Evaluation of HLA Polymorphisms in Relation to Schizophrenia Risk and Infectious Exposure

Abstract

Background: Genome-wide association studies (GWAS) implicate single nucleotide polymorphisms (SNPs) on chromosome 6p21.3-22.1, the human leukocyte antigen (HLA) region, as common risk factors for schizophrenia (SZ). Other studies implicate viral and protozoan exposure. Our study tests chromosome 6p SNPs for effects on SZ risk with and without exposure. Method: GWASsignificant SNPs and ancestry-informative marker SNPs were analyzed among African American patients with SZ (n = 604) and controls (n = 404). Exposure to herpes simplex virus, type 1 (HSV-1), cytomegalovirus (CMV), and Toxoplasma gondii (TOX) was assayed using specific antibody assays. Results: Five SNPs were nominally associated with SZ, adjusted for population admixture (P < .05, uncorrected for multiple comparisons). These SNPs were next analyzed in relation to infectious exposure. Multivariate analysis indicated significant association between rs3130297 genotype and HSV-1 exposure; the associated allele was different from the SZ risk allele. Conclusions: We propose a model for the genesis of SZ incorporating genomic variation in the HLA region and neurotropic viral exposure for testing in additional, independent African American samples.

Beyond the association. Toxoplasma gondii in schizophrenia, bipolar disorder, and addiction: systematic review and meta‐analysis

“…Following our systematic search 2866 studies were found, from which 50 studies were finally included (see flowchart in Fig. ) . Of these studies, four were unpublished (Hammer C, Ehrenreich H. 2014, personal communication, Torrey E. 2003, personal communication, Gallo C. 2005, personal communication, and Dickerson F. 2005, personal communication).…”

“…Other authors set the cut‐off at the 75th or 90th percentile of seropositive control subjects to distinguish subjects with high titers . We calculated ORs using above‐mentioned studies and six studies that did not publish their serointensity rates (Torrey E. 2003, personal communication, Gallo C. 2005, personal communication), whereby we used the 75th and 90th percentile cut‐offs of the provided data.…”

HLA Class I and II alleles, heterozygosity and HLA-KIR interactions are associated with rates of genital HSV shedding and lesions

“…Except for the APOE and TLR studies, viral shedding rates were not reported. Additional genetic loci within the extended HLA region on chromosome 6, aside from classical HLA class I and II, have also been shown to influence HSV severity, including an allelic variant at SNP rs3130297 genotype in the HLA class II region between the 3’ UTR of BTNL2 and the 5’ UTR of NOTCH4 (13). Several complement protein genes are also located in the HLA major histocompatibility complex (MHC) region.…”

Inflammation Effects on Motivation and Motor Activity: Role of Dopamine

“…Several functional allelic variants and single-nucleotide polymorphisms of genes encoding immune and inflammatory molecules have been associated with depression and schizophrenia, including those encoding the expression of inflammatory cytokines, major histocompatibility complex proteins, B and T cells, and inflammatory mediators such as cyclo-oxygenase2 (Bamne et al, 2012;Bosker et al, 2011;Bufalino et al, 2012;Raison and Miller, 2013; Schizophrenia Working Group of the Psychiatric Genomics, 2014). These findings have engendered speculation as to whether alleles that promote enhanced inflammatory cytokine secretion were evolutionarily advantageous and thus conserved (Raison and Miller, 2013).…”