Genetic Evidence for a Neuroimmune Model of Schizophrenia

Since the early 1900s, clinical and epidemiological observations have suggested a link between schizophrenia and the immune system, yet genetic evidence for a pathophysiological connection has remained elusive. Here, we review evidence for immune involvement from a variety of genetic studies to characterize the contribution of genetic variation in immune genes and pathways to schizophrenia risk. Across studies, the strongest and most consistent associations remain in neuronal pathways, but several studies have revealed involvement of peripheral lymphocyte populations, including CD4+ T cells, mature B cells, and, to a lesser extent, natural killer (NK) cells. Cross-trait genetic analyses are mixed but point to a modest shared genetic architecture between schizophrenia and several immune traits. Collectively, current evidence supports a primarily neuronal genetic architecture for schizophrenia with a modest immunogenetic component. Advancing our understanding of the immune contribution to schizophrenia risk will require integration of genomic, proteomic, and deep immunophenotyping approaches to capture these subtle and dynamic processes. Ultimately, combining genetic, immunologic, and clinical data will be essential for improving diagnostic precision, identifying novel therapeutic targets, and tailoring treatment to individual biological profiles.