Using Major Depression Polygenic Risk Scores to Explore the Depressive Symptom Continuum

Background It is not clear whether major depression (MD) is a categorical disorder or if depressive symptoms exist on a continuum based on severity. Observational studies comparing sub-threshold and clinical depression suggest MD is continuous, but many do not explore the full continuum and are yet to consider genetics as a risk factor. This study sought to understand if polygenic risk for MD could provide insight into the continuous nature of MD. Methods Factor analysis on symptom-level data from the UK Biobank (N=148,957) was used to derive continuous depression phenotypes which were tested for association with polygenic risk scores for a categorical definition of MD (N=119,692). Results Confirmatory factor analysis showed a five-factor hierarchical model, incorporating 15 of the original 18 items, produced good fit to the observed covariance matrix (CFI = 0.992, TLI = 0.99, RMSEA = 0.038, SRMR = 0.031). MD PRS associated with each factor score (standardised ß range: 0.057 – 0.064) and the association remained when the sample was stratified into case- and control-only subsets. The case-only subset had an increased association compared to controls for all factors, shown via a significant interaction between lifetime MD diagnosis and MD PRS (p-value range: 2.28×10 −3 - 4.56×10 −7 ). Conclusions An association between MD PRS and a continuous phenotype of depressive symptoms in case- and control-only subsets provides support against a purely categorical phenotype; indicating further insights into MD can be obtained when this within-group variation is considered. The stronger association within cases suggests this variation may be of particular importance.