Commentary on Immune‐Genomic Approaches to Schizophrenia: Highlighting <scp>IRF3</scp> , <scp>L3HYPDH</scp> , and Drug Repurposing Targets

We read with great interest the recent article by Stacey et al. (Stacey et al. 2025) entitled “A Transcriptome-Wide Mendelian Randomization Study in Isolated Human Immune Cells Highlights Risk Genes Involved in Viral Infections and Potential Drug Repurposing Opportunities for Schizophrenia” in the American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. This work advances our understanding of schizophrenia pathophysiology by underscoring immune-related mechanisms and their potential interactions with viral infections, complementing broader evidence suggesting that inflammation and autoimmunity may shape schizophrenia risk (Cao et al. 2024; Rong et al. 2024). Stacey and colleagues (Stacey et al. 2025) leveraged cis-eQTL resources across diverse immune cell types to identify candidate effector genes for schizophrenia. Their finding that interferon regulatory factor 3 (IRF3) may function as a transcriptional “hub gene” is particularly compelling in light of converging immune-signaling evidence in schizophrenia and related neuropsychiatric outcomes (Cao et al. 2024). Additionally, the identification of L3HYPDH as a putative novel schizophrenia risk locus is consistent with the broader view that risk architecture may extend beyond the most frequently replicated loci and that systematic functional prioritization remains essential (Aberg et al. 2013). The proposed drug repurposing opportunities—particularly DPYD and MAPK3—are timely given the need for more effective schizophrenia treatments, including for individuals with suboptimal response to existing antipsychotics. This translational framing also aligns with the expanding Mendelian randomization (MR) literature that uses genetic proxies to inform drug-target evaluation and potential repositioning strategies (Fan et al. 2024). In parallel, studies examining modifiable factors such as vitamin D have increasingly used cross-trait genetic approaches, including shared genetic correlation and colocalization, to better delineate overlapping biology across tissues and immune cell contexts (Rong et al. 2024). In response to the reviewer's helpful suggestions, we emphasize two additional directions that may further strengthen immune-genomic inference in schizophrenia. First, we agree that combining cis-MR with formal colocalization analyses is critical to reduce confounding by linkage disequilibrium (LD). While cis-MR can prioritize genes proxied by local regulatory variants, LD structure can still induce spurious associations when the variant driving expression differs from the variant driving disease risk. Therefore, integrating colocalization (to evaluate whether the same causal signal underlies both gene expression and schizophrenia association at a locus) can substantially increase confidence when nominating effector genes and downstream drug targets. This consideration is particularly relevant for the broader MR literature in schizophrenia, including proteome-wide or target-screening efforts in which colocalization is not uniformly implemented across all reported signals (Cao et al. 2024). Second, we expand on the importance of tissue- and cell-type–specific functional assays—especially in microglia and astrocytes—to clarify the causal role of brain-resident immune cells suggested by immune-cell transcriptomic MR findings. For example, induced pluripotent stem cell (iPSC)–derived microglial or astrocytic models, microglia–neuron co-culture systems, or organoid-based platforms could be used to perturb IRF3-related pathways (e.g., via CRISPR-based modulation of gene expression) and to quantify downstream effects relevant to schizophrenia biology. Mechanistically informative readouts may include interferon-response transcriptional programs, cytokine and chemokine secretion profiles, synapse-associated phagocytic activity, metabolic shifts under immune stimulation, and transcriptomic/proteomic signatures under viral mimetics. Such functional assays can help bridge statistical causal inference to cellular mechanisms, thereby improving biological interpretability and informing therapeutic prioritization. In conclusion, Stacey et al. (Stacey et al. 2025) provide robust support for the involvement of immune dysregulation, viral susceptibility, and host inflammatory responses in schizophrenia's genetic architecture. Their systematic exploration of potential drug repurposing opportunities strengthens translational prospects and underscores the value of continued immune-genomic research—particularly when paired with rigorous locus-level colocalization and mechanistic validation through brain-relevant functional assays. Thank you for the opportunity to comment on this insightful study. We believe the framework set forth by Stacey et al. (Stacey et al. 2025) will be valuable for researchers and clinicians alike, and we look forward to future work that integrates statistical genetics with cell-type–specific functional follow-up to accelerate therapeutic discovery. C.-P.L. conceived the initial idea for the commentary, conducted the literature review, and drafted the first version of the manuscript. L.-C.W. provided conceptual guidance, supervised the development of the manuscript, and critically revised it for important intellectual content. Both authors reviewed and approved the final version of the manuscript. As my native language is not English, I used Microsoft 365 Copilot to check for spelling errors and enhance the overall flow of the text. All intellectual content, critical analysis, and interpretations were solely developed by the authors. The final manuscript was thoroughly reviewed and verified for accuracy, and I take full responsibility for its content. The authors have nothing to report. The authors declare no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.