their association with BD sub-phenotypes. We aimed to review the studies investigating the association between diverse PRSs and BD sub-phenotypes. We conducted a systematic review following the PRISMA 2020 statement (PROSPERO CRD42022377199). Medline, Cochrane, Embase, Scopus, and Web of Science databases were searched in October 2022 for the terms “bipolar disorder”, “polygenic risk score” and “sub-phenotype”. Title, abstract and full-text screening, data extraction, and risk of bias assessment were conducted by two reviewers independently. Disagreements were solved by consensus and discussion with a senior researcher. We verified that no two studies investigating the same sub-phenotype shared both base and target samples, ensuring that the consistency of the findings was not overestimated. From 1,248 records, 20 studies met inclusion criteria. The majority of the studies had a low risk of bias. Only 2 included subjects of non-European ancestries. The most frequently tested PRSs were for schizophrenia (SCZ, n=17), BD (n=14), and major depressive disorder (MDD, n=9). The most studied sub-phenotypes were psychosis (n=9), BD subtype [BDI, BDII, schizoaffective disorder, bipolar type (SABD)] (n=5), age at onset (n=5), and suicide attempt (SA, n=4). Overall, the most consistent association was observed between a higher SCZ-PRS and BD with psychosis, especially with mood-incongruent symptoms. SCZ-PRS was the highest in SABD, followed by BDI, and lowest in BDII. The absence of an association between early onset BD and BD PRS or MDD PRS was consistent across studies. Associations between various PRSs and SA had mixed findings. Our findings suggest an association between an increased genetic risk for SCZ and a severity spectrum in BD, starting from SABD, followed by BD I and BD II sub-phenotypes. BD with psychosis, especially with mood-incongruent symptoms, seems to be the main driver of this finding. This is in line with previous substantial evidence for partial polygenic overlap of SCZ and BD. Current evidence up to this point did not demonstrate an association between any other studied PRS and BD sub-phenotype. Contrary to our expectations, a greater polygenic load for BD does not seem to be related to earlier BD onset, nor does a higher MDD PRS correlate with suicide attempts to this point. Overall, our results point towards BD sub-phenotypes having different polygenic contributors, which are sometimes shared with other psychiatric diseases. An important limitation of the findings is the strong Eurocentric bias present in PRS analysis studies, highlighting a need for including more ancestrally diverse populations in such studies.