Polygenic risk scores mediating functioning outcomes through cognitive and clinical features in youth at family risk and controls.

Schizophrenia and bipolar disorder exhibit substantial clinical overlap, particularly in individuals at familial high risk, who frequently present sub-threshold symptoms before the onset of illness. Severe mental disorders are highly polygenic traits, but their impact on the stages preceding the manifestation of mental disorders remains relatively unexplored. Our study aimed to examine the influence of polygenic risk scores (PRS) on sub-clinical outcomes over a 2-year period in youth at familial high risk for schizophrenia and bipolar disorder and controls. The sample included 222 children and adolescents, comprising offspring of parents with schizophrenia (n = 38), bipolar disorder (n = 80), and community controls (n = 104). We calculated PRS for psychiatric disorders, neuroticism and cognition using the PRS-CS method. Linear mixed-effects models were employed to investigate the association between PRS and cognition, symptom severity and functioning. Mediation analyses were conducted to explore whether clinical features acted as intermediaries in the impact of PRS on functioning outcomes. SZoff exhibited elevated PRS for schizophrenia. In the entire sample, PRS for depression, neuroticism, and cognitive traits showed associations with sub-clinical features. The effect of PRS for neuroticism and general intelligence on functioning outcomes were mediated by cognition and symptoms severity, respectively. This study delves into the interplay among genetics, the emergence of sub-clinical symptoms and functioning outcomes, providing novel evidence on mechanisms underpinning the continuum from sub-threshold features to the onset of mental disorders. The findings underscore the interplay of genetics, cognition, and clinical features, providing insights for personalized early interventions.

Cognitive heterogeneity in the offspring of patients with schizophrenia or bipolar disorder: a cluster analysis across family risk.

BACKGROUND: Neurocognitive impairment is considered to lie on a continuum of severity across schizophrenia (SZ) and bipolar disorder (BP), possibly reflecting a gradient of neurodevelopmental load. Cluster analyses have identified different levels of impairment across the two disorders, from none to widespread and severe. We for the first time used this approach to examine cognitive function pooling together children and adolescents at familial risk of SZ or BP. METHODS: 220 participants, 49 offspring of individuals with schizophrenia (SZO), 90 offspring of individuals with bipolar disorder (BPO) and 81 offspring of healthy control parents (HC), aged 6 to 17 years, underwent a comprehensive clinical and cognitive assessment. Cognitive measures were used to group SZO and BPO using K-means clustering. Cognitive performance within each of the clusters was compared to that of HC and clinical variables were compared between clusters. RESULTS: We identified three cognitive subgroups: a moderate impairment group, a mild impairment group, and a cognitively intact group. Both SZO and BPO were represented in each of the clusters, yet not evenly, with a larger proportion of the SZO in the moderately impaired cluster, but also a subgroup of BPO showing moderate cognitive dysfunction. LIMITATIONS: Participants have yet to reach the age of onset for the examined disorders. CONCLUSIONS: The findings point to a range of neurodevelopmental loadings across youth at familial risk of both SZ and BP. They have therefore important implications for the stratification of cognitive functioning and the possibility to tailor interventions to individual levels of impairment.

Functional MRI with a set-shifting task in adolescent anorexia nervosa: A cross-sectional and follow-up study.

Studies of set-shifting in adolescent AN present conflicting results, since not all have found differences with regard to controls. To date, no functional Magnetic Resonance Imaging (fMRI) studies have been carried out in adolescent patients, nor have patients been assessed after weight recovery. In this study, 30 female AN patients aged 12-17 and 16 matched control subjects were assessed both at baseline and after six months and renutrition using a structured diagnostic interview, clinical and neurocognitive scales, and fMRI during a set-shifting task. Adolescent AN patients presented similar performance on different neurocognitive tests and also on a set-shifting task during fMRI, but they showed a lower activation in the inferior and middle occipital and lingual gyri, fusiform gyri and cerebellum during the set-shifting task. No correlations were found between decreased activation and clinical variables such as body mass index, eating or depressive symptoms. After six months of treatment and renutrition in AN patients, there were no differences between patients and controls. These results show that adolescent AN patients have lower activation in relevant brain areas during a set-shifting task, and support the use of fMRI with set-shifting paradigms as a biomarker in future studies.