AbstractBackgroundThe interaction of polygenic risk (PRS) and environmental effects on development of bipolar disorder (BD) is understudied, as are high‐risk offspring perceptions of their family environment (FE). We tested the association of offspring‐perceived FE in interaction with BD‐PRS on liability for BD in offspring at high or low familial risk for BD.MethodsOffspring of a parent with BD (oBD;n= 266) or no psychiatric disorders (n= 174), aged 12–21 at recruitment, participated in the US and Australia. Empirically‐derived profiles of FE classified offspring by their perceived levels of familial cohesion, flexibility, and conflict. Offspring BD‐PRS were derived from Psychiatric Genomics Consortium BD‐GWAS. Lifetime DSM‐IV bipolar disorders were derived from the Schedule for Affective Disorders and Schizophrenia for School‐Aged Children. We used a novel stepwise approach for latent class modeling with predictors and distal outcomes.ResultsFifty‐two offspring were diagnosed with BD. For those with well‐functioning FE (two‐thirds of the sample), higher BD‐PRS tracked positively with liability for BD. However, for those with high‐conflict FEs, the relationship between BD‐PRS and liability to BD was negative, with highest risk for BD observed with lower BD‐PRS. In exploratory analyses, European‐ancestry offspring with BD had elevated history of suicidal ideation in high‐conflict FE compared to well‐functioning‐FE, and of suicide attempt with low‐BD‐PRS and high‐conflict FE.ConclusionsThe data suggest that the relationship of BD‐PRS and offspring liability for BD differed between well‐functioning versus high‐conflict FE, potentially in line with a multifactorial liability threshold model and supporting future study of and interventions improving family dynamics.