Comparative TWAS suggests predominantly shared ageing-related gene expression patterns with quantitative differences in treatment-resistant schizophrenia

Treatment-resistant schizophrenia (TRS) affects roughly 20–30% of people diagnosed with schizophrenia and is linked to poorer clinical and functional outcomes. Its molecular basis, however, remains only partly understood. In this study, we integrated transcriptome-wide association study (TWAS) results from two large schizophrenia genome-wide association studies (GWAS): one reflecting broad schizophrenia liability and another using a clozapine-treated phenotype as a proxy for treatment resistance. These TWAS profiles were intersected with 48 curated ageing-related gene sets covering NAD metabolism, mitochondrial function, cellular senescence, synaptic plasticity, complement signalling and glial biology. In the original curated analysis, both general schizophrenia and TRS showed enrichment in long-term potentiation, mitochondrial bioenergetics, NAD and sirtuin pathways, complement-mediated pruning and glial signatures. This pattern is consistent with shared ageing-related vulnerability across schizophrenia phenotypes. At the same time, TRS showed selected quantitative and directional differences at key nodes within this shared architecture. Key differences included nominal shifts in PPP1R1B (DARPP-32), stronger influence of PPP3CC, DRD2, DRD3, DRD5 and synaptic vesicle genes, broader mitochondrial and oxidative phosphorylation burden, a stronger negative NAMPT signal with TFAM elevation, mixed mitochondrial sirtuin signals, elevated SLC2A1 and amplified complement enrichment. Sensitivity analyses showed that while most pathway enrichments were attenuated under stricter TWAS-filtered membership, formal matched-tissue key-gene tests confirmed significant differences for only four key genes: TFAM, SIRT5, SLC2A1 and C4A, and high concordance persisted in a broader Hallmark comparator set. The findings support a working model in which TRS shares broad ageing-related transcriptomic architecture with schizophrenia but shows selected quantitative and directional differences at key nodes, potentially constraining circuit adaptability under chronic D2 receptor blockade. The identified gene modules provide a hypothesis-generating foundation for future biomarker studies and stratified adjunctive trials targeting mitochondrial resilience, NAD metabolism and metabolic flexibility; however, extensive independent replication, functional validation and clinical testing would be required before any translational application.