There has been intense debate over the immunological basis of
schizophrenia, and the potential utility of adjunct
immunotherapies. The major histocompatibility complex is consistently the most powerful region of association in genome-wide association studies (GWASs) of
schizophrenia and has been interpreted as strong genetic evidence supporting the immune hypothesis. However, global pathway analyses provide inconsistent evidence of immune involvement in
schizophrenia, and it remains unclear whether genetic data support an immune etiology per se. Here we empirically test the hypothesis that variation in immune genes contributes to
schizophrenia. We show that there is no enrichment of immune loci outside of the MHC region in the largest genetic study of
schizophrenia conducted to date, in contrast to 5 diseases of known immune origin. Among 108 regions of the genome previously associated with
schizophrenia, we identify 6 immune candidates (DPP4, HSPD1, EGR1, CLU, ESAM,
NFATC3) encoding
proteins with alternative, nonimmune roles in the brain. While our findings do not refute evidence that has accumulated in support of the immune hypothesis, they suggest that genetically mediated alterations in immune function may not play a major role in
schizophrenia susceptibility. Instead, there may be a role for pleiotropic effects of a small number of immune genes that also regulate brain development and plasticity. Whether immune alterations drive
schizophrenia progression is an important question to be addressed by future research, especially in light of the growing interest in applying
immunotherapies in
schizophrenia.