The emergence of neuropsychiatric disorders, conditions that affect various brain functions and behaviors, is known to be driven by an intricate combination of factors. These can include both a genetic predisposition and exposure to traumatic events or other external circumstances.
Over the past decades, many neuroscience studies have tried to shed light on the origins of different mental health disorders. However, the biological, cellular and molecular mechanisms underpinning these disorders have not yet been clearly elucidated.
Researchers at Peking University Sixth Hospital and Peking University Institute of Mental Health recently analyzed genetic data collected from patients diagnosed with six different neuropsychiatric disorders, to better delineate the genes and cell types that contribute to their emergence. Their paper, published in Molecular Psychiatry, identifies 345 genes expressed in different types of cells that were linked to an increased risk of developing these disorders.
“Neuropsychiatric disorders exhibit complex polygenic architectures, yet the cell-type-specific mechanisms underlying most risk loci remain unclear,” wrote Xinyue Wang, Lingxue Luo and their colleagues in their paper.
“We integrate single-cell expression quantitative trait locus (sc-eQTL) data from brain and blood tissues with genome-wide association studies (GWAS) of six disorders (schizophrenia (SCZ), Parkinson’s disease (PD), bipolar disorder (BP), major depressive disorder (MDD), attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD)) to systematically identify putative causal genes at cellular resolution.”
Studying the cellular underpinnings of various disorders
Instead of only identifying genes associated with a higher risk of developing specific neuropsychiatric disorders, the researchers also wanted to understand the cell types in which these genes are expressed. To do this, they analyzed previously collected large-scale genetic datasets and tried to link genetic variants to the expression of genes in specific cells.
“Employing summary-data-based Mendelian randomization (SMR) across diverse neuronal and immune cell types, we discovered 345 cell-type-specific risk genes for various diseases, including both replicated candidates (such as MAPT in astrocytes for SCZ and PD and FLOT1 in excitatory neurons and inhibitory neurons for SCZ, BP and MDD) and novel associations (such as APTX in microglia for SCZ),” wrote the authors.
“Cross-disorder analyses revealed shared pathways in synaptic function and immune regulation. In contrast, disease-specific and tissue-specific patterns were observed across different disorders.”
The researchers identified 345 genes that were associated with a higher risk of developing the six disorders they examined. Some of these genes (e.g., the MAPT and FLOT1 genes) had already been linked to the risk of these conditions in the past, while others had never been identified before.
“Strikingly, we found that brain-derived risk genes exhibited significantly higher cell-type specificity than those identified in blood, underscoring the more focused cellular context of genetic effects in the central nervous system,” wrote Wang, Luo and their colleagues. “Our findings suggest that neuropsychiatric disorders arise from a combination of neuronal dysfunction and immune system dysregulation.”
New insight on the roots of mental health disorders
The analyses run by Wang, Luo and their colleagues uncovered patterns in the cell-specific activity of different genes associated with each of the six disorders they considered. Overall, the team’s findings suggest that neurons and immune cells both play a role in the emergence of neuropsychiatric conditions.
“The study demonstrates how cell-type-specific mapping uncovers etiological mechanisms obscured in bulk-tissue analyses, proving novel information for clarifying the biological mechanism of gene expression implicated in the development of the six neuropsychiatric disorders,” wrote the authors.
Future research could try to validate the results of this study in experimental settings or explore the cellular underpinnings of specific disorders in more depth. Eventually, these efforts could pave the way for the development of new treatments that target types of cells that play a greater role in the development of specific disorders.
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Publication details
Xinyue Wang et al, Cell-type-specific genetic architecture reveals neuronal and immune contributions to neuropsychiatric disorders, Molecular Psychiatry (2026). DOI: 10.1038/s41380-026-03606-3.
Journal information:
Molecular Psychiatry
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