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  1. 1. Evaluation of HLA polymorphismsin relation to schizophrenia risk and infectious exposure Bamne et al, Schizophr Bull (2012) 38(6): 1149-1154 September 10, 2012 doi:10.1093/schbul/sbs087 Funds: NIMH, Stanley Medical Research Institute
  2. 2. HLA variants in schizophrenia: older studies
  3. 3. HLA variants and schizophrenia: GWAS
  4. 4. Motivation for current studyCaveats RationalePathogenic basis uncertain Exposure to infectious factors?Modest odds ratios ~ 1.2-1.8 Gene-environment interactions?Associations in Caucasian ancestry samples African-Americans (trans- ethnic mapping)
  5. 5. PAARTNERS schizophrenia study ofAfrican-Americans• Largest genetic study, eight US collaborative sites.• Diagnostic evaluations, DNA, serum for all participants • Cases: schizophrenia / schizoaffective disorder (N = 604) • Screened adult controls from each site (N = 404)• SNPs: iplex assays • GWAS (N=16) • Ancestry Informative Markers (N=22)• Exposure using specific, sensitive antibody titers • Herpes Simplex virus, type 1 (HSV-1), • Cytomegalovirus (CMV), • Toxoplasma Gondii (TOX)
  6. 6. GWAS SNPs analyzed
  7. 7. Scheme for multivariate analysis SNPs associations with schizophrenia? SNP associations with exposure to HSV-1, CMV or Tox Interactions: SNP x HSV-1 exposure
  8. 8. Results Associations with schizophrenia: Five SNPs: p < 0.05, uncorrected; OR 0.41-0.79 SNP associations with infectious exposure:rs3130297 associated with HSV-1 exposure (OR 4.76) Interactions: SNP x HSV-1 exposure: rs3130297 A allele: SZ; G allele: HSV-1
  9. 9. GWAS SNPs analyzed
  10. 10. A model for schizophrenia genesis based on HLA associations p < 0.05, uncorrected
  11. 11. Conclusions / Future Directions Validation of HLA associations with schizophrenia risk among African-Americans Suggestive association with HSV-1 exposure  Novel pleiotropic effect?Ongoing studies: Independent replications Correlations with cognitive functions Brain imaging studies