J. Glessner

Shared genetic architecture and therapeutic targets across paediatric immune-mediated diseases.

OBJECTIVES Paediatric-onset immune-mediated inflammatory diseases (IMIDs), including juvenile idiopathic arthritis and related rheumatic diseases, remain genetically undercharacterised. We aimed to define shared and category-specific genetic architecture across paediatric IMIDs, compare signals with adult IMIDs, and identify therapeutic opportunities. METHODS We analysed 24 paediatric IMIDs classified as autoimmune, polygenic-autoinflammatory, mixed-pattern, or allergic. Genome-wide association analyses included 18,086 cases and 131,019 controls of European ancestry. We estimated single nucleotide polymorphism (SNP)-based heritability, genetic correlations, and polygenic overlap; performed subset-based meta-analysis; and conducted functional annotation, gene prioritisation, pathway and protein network analyses, adult-IMID comparison, and drug-target prioritisation. RESULTS SNP-based heritability ranged from 28.9% for allergic IMIDs to 61.9% for autoimmune IMIDs. Genetic correlation and polygenic modelling supported partial sharing across categories with category-specific components. Meta-analysis identified 39 genome-wide significant loci outside the Major Histocompatibility Complex (MHC) region, including 15 previously unreported loci; 19 loci were shared between categories. Gene-prioritisation and protein interaction analyses identified a core MHC-centred antigen-presentation network, with category-enriched modules involving complement, innate/barrier pathways, epithelial biology, and type 2 immunity. Enriched pathways included nuclear factor κB signalling, T helper 17 related pathways, Janus kinase-signal transducer and activator of transcription signalling, programmed cell death protein 1/programmed death‑ligand 1, cytotoxic T‑lymphocyte associated protein 4 regulation, and osteoclast differentiation, several of which are relevant to rheumatic diseases. Paediatric IMIDs shared broad polygenic architecture with adult IMIDs, whereas top-ranked genes converged strongly with adult rheumatic diseases. Priority Index analysis identified 178 high-scoring genes, including 43 approved or investigational IMID drug targets. CONCLUSIONS Paediatric-onset IMIDs share core pathways with adult forms but exhibit distinct genetic architecture shaped by age-specific immune and neurodevelopmental biology. These findings provide a genomic framework for paediatric precision medicine, guiding classification, risk prediction, and therapeutic development.

Drug repurposing opportunities across 92 CNS-related conditions using deep learning and whole-genome sequencing

CNS-related conditions span tumors, vascular, neurodevelopmental, and psychiatric disorders, yet therapeutic development for CNS disorders continues to face persistent delays and high attrition due to blood–brain barrier constraints, biological heterogeneity, and limited predictive models. Drug repurposing can shorten development timelines but requires scalable, mechanism-grounded prioritization. We curated 213 approved/clinical-stage drugs with KEGG pathway signatures and integrated them with whole-genome sequencing (WGS) pathway-importance profiles from 4392 individuals across 92 diagnoses. For each diagnosis and variant class, the top 30 KEGG pathways were defined as the core signature. Drugs were linked to diagnoses by pathway overlap, excluding on-label indications and infection-only supports, and ranked using a composite Repurposing Score integrating drug maturity/evidence, diagnosis-specific pathway concordance, and WGS-derived genetic support. Score-weight sensitivity analyses increased the contribution of genetic support. Evidence support was assessed by automated screening of publications and ClinicalTrials.gov records. Collectively, 906 drug-linked shared pathways yielded 12,040 unique repurposing pairs; 25.4% were supported by three or more variant classes. Downstream validation-priority annotation identified 1430 high-confidence drug–diagnosis pairs after stratifying candidates by cohort size, variant-class support, supporting-pathway count, and broad KEGG disease-module support. Frequently implicated mechanisms included RTK-MAPK/PI3K, VEGF, immune/checkpoint, and neurotrophin signaling. Variant-class-resolved WGS pathway prioritization coupled to curated pharmacology enables scalable cross-diagnosis repurposing using existing drugs, recovering clinically explored strategies and generating genetically supported hypotheses for biomarker-guided validation.

Deep generative models in biological sequence and structure analysis and design.