Different neuropsychiatric and neurodevelopmental conditions, such as schizophrenia, bipolar disorder, attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), are characterized by highly distinct patterns of behavior and associated challenges. While many past neuroscience studies have tried to uncover the unique neurobiological underpinnings of each condition, whether they share any common markers remains unclear.
Researchers at Fudan University, King’s College London, University Paris-Saclay and other institutes carried out one of the most comprehensive analyses to date exploring the shared genetic and immune system-related signatures of neuropsychiatric and neurodevelopmental conditions.
Their paper, published in Nature Mental Health, pinpoints three key genes that appear to mediate molecular changes associated with a greater risk of developing six distinct neurodevelopmental, psychiatric and sleep-related conditions.
“The biological mechanisms underlying major neuropsychiatric disorders remain largely elusive,” wrote Luheng Qian, Runye Shi and their colleagues in their paper.
“Given the frequent association of immune dysregulation with these conditions, we used blood-derived multi-omics data from healthy adolescents in the IMAGEN cohort to identify transdiagnostic biomarkers and mechanisms that could inform diagnosis and treatment.”
Uncovering genetic and immune signatures of psychiatric disorders
Qian, Shi and their collaborators analyzed blood-derived biological data collected from 1,274 adolescents who were not diagnosed with any diseases or mental health conditions. These teenagers were screened as part of the IMAGEN project, a large European research study exploring how distinct biological, psychological and environmental factors during adolescence affect the development of the brain and the risk of facing mental health conditions.
The researchers analyzed data collected by the IMAGEN project to identify genetic variants that were linked to specific patterns in DNA methylation and gene expression. DNA methylation is a process by which methyl groups (chemical “tags”) attach themselves to people’s DNA, influencing how strongly genes are expressed.
“We first conducted genome-wide analyses to identify single nucleotide polymorphisms associated with DNA methylation and gene expression, with findings replicated in external datasets,” wrote the authors.
“These quantitative trait loci were further explored through Mendelian randomization analyses across six neuropsychiatric disorders, leading to the identification of 73 putatively causal CpG sites and 62 genes that were either unique to individual disorders or, as in the case of MRPL2, shared among the disorders.”
The researchers’ analyses led to the identification of various molecular markers that were found to either be unique to specific conditions or associated with several conditions. Moreover, they allowed the team to uncover genes that appeared to mediate DNA methylation changes associated with six different conditions: ADHD, ASD, bipolar disorder, major depressive disorder, schizophrenia and insomnia.
“The identified genes were significantly enriched in pathways linked to both psychiatric and autoimmune diseases, suggesting a shared genomic architecture between autoimmune and neuropsychiatric disorders,” wrote the authors.
“Two-step Mendelian randomization and colocalization analyses revealed potential transdiagnostic regulatory pathways, in which the expression of three genes (MAD1L1, MRPL2 and HLA-DRB1) mediated the effects of CpG methylation on schizophrenia and insomnia.
“Specifically, DNA methylation at cg06770790 repressed MRPL2, which was putatively causal for insomnia and schizophrenia. Conversely, increased expression of MAD1L1 and HLA-DRB1, driven by methylation at several CpG sites, was potentially causal for schizophrenia.”
Promising targets for future treatments
Qian, Shi and their colleagues uncovered molecular mechanisms that appear to be common across multiple psychiatric and neurodevelopmental conditions, as well as genes that appeared to be linked to specific conditions. Their work led to the identification of three genes, called MAD1L1, MRPL2 and HLA-DRB1, that appear to link DNA methylation changes and biological pathways associated with different conditions.
“Our findings highlight key molecular mechanisms and genes implicated in neuropsychiatric disorders, offering promising new targets for therapeutic intervention,” wrote Qian, Shi and their colleagues.
Other researchers could soon build on the team’s findings and set out to further explore the biomarkers and molecular processes they uncovered, while also potentially assessing their contribution to other conditions that were not considered in this study.
In the future, these efforts could inform the development of new diagnostic tools or treatments targeting biological pathways shared across several disorders and conditions.
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Publication details
Luheng Qian et al, Adolescent multi-omics and Mendelian randomization reveal transdiagnostic molecular mechanisms in psychiatric disorders, Nature Mental Health (2026). DOI: 10.1038/s44220-026-00660-2.
Journal information:
Nature Mental Health
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