Adolescent multi-omics and Mendelian randomization reveal transdiagnostic molecular mechanisms in psychiatric disorders

07/08/2026

AI Summary

Blood multi-omics and Mendelian randomization in 1,274 adolescents identified 73 causal CpG sites and 62 genes across six neuropsychiatric disorders.
Identified genes are enriched in pathways linking psychiatric and autoimmune diseases, indicating a shared genomic architecture and transdiagnostic mechanisms.
Methylation at cg06770790 represses MRPL2, causal for insomnia and schizophrenia; MAD1L1 and HLA-DRB1 expression also mediates schizophrenia risk.

AI Summary

These quantitative trait loci were further explored through Mendelian randomization analyses across 6 neuropsychiatric disorders (attention deficit hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia and insomnia), 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.

Notably, 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.

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.

Basic summary

Nat Ment Health. 2026;4(8):1248-1261. doi: 10.1038/s44220-026-00660-2. Epub 2026 Jun 5.

ABSTRACT

The biological mechanisms underlying major neuropsychiatric disorders remain largely elusive. Given the frequent association of immune dysregulation with these conditions, we used blood-derived multi-omics data from 1,274 healthy adolescents in the IMAGEN cohort to identify transdiagnostic biomarkers and mechanisms that could inform diagnosis and treatment. We first conducted genome-wide analyses to identify single nucleotide polymorphisms associated with DNA methylation and gene expression, with findings replicated in external datasets. These quantitative trait loci were further explored through Mendelian randomization analyses across 6 neuropsychiatric disorders (attention deficit hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia and insomnia), 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. Notably, 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. 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 (β = -0.38, P = 1.29 × 10^-4) and schizophrenia (β = -0.38, P = 1 × 10^-4). Conversely, increased expression of MAD1L1 and HLA-DRB1, driven by methylation at several CpG sites, was potentially causal for schizophrenia. Our findings highlight key molecular mechanisms and genes implicated in neuropsychiatric disorders, offering promising new targets for therapeutic intervention.