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

Department of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, PA
Schizophrenia Bulletin (Impact Factor: 8.45). 09/2012; 38(6). DOI: 10.1093/schbul/sbs087
Source: PubMed


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.

GWAS-significant 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.

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.

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.

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    • ". There have been prior efforts to conduct GWAS in non-Caucasian ancestry samples, including Japanese [Ikeda et al., 2013] and African-American samples [Shi et al., 2009]. Associations corrected for multiple comparisons have not been detected in the HLA region in these samples (possibly due to insufficient sample size), but suggestive associations have been reported [Bamne et al., 2012; Ikeda et al., 2013]. MANTRA analysis may be worthwhile in these samples. "
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    ABSTRACT: Associations between human leukocyte antigen (HLA) polymorphisms on chromosome 6p and schizophrenia (SZ) risk have been evaluated for over five decades. Numerous case-control studies from the candidate gene era analyzed moderately sized samples and reported nominally significant associations with several loci in the HLA region (sample sizes, n = 100-400). The risk conferred by individual alleles was modest (odds ratios < 2.0). The basis for the associations could not be determined, though connections with known immune and auto-immune abnormalities in SZ were postulated. Interest in the HLA associations has re-emerged following several recent genome-wide association studies (GWAS); which utilized 10- to 100-fold larger samples and also identified associations on the short arm of chromosome 6. Unlike the earlier candidate gene studies, the associations are statistically significant following correction for multiple comparisons. Like the earlier studies; they have modest effect sizes, raising questions about their utility in risk prediction or pathogenesis research. In this review, we summarize the GWAS and reflect on possible bases for the associations. Suggestions for future research are discussed. We favor, in particular; efforts to evaluate local population sub-structure as well as further evaluation of immune-related variables in future studies. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 01/2014; 165(1). DOI:10.1002/ajmg.b.32195 · 3.42 Impact Factor
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    • "The development of schizophrenia has been associated with maternal infection and perinatal viral infections (Khandaker et al. 2012, 2013) in addition to a personal history of severe infection (Benros et al. 2011). An association with particular human leucocyte antigen (HLA) genes has long been recognized (Wright et al. 2001), and further strengthened by identification of disease-linked single nucleotide polymorphisms within the HLA region (Bamne et al. 2012). Schizophrenia has been associated with antibodies against pathogens such as cytomegalovirus and Toxoplasma gondii in the CSF of untreated patients (Leweke et al. 2004) and on retrospective analysis of patients' serum taken at birth (Blomstrom et al. 2012). "
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    ABSTRACT: Epidemiological, genetic, transcriptome, postmortem, peripheral biomarker, and therapeutic studies of schizophrenia all point to a dysregulation of both innate and adaptive immune systems in the disease, and it is likely that these immune changes actively contribute to disease symptoms. Gene expression disturbances in the brain of subjects with schizophrenia show complex, region-specific changes with consistently replicated and potentially interdependent induction of serpin peptidase inhibitor, clade A member 3 (SERPINA3) and interferon inducible transmembrane protein (IFITM) family transcripts in the prefrontal cortex. Recent data suggest that IFITM3 expression is a critical mediator of maternal immune activation. Because the IFITM gene family is primarily expressed in the endothelial cells and meninges, and because the meninges play a critical role in interneuron development, we suggest that these two non-neuronal cell populations might play an important role in the disease pathophysiology. Finally, we propose that IFITM3 in particular might be a novel, appealing, knowledge-based drug target for treatment of schizophrenia.
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