HLA typing using genome wide data reveals susceptibility types for infections in a psychiatric disease enriched sample

Background: The infections Toxoplasma gondii (T. gondii), cytomegalovirus, and Herpes Simplex Virus Type 1 (HSV1) are common persistent infections that have been associated with schizophrenia and bipolar disorder. The major histocompatibility complex (MHC, termed HLA in humans) region has been implicated in these infections and these mental illnesses. The interplay of MHC genetics, mental illness, and infection has not been systematically examined in previous research. Methods: In a cohort of 1636 individuals, we used genome-wide association data to impute 7 HLA types (A, B, C, DRB1, DQA1, DQB1, DPB1), and combined this data with serology data for these infections. We used regression analysis to assess the association between HLA alleles, infections (individually and collectively), and mental disorder status (schizophrenia, bipolar disorder, controls). Results: After Bonferroni correction for multiple comparisons, HLA C∗07:01 was associated with increased HSV1 infection among mentally healthy controls (OR 3.4, p = 0.0007) but not in the schizophrenia or bipolar groups (P > 0.05). For the multiple infection outcome, HLA B∗ 38:01 and HLA C∗12:03 were protective in the healthy controls (OR ≈ 0.4) but did not have a statistically-significant effect in the schizophrenia or bipolar groups. T. gondii had several nominally-significant positive associations, including the haplotypes HLA DRB∗03:01 ∼ HLA DQA∗05:01 ∼ HLA DQB∗02:01 and HLA B∗08:01 ∼ HLA C∗07:01. Conclusions: We identified HLA types that showed strong and significant associations with neurotropic infections. Since some of these associations depended on mental illness status, the engagement of HLA-related pathways may be altered in schizophrenia due to immunogenetic differences or exposure history.