Evaluating the Contribution of Immune Gene Variants to Schizophrenia

Schizophrenia is a devastating mental illness of unknown etiology. There is a longstanding theory that dysregulation of the immune system causes schizophrenia in at least a subset of patients. Many schizophrenia patients show hallmarks of immune disease – such as prior infections, presence of autoantibodies, co-occurring autoimmunity, and inflammation – supporting this immune hypothesis. Given that another hallmark of immune disease is the convergence of genetic risk factors on key immune pathways, this thesis evaluates the immune hypothesis of schizophrenia using both focused candidate gene and large-scale genome-wide association study (GWAS) approaches. In study one, we performed a candidate gene study of the neuroinflammatory biomarker TSPO and identified a loss-of-function variant (Thr allele of rs6971 or Ala147Thr) associated with increased antipsychotic-induced weight gain in two independent samples. In study two, we performed conditional analysis of the extended major histocompatibility complex (xMHC) – the strongest region of association in schizophrenia GWASs – and discovered three independent genetic variants explaining the association that do not appear to represent canonical immune genes in the MHC region. In study three we compared enrichment of SNPs representing immune genes in GWASs of schizophrenia and five immune diseases, and found that the genetic architecture of schizophrenia was distinct from diseases of known immune origin. Finally, in study four, we evaluated the extent of shared genetic risk factors for schizophrenia and 19 immune-mediated diseases again using GWAS results. We found evidence of subtle genome-wide sharing of risk alleles for schizophrenia and a subset of five immune diseases, the biological significance of which remains unclear. Taken together these studies indicate a non-genetic etiology for the immune disturbances observed in schizophrenia, and suggest that immune genes and variants conferring risk for immune-mediated diseases do not play a major role in schizophrenia susceptibility. It remains to be seen whether immune processes act as a second non-genetic hit that contributes to disease susceptibility, progression, or treatment outcomes. Whether this is the case is an important question to be addressed by longitudinal studies, particularly given burgeoning interest in the potential use of immunotherapies.Ph.D