Genome-Wide Association Study Implicates HLA-C*01:02 as a Risk Factor at the Major Histocompatibility Complex Locus in Schizophrenia

Biological Psychiatry (Impact Factor: 10.26). 10/2012; 72(8):620-628. DOI: 10.1016/j.biopsych.2012.05.035


Background: We performed a genome-wide association study (GWAS) to identify common risk variants for schizophrenia. Methods: The discovery scan included 1606 patients and 1794 controls from Ireland, using 6,212,339 directly genotyped or imputed single nucleotide polymorphisms (SNPs). A subset of this sample (270 cases and 860 controls) was subsequently included in the Psychiatric GWAS Consortium-schizophrenia GWAS meta-analysis. Results: One hundred eight SNPs were taken forward for replication in an independent sample of 13,195 cases and 31,021 control subjects. The most significant associations in discovery, corrected for genomic inflation, were (rs204999, p combined = 1.34 x 10(-9) and in combined samples (rs2523722 p combined = 2.88 x 10(-16)) mapped to the major histocompatibility complex (MHC) region. We imputed classical human leukocyte antigen (HLA) alleles at the locus; the most significant finding was with HLA-C*01:02. This association was distinct from the top SNP signal. The HLA alleles DRB1*03:01 and B*08:01 were protective, replicating a previous study. Conclusions: This study provides further support for involvement of MHC class I molecules in schizophrenia. We found evidence of association with previously reported risk alleles at the TCF4, VRK2, and ZNF804A loci.

Download full-text


Available from: Brien Patrick Riley, Oct 04, 2015
1 Follower
36 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: Autism spectrum disorder (ASD) is a highly heterogeneous disorder diagnosed based on the presence and severity of core abnormalities in social communication and repetitive behavior, yet several studies converge on immune dysregulation as a feature of ASD. Widespread alterations in immune molecules and responses are seen in the brains and periphery of ASD individuals, and early life immune disruptions are associated with ASD. This chapter discusses immune-related environmental and genetic risk factors for ASD, emphasizing population-wide studies and animal research that reveal potential mechanistic pathways involved in the development of ASD-related symptoms. It further reviews immunologic pathologies seen in ASD individuals and how such abnormalities can impact neurodevelopment and behavior. Finally, it evaluates emerging evidence for an immune contribution to the pathogenesis of ASD and a potential role for immunomodulatory effects in current treatments for ASD.
    International Review of Neurobiology 12/2013; 113:269-302. DOI:10.1016/B978-0-12-418700-9.00009-5 · 1.92 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Large and rare copy number variants (CNVs) at several loci have been shown to increase risk for schizophrenia. Aiming to discover novel susceptibility CNV loci, we analyzed 6882 cases and 11 255 controls genotyped on Illumina arrays, most of which have not been used for this purpose before. We identified genes enriched for rare exonic CNVs among cases, and then attempted to replicate the findings in additional 14 568 cases and 15 274 controls. In a combined analysis of all samples, 12 distinct loci were enriched among cases with nominal levels of significance (P < 0.05); however, none would survive correction for multiple testing. These loci include recurrent deletions at 16p12.1, a locus previously associated with neurodevelopmental disorders (P = 0.0084 in the discovery sample and P = 0.023 in the replication sample). Other plausible candidates include non-recurrent deletions at the glutamate transporter gene SLC1A1, a CNV locus recently suggested to be involved in schizophrenia through linkage analysis, and duplications at 1p36.33 and CGNL1. A burden analysis of large (>500 kb), rare CNVs showed a 1.2% excess in cases after excluding known schizophrenia-associated loci, suggesting that additional susceptibility loci exist. However, even larger samples are required for their discovery.
    Human Molecular Genetics 02/2013; 23(6):1669-1676. DOI:10.1093/hmg/ddt540 · 6.39 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: There is extensive bi-directional communication between the brain and the immune system in both health and disease. In recent years, the role of an altered immune system in the etiology of major psychiatric disorders has become more apparent. Studies have demonstrated that some patients with major psychiatric disorders exhibit characteristic signs of immune dysregulation and that this may be a common pathophysiological mechanism that underlies the development and progression of these disorders. Furthermore, many psychiatric disorders are also often accompanied by chronic medical conditions related to immune dysfunction such as autoimmune diseases, diabetes and atherosclerosis. One of the major psychiatric disorders that has been associated with an altered immune system is schizophrenia, with approximately one third of patients with this disorder showing immunological abnormalities such as an altered cytokine profile in serum and cerebrospinal fluid. An altered cytokine profile is also found in a proportion of patients with major depressive disorder and is thought to be potentially related to the pathophysiology of this disorder. Emerging evidence suggests that altered immune parameters may also be implicated in the neurobiological etiology of autism spectrum disorders. Further support for a role of immune dysregulation in the pathophysiology of these psychiatric disorders comes from studies showing the immunomodulating effects of antipsychotics and antidepressants, and the mood altering effects of anti-inflammatory therapies. This review will not attempt to discuss all of the psychiatric disorders that have been associated with an augmented immune system, but will instead focus on several key disorders where dysregulation of this system has been implicated in their pathophysiology including depression, schizophrenia and autism spectrum disorder.
    Journal of Neuroimmune Pharmacology 05/2013; 8(4). DOI:10.1007/s11481-013-9462-8 · 4.11 Impact Factor
Show more