Does Immune Dysfunction Contribute to Schizophrenia? Genetic Findings from New Study
ScienceDaily (Oct. 10, 2012) — A new study reinforces the finding that a region of the genome involved in immune system function, called the major histocompatibility complex (MHC), is involved in the genetic susceptibility to schizophrenia.
Schizophrenia is among the most disabling psychiatric disorders. Approximately 80% of the risk for developing schizophrenia is heritable, but there has been slow progress in identifying genetic variation that contributes to the risk for schizophrenia.
The current paper contributes to this growing literature by identifying variants of genes that influence the function of the immune system which may contribute to the heritable risk for schizophrenia.
Two large, international, collaborating groups of scientists — the Wellcome Trust Case Control Consortium 2 and the Irish Schizophrenia Genomics Consortium — conducted this new study.
They first performed what is called a discovery scan, where they analyzed over 6 million genetic variants in schizophrenia patients and controls from Ireland. This allowed them to compile a list of variants that showed the strongest association signals with schizophrenia.
They then performed similar work in an independent sample of 13,195 cases and 31,021 controls from around the world in order to search for the same top ‘hits’. This wealth of data was provided by the international schizophrenia genetics community. This replication work is an important scientific strategy, particularly in the field of genetics, to strengthen and support the original findings.
Using these multiple datasets and approaches, their findings lend further support for the involvement of the MHC genes in schizophrenia susceptibility..
“In this large collaborative effort, we have replicated evidence for specific risk and protective alleles at the MHC locus — a critical step teasing apart the genetic risk mechanisms involved,” commented Dr. Aiden Corvin, one of the lead authors and a professor at Trinity College Dublin. “However, pinpointing specific risk genes or alleles has been challenging because this is a region of great genomic variation within and between populations.”
These genetic findings also highlight an important gap in our understanding of the biology of schizophrenia. There is a long history of interest in immunologic contribution to schizophrenia including wide ranging observations linking viral infection, gluten sensitivity, changes in cytokine levels in blood and cerebrospinal fluid, and other factors to schizophrenia.
“Despite this, we have relatively little understanding how alterations in immune function are involved in the etiology and pathophysiology of this disorder,” commented Dr. John Krystal, Editor of Biological Psychiatry. “Immunologic studies in schizophrenia that illuminate the nature of the contribution of variation in immune system genes to schizophrenia will be an important new direction in schizophrenia research.”
Genome-Wide Association Study Implicates HLA-C*01:02 as a Risk Factor at the Major Histocompatibility Complex Locus in Schizophrenia.
We performed a genome-wide association study (GWAS) to identify common risk variants for schizophrenia.
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.
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 × 10(-9) and in combined samples (rs2523722 p combined = 2.88 × 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.
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.
Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
Major Histocompatibility Complex and Autism
The major histocompatibility complex and autism spectrum disorder.
Autism spectrum disorder (ASD) is a complex disorder that appears to be caused by interactions between genetic changes and environmental insults during early development. A wide range of factors have been linked to the onset of ASD, but recently both genetic associations and environmental factors point to a central role for immune-related genes and immune responses to environmental stimuli.
Specifically, many of the proteins encoded by the major histocompatibility complex (MHC) play a vital role in the formation, refinement, maintenance, and plasticity of the brain. Manipulations of levels of MHC molecules have illustrated how disrupted MHC signaling can significantly alter brain connectivity and function.
Thus, an emerging hypothesis in our field is that disruptions in MHC expression in the developing brain caused by mutations and/or immune dysregulation may contribute to the altered brain connectivity and function characteristic of ASD. This review provides an overview of the structure and function of the three classes of MHC molecules in the immune system, healthy brain, and their possible involvement in ASD.