Cognitive impairments are a core feature in schizophrenia patients (SCZ) and are also observed in first-degree relatives (FR) of SCZ. However, substantial variability in the impairments exists within and among SCZ, FR and healthy controls (HC). A cluster-analytic approach can group individuals based on profiles of traits and create more homogeneous groupings than predefined categories. Here, we investigated differences in the Brief Assessment of Cognition in Schizophrenia (BACS) neuropsychological battery (six subscales) among SCZ, unaffected FR and HC. To identify three homogeneous and meaningful cognitive groups regardless of categorical diagnoses (SCZ, FR and HC), cognitive clustering was performed, and differences in the BACS subscales among the cognitive cluster groups were investigated. Finally, the effects of diagnosis and cognition on brain volumes were examined. As expected, there were significant differences in the five BACS subscales among the diagnostic groups. The cluster-analytic approach generated three meaningful subgroups: (i) neuropsychologically normal, (ii) intermediate impaired and (iii) widespread impaired. The cognitive subgroups were mainly affected by the clinical diagnosis, and significant differences in all BACS subscales among clusters were found. The effects of the diagnosis and cognitive clusters on brain volumes overlapped in the frontal, temporal and limbic regions. Frontal and temporal volumes were mainly affected by the diagnosis, whereas the anterior cingulate cortex (ACC) volumes were affected by the additive effects of diagnosis and cognition. Our findings demonstrate a cognitive continuum among SCZ, FR and HC and support the concept of cognitive impairment and the related ACC volumes as intermediate phenotypes in SCZ.

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These findings suggest that of five anatomical subregions in the STG, the lateral STG is one of the most meaningful regions for brain pathophysiology in schizophrenia.

SummaryPsychiatric disorders as well as subcortical brain volumes are highly heritable. Large-scale genome-wide association studies (GWASs) for these traits have been performed. We investigated the genetic correlations between five psychiatric disorders and the seven subcortical brain volumes and the intracranial volume from large-scale GWASs by linkage disequilibrium score regression. We revealed weak overlaps between the genetic variants associated with psychiatric disorders and subcortical brain and intracranial volumes, such as in schizophrenia and the hippocampus and bipolar disorder and the accumbens. We confirmed shared aetiology and polygenic architecture across the psychiatric disorders and the specific subcortical brain and intracranial volume.

Family history (FH) is predictive of the development of major psychiatric disorders (PSY). Familial psychiatric disorders are largely a consequence of genetic factors and typically exhibit more severe impairments. Decreased prefrontal activity during verbal fluency testing (VFT) may constitute an intermediate phenotype for PSY. We investigated whether familial PSY were associated with a greater severity of prefrontal dysfunction in accordance with genetic loading. We measured prefrontal activity during VFT using near-infrared spectroscopy (NIRS) in patients with schizophrenia (SCZ, n = 45), major depressive disorder (MDD, n = 26) or bipolar disorder (BIP, n = 22) and healthy controls (HC, n = 51). We compared prefrontal activity among patients with or without FH and HC. Patients in the SCZ, MDD and BIP patient groups had lower prefrontal activity than HC subjects. Patients with and without FH in all diagnostic groups had lower prefrontal activity than HC subjects. Moreover, SCZ patients with FH had lower prefrontal activity than SCZ patients without FH. When we included patients with SCZ, MDD or BIP in the group of patients with PSY, the effects of psychiatric FH on prefrontal activity were enhanced. These findings demonstrate the association of substantially more severe prefrontal dysfunction with higher genetic loading in major psychiatric disorders.