👤 Alessandro Serretti

The brain's default mode network (DMN) plays a role in social cognition, with altered DMN function being associated with social impairments across various neuropsychiatric disorders. However, the genetic basis linking sociability with DMN function remains underexplored. This study aimed to elucidate the shared genetics and causal relationship between sociability and DMN-related resting-state functional MRI (rs-fMRI) traits. We conducted a comprehensive genomic analysis using large-scale genome-wide association study (GWAS) summary statistics for sociability and 31 activity and 64 connectivity DMN-related rs-fMRI traits ( Significant local genetic correlations were identified between sociability and two rs-fMRI traits, one representing spontaneous activity within the temporal cortex, the other representing connectivity between the cingulate and angular/temporal cortices. MR analyses suggested potential causal effects of sociability on 12 rs-fMRI traits. Seventeen genes were highly prioritized, with By combining genomic and transcriptomic data, our gene prioritization strategy may serve as a blueprint for future studies. Our findings can guide further research into the biological mechanisms underlying sociability and its role in the development, prognosis, and treatment of neuropsychiatric disorders. Show less

Treatment response and resistance in major depressive disorder (MDD) show a significant genetic component, but previous studies had limited power also due to MDD heterogeneity. This literature review focuses on the genetic factors associated with treatment outcomes in MDD, exploring their overlap with those associated with clinically relevant symptom dimensions. We searched PubMed for: (1) genome-wide association studies (GWASs) or whole exome sequencing studies (WESs) that investigated efficacy outcomes in MDD; (2) studies examining the association between MDD treatment outcomes and specific depressive symptom dimensions; and (3) GWASs of the identified symptom dimensions. We identified 13 GWASs and one WES of treatment outcomes in MDD, reporting several significant loci, genes, and gene sets involved in gene expression, immune system regulation, synaptic transmission and plasticity, neurogenesis and differentiation. Nine symptom dimensions were associated with poor treatment outcomes and studied by previous GWASs (anxiety, neuroticism, anhedonia, cognitive functioning, melancholia, suicide attempt, psychosis, sleep, sociability). Four genes were associated with both treatment outcomes and these symptom dimensions: CGREF1 (anxiety); MCHR1 (neuroticism); FTO and NRXN3 (sleep). Other overlapping signals were found when considering genes suggestively associated with treatment outcomes. Genetic studies of treatment outcomes showed convergence at the level of biological processes, despite no replication at gene or variant level. The genetic signals overlapping with symptom dimensions of interest may point to shared biological mechanisms and potential targets for new treatments tailored to the individual patient's clinical profile. Show less

The brain's default mode network (DMN) plays a role in social cognition, with altered DMN function being associated with social impairments across various neuropsychiatric disorders. In the present study, we examined the genetic relationship between sociability and DMN-related resting-state functional magnetic resonance imaging (rs-fMRI) traits. To this end, we used genome-wide association summary statistics for sociability and 31 activity and 64 connectivity DMN-related rs-fMRI traits (N=34,691-342,461). First, we examined global and local genetic correlations between sociability and the rs-fMRI traits. Second, to assess putatively causal relationships between the traits, we conducted bi-directional Mendelian randomisation (MR) analyses. Finally, we prioritised genes influencing both sociability and rs-fMRI traits by combining three methods: gene-expression eQTL MR analyses, the CELLECT framework using single-nucleus RNA-seq data, and network propagation in the context of a protein-protein interaction network. Significant local genetic correlations were found between sociability and two rs-fMRI traits, one representing spontaneous activity within the temporal cortex, the other representing connectivity between the frontal/cingulate and angular/temporal cortices. Sociability affected 12 rs-fMRI traits when allowing for weakly correlated genetic instruments. Combing all three methods for gene prioritisation, we defined 17 highly prioritised genes, with Show less

Pruning in neurons has been suggested to be strongly involved in Schizophrenia's (SKZ) etiopathogenesis in recent biological, imaging, and genetic studies. We investigated the impact of protein-coding genes known to be involved in pruning, collected by a systematic literature research, in shaping the risk for SKZ in a case-control sample of 9,490 subjects (Psychiatric Genomics Consortium). Moreover, their modifications through evolution (humans, chimpanzees, and rats) and subcellular localization (as indicative of their biological function) were also investigated. We also performed a biological pathways (Gene Ontology) analysis. Genetics analyses found four genes (DLG1, NOS1, THBS4, and FADS1) and 17 pathways strongly involved in pruning and SKZ in previous literature findings to be significantly associated with the sample under analysis. The analysis of the subcellular localization found that secreted genes, and so regulatory ones, are the least conserved through evolution and also the most associated with SKZ. Their cell line and regional brain expression analysis found that their areas of primary expression are neuropil and the hippocampus, respectively. At the best of our knowledge, for the first time, we were able to describe the SKZ neurodevelopmental hypothesis starting from a single biological process. We can also hypothesize how alterations in pruning fine regulation and orchestration, strongly related with the evolutionary newest (and so more sensitive) secreted proteins, may be of particular relevance in the hippocampus. This early alteration may lead to a mis-structuration of neural connectivity, resulting in the different brain alteration that characterizes SKZ patients. Show less