Cumulative Impact of Morphometric Features in Schizophrenia in Two Independent Samples

Schizophrenia and bipolar disorder share a common structural brain alteration profile. However, there is considerable between- and within-diagnosis variability in these features, which may underestimate informative individual differences. Using a recently established morphometric risk score (MRS) approach, we aim to provide confirmation that individual MRS scores are higher in individuals with a psychosis diagnosis, helping to parse individual heterogeneity. Using the Human Connectome Project Early Psychosis (N = 124), we estimate MRS for psychosis and specifically for bipolar/schizophrenia using T1-weighted MRI data and prior meta-analysis effect sizes. We confirm associations in an independent replication sample (N = 69). We assess (1) the impact of diagnosis on these MRS, (2) compare effect sizes of MRS to all individual, cytoarchitecturally defined brain regions, and (3) perform negative control analyses to assess MRS specificity. The MRS specifically for SCZ was higher in the whole psychosis group (Cohen's d = 0.56; P = 0.003) and outperformed any single region of interest in standardized mean difference (Z_{MRS>75 ROIS} = 2.597; P = 0.009) and correlated with previously reported effect sizes (P_SPIN/SHUFFLE < 0.005). MRS without Enhancing Neuroimaging Genomics through Meta-Analysis weights did not delineate groups with empirically null associations (t = 2.29; P = 0.02). We replicate MRS specifically for SCZ associations in the independent sample. Akin to polygenic risk scoring and individual allele effect sizes, these observations suggest that assessing the combined impact of regional structural alterations may be more informative than any single cytoarchitecturally constrained cortical region, where well-powered, meta-analytical samples are informative in the delineation of diagnosis and within psychosis case differences, in smaller independent samples.