Integrative multi-omics insights into molecular mechanisms of neurodevelopmental conditions from a twin cohort

Neurodevelopmental conditions (NDCs) arise from complex genetic-environmental interactions, yet their molecular underpinnings remain poorly defined. We applied an integrative multi-omics approach within a deeply phenotyped twin cohort to identify systemic molecular signatures and pathways associated with NDCs. Our study included 237 twins between the age of 8-28 years from the Roots of Autism and ADHD Twin Study in Sweden (RATSS), combining one or more omics layers, including serum and cerebrospinal fluid proteomics, urine and fecal metabolomics, blood metallomics, and whole-genome sequencing in a subset of monozygotic twin pairs. Using the DIABLO (Data Integration Analysis for Biomarker Discovery using Latent Variable Approaches for Omics Studies) framework, we identified cross-omics features that distinguish individuals with and without NDCs. The identified features were convergently enriched in metabolic and immune-related pathways, such as purine metabolism, lysine degradation, PI3K-Akt and MAPK signaling cascades. Key molecules, such as ADA protein, flavinmononucleotide, pyrimidine-related metabolites (e.g., thymidine, glutamine), and specific metal ions (e.g., manganese, copper), were furthermore significantly associated with NDC status in generalized estimation equation models across individuals or within twin pairs. Patterns of molecular variation suggest both individual-level modulation and influences of shared genetic or familial environmental factors. Our findings demonstrate that NDC-related molecular alterations manifest across multiple biological layers and tissues, detectable through integrative systems-level analysis. Our scalable framework provides critical insights into altered metabolic and immune mechanisms in NDCs and highlights candidate features that may inform future biomarker development and mechanistic research in precision psychiatry.