Genetic insights into psychotic major depressive disorder: bridging the mood-psychotic disorder spectrum

Abstract

Background: Psychotic major depressive disorder (MDD), a subtype of MDD characterised by psychotic symptoms that occur exclusively during mood episode, is clinically significant yet underexplored genetically due to its rarity. This study comprehensively examines the genetic basis of psychotic MDD and elucidates its position within the mood-psychotic spectrum.

Methods: This population-based cohort study used Swedish and Danish registry data for over 5.1 M individuals born between 1958 and 1993/1996. Specialist-diagnosed psychotic MDD was defined using ICD-10 sub-codes of MDD, F32.2/F32.3. We estimated familial aggregation/coaggregation using generalised estimating equations, heritability and genetic correlations using structural equation modelling. We also analysed ∼30,000 genotyped MDD cases from the UK Biobank and a Swedish cohort to explore which polygenic risk score (PRS) may predispose individuals to psychotic MDD.

Findings: With over 10,000 psychotic MDD identified from the two nationwide patient registers, this study highlights the familial aggregation of psychotic MDD, co-aggregation with mood and psychotic disorders, and its stronger genetic correlation with schizophrenia compared to non-psychotic MDD. The familial risks increased with closer biological relatedness, suggesting genetic influence. Pedigree-heritability of psychotic MDD was 30.17% (95% CI 23.53-36.80%). While the genetic correlation between psychotic and non-psychotic MDD was high (0.82, 95% CI 0.73-0.92), the psychotic subgroup showed a higher genetic correlation with schizophrenia than non-psychotic MDD (0.67 vs 0.46, p-value 7.55∗10^-4). Within 30,000 genotyped MDD cases, individuals with psychotic MDD had higher mean PRS for schizophrenia and BD but a lower MDD PRS than non-psychotic MDD. PRS for BD type-I was associated with increased odds of psychotic MDD, while BD type-II PRS showed no significant association with psychotic MDD.

Interpretation: This study provides evidence for the genetic basis of psychotic MDD, underscoring its unique position bridging the spectrum of mood and psychotic disorders. These findings advance our understanding of the aetiology of psychotic MDD and contribute to the limited body of evidence on this phenotype by utilising large-scale population-based data.

Funding: European Research Council; US National Institutes of Mental Health; European Union Horizon 2020 Program; Swedish Research Council; Research Council of Norway; Swedish Foundation for Strategic Research; Hjärnfonden.

Keywords: Epidemiology; Genetic; Psychotic disorders; Psychotic major depressive disorder.

Fig. 1

Conversion between psychotic/non-psychotic major depressive disorder (MDD) and other psychotic disorders. The Sankey diagram shows the proportions of individuals diagnosed with bipolar disorders, schizophrenia/schizoaffective disorder and other psychotic disorders (not including BD/SCZ/SAD) before and after the first MDD diagnosis, separately for psychotic and non-psychotic MDD. The width of the links represents the proportion of individuals with these psychotic disorders in psychotic/non-psychotic MDD group. Groups are non-mutually exclusive. BD: Bipolar disorder, SCZ/SAD: Schizophrenia/Schizoaffective disorder, Psy. Disorder: Psychotic disorder.

Fig. 2

Familial risk. a. Familial aggregation of psychotic MDD, and all MDD; b. Familial coaggregation of psychotic MDD with MDD, schizophrenia/schizoaffective disorder, bipolar disorder and all psychotic disorders within family separately for full-siblings, half-siblings, and cousins. Bars and dots show OR, error bars show 95% CI for the estimates. Colours represent types of siblings. Combined estimates from meta-analyses of Sweden and Denmark. MDD: Major depressive disorder, SCZ/SAD: Schizophrenia/Schizoaffective disorder, BD: Bipolar disorder, FS: Full-siblings, HS: Half-siblings, CS: Cousins.

Fig. 3

Genetic correlation between psychotic MDD and other psychiatric traits. a. Genetic correlation between psychotic and non-psychotic MDD, and their correlations with schizophrenia & bipolar disorder. R_g with schizophrenia/schizoaffective disorder and bipolar disorder. Colour and width of arrows represent magnitude of the estimates. b. Genetic correlation with other psychiatric traits. R_g with other psychiatric traits. Coloured shapes represent point estimates, error bars represent 95% CI. Estimates from AE models. 95% CI from Bootstrap resampling analyses (1000 replicates). MDD: Major depressive disorder, SCZ/SAD: Schizophrenia/Schizoaffective disorder, BD: Bipolar disorder, OCD: Obsessive-Compulsive Disorder, PTSD: Post-Traumatic Stress Disorder, ASD: Autism Spectrum Disorder, ADHD: Attention-Deficit/Hyperactivity Disorder.

Fig. 4

Regression analyses investigating the association between various polygenic risk scores and the occurrence of psychotic MDD. Forest plots display the association between PRS of schizophrenia, bipolar disorders, MDD and psychotic MDD. Results are from joint models including PRS of multiple disorders and covariates. Black squares and error bars represent the odds ratio and 95% CI for having psychotic MDD instead of non-psychotic MDD associated with a 1-SD-increase in PRS, shown separately for PREFECT and UK-Biobank data. The coloured diamonds show combined estimates. MDD: Major depressive disorder, BD: Bipolar disorder.