Factor analysis of lifetime psychopathology and its brain morphometric and genetic correlates in a transdiagnostic sample

Abstract

There is a lack of knowledge regarding the relationship between proneness to dimensional psychopathological syndromes and the underlying pathogenesis across major psychiatric disorders, i.e., Major Depressive Disorder (MDD), Bipolar Disorder (BD), Schizoaffective Disorder (SZA), and Schizophrenia (SZ). Lifetime psychopathology was assessed using the OPerational CRITeria (OPCRIT) system in 1,038 patients meeting DSM-IV-TR criteria for MDD, BD, SZ, or SZA. The cohort was split into two samples for exploratory and confirmatory factor analyses. All patients were scanned with 3-T MRI, and data was analyzed with the CAT-12 toolbox in SPM12. Psychopathological factor scores were correlated with gray matter volume (GMV) and cortical thickness (CT). Finally, factor scores were used for exploratory genetic analyses including genome-wide association studies (GWAS) and polygenic risk score (PRS) association analyses. Three factors (paranoid-hallucinatory syndrome, PHS; mania, MA; depression, DEP) were identified and cross-validated. PHS was negatively correlated with four GMV clusters comprising parts of the hippocampus, amygdala, angular, middle occipital, and middle frontal gyri. PHS was also negatively associated with the bilateral superior temporal, left parietal operculum, and right angular gyrus CT. No significant brain correlates were observed for the two other psychopathological factors. We identified genome-wide significant associations for MA and DEP. PRS for MDD and SZ showed a positive effect on PHS, while PRS for BD showed a positive effect on all three factors. This study investigated the relationship of lifetime psychopathological factors and brain morphometric and genetic markers. Results highlight the need for dimensional approaches, overcoming the limitations of the current psychiatric nosology.

Fig. 1. Local GMV correlates of the lifetime paranoid-hallucinatory syndrome (PHS).

Negative association of factor 1 paranoid-hallucinatory syndrome (PHS) and gray matter volume (GMV) comprising parts of the bilateral hippocampus, amygdala, and right angular gyrus across patients with major depressive disorder, bipolar disorder, and schizophrenia spectrum disorders. Clusters are shown at p < 0.05 peak-level, family-wise error-corrected.

Fig. 2. CT correlates of the paranoid-hallucinatory syndrome (PHS).

Negative association of factor 1 paranoid-hallucinatory syndrome (PHS) and cortical thickness (CT) comprising parts of left supramariginal, bilateral superior temporal, and right lateral occipital clusters across patients with major depressive disorder, bipolar disorder, and schizophrenia spectrum disorders. Clusters are shown at p < 0.05 peak-level, family-wise error-corrected.

Fig. 3. Genetic loci with genome-wide significant association.

Regional plots with a window size of 500 kb are shown for the genome-wide significant associations with MA “mania” (A), and DEP “depression” (B). The respective lead variants rs10062519 and rs11131155 are depicted as linkage disequilibrium reference variants (purple diamonds). cM centimorgan, LD Ref Var, linkage disequilibrium reference variant, Mb megabase.

Fig. 4. PRS association analysis.

Regression of the three factors on the PRS for MDD, BD, and SZ shows significant effects of PRS for MDD, BD, and SZ on PHS “paranoid-hallucinatory syndrome” and of PRS for BD on MA “mania” and DEP “depression” in the full transdiagnostic sample. BD bipolar disorder, BH Benjamini–Hochberg, MDD major depressive disorder, SZ schizophrenia.