Stapp, Emma K.Fullerton, Janice M.Musci, Rashelle J.Zandi, Peter P.McInnis, Melvin G.Mitchell, Philip B.Hulvershorn, Leslie A.Ghaziuddin, NeeraRoberts, GloriaFerrera, Alessandra G.Nurnberger, John I.Wilcox, Holly C.2024-01-232024-01-232023-03-16Stapp EK, Fullerton JM, Musci RJ, et al. Family environment and polygenic risk in the bipolar high-risk context. JCPP Adv. 2023;3(2):e12143. Published 2023 Mar 16. doi:10.1002/jcv2.12143https://hdl.handle.net/1805/38126Background: The 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. Methods: Offspring 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. Results: Fifty-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. Conclusions: The 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.en-USAttribution 4.0 InternationalAttemptedBipolar disorderGene‐environment interactionMultifactorial inheritanceParent‐child relationsSuicideArticle