Co-Expression Network Analysis Identifies Molecular Determinants of Loneliness Associated with Neuropsychiatric and Neurodegenerative Diseases

Abstract

Loneliness and social isolation are detrimental to mental health and may lead to cognitive impairment and neurodegeneration. Although several molecular signatures of loneliness have been identified, the molecular mechanisms by which loneliness impacts the brain remain elusive. Here, we performed a bioinformatics approach to untangle the molecular underpinnings associated with loneliness. Co-expression network analysis identified molecular 'switches' responsible for dramatic transcriptional changes in the nucleus accumbens of individuals with known loneliness. Loneliness-related switch genes were enriched in cell cycle, cancer, TGF-β, FOXO, and PI3K-AKT signaling pathways. Analysis stratified by sex identified switch genes in males with chronic loneliness. Male-specific switch genes were enriched in infection, innate immunity, and cancer-related pathways. Correlation analysis revealed that loneliness-related switch genes significantly overlapped with 82% and 68% of human studies on Alzheimer's (AD) and Parkinson's diseases (PD), respectively, in gene expression databases. Loneliness-related switch genes, BCAM, NECTIN2, NPAS3, RBM38, PELI1, DPP10, and ASGR2, have been identified as genetic risk factors for AD. Likewise, switch genes HLA-DRB5, ALDOA, and GPNMB are known genetic loci in PD. Similarly, loneliness-related switch genes overlapped in 70% and 64% of human studies on major depressive disorder and schizophrenia, respectively. Nine switch genes, HLA-DRB5, ARHGAP15, COL4A1, RBM38, DMD, LGALS3BP, WSCD2, CYTH4, and CNTRL, overlapped with known genetic variants in depression. Seven switch genes, NPAS3, ARHGAP15, LGALS3BP, DPP10, SMYD3, CPXCR1, and HLA-DRB5 were associated with known risk factors for schizophrenia. Collectively, we identified molecular determinants of loneliness and dysregulated pathways in the brain of non-demented adults. The association of switch genes with known risk factors for neuropsychiatric and neurodegenerative diseases provides a molecular explanation for the observed prevalence of these diseases among lonely individuals.

Keywords: Alzheimer’s disease; Parkinson’s disease; loneliness; major depressive disorder; network analysis; neurodegenerative disease; neuropsychiatric diseases; schizophrenia; social isolation.

Figure 1

Overall bioinformatics workflow. We searched the GEO, ArrayExpress, and BaseSpace Correlation Engine to identify RNA expression studies on loneliness or social isolation. The arrays that met our inclusion/exclusion criteria were analyzed further using SWIM analysis, pathways, disease–gene networks, and transcription factors. Finally, we performed correlation analyses in BaseSpace between gene expression patterns induced by loneliness and neuropsychiatric and neurodegenerative diseases. We identified shared genetic risk factors between loneliness and neuropsychiatric and neurodegenerative diseases.

Figure 2

Identification of switch genes. SWIM analysis of postmortem nucleus accumbens of subjects with chronic loneliness compared to those with low loneliness (GSE80696). (a) Distribution of log2 fold change values where the red bars were selected for further analysis. (b) Heat cartography map with nodes colored by their average Pearson’s correlation coefficient. Blue nodes in region R4 represent switch genes. (c) Dendrogram and heatmap for switch genes. The red markers indicate samples from subjects with chronic loneliness. (d) Robustness of the correlation network.

Figure 3

Network and pathway analysis of switch genes. (a) Network analysis of loneliness switch genes. Switch genes are depicted in orange and interacting proteins are in gray. (b) Unique pathways dysregulated in individuals with chronic loneliness. (c) Network analysis of switch genes identified in males with chronic loneliness. (d) Unique pathways dysregulated in males with chronic loneliness. Network and pathway analysis was performed in NetworkAnalyst.

Figure 4

Disease–gene network analysis. (a) Disease–gene network analysis of switch genes from subjects with chronic loneliness and (b) diseases associated with switch genes from males with chronic loneliness. Switch genes are depicted in orange and diseases are in blue.

Figure 5

The impact of loneliness on brain health. Loneliness, social isolation, environmental stressors, and genetic factors can have detrimental effects on the brain and may lead to several neuropsychiatric and neurodegenerative diseases. Several switch genes responsible for the dramatic transcriptional changes in the brains of lonely individuals have been reported to play a role in the pathogenesis of neuropsychiatric and neurodegenerative diseases.