Review articleVariation in the major histocompatibility complex [MHC] gene family in schizophrenia: Associations and functional implications
Highlights
► MHC molecules regulate immunity and core functions of the brain. ► Infection and MHC might affect schizophrenia by inducing autoimmunity or inflammation. ► MHC variants are associated with various schizophrenia endophenotypes. ► MHC might increase the risk of schizophrenia by affecting neurodevelopment. ► MHC possibly enhances the risk of schizophrenia by disrupting synaptic transmission.
Introduction
Schizophrenia is a complex, highly heritable and polygenic neuropsychiatric disorder (McGuffin and Gottesman, 1999, Purcell et al., 2009, Sullivan et al., 2003). Although multiple genetic, immune and environmental risk factors (Muller and Schwarz, 2010, Owen et al., 2010, van Os et al., 2010) are known to influence an individual's susceptibility to develop schizophrenia, its neurobiological underpinnings are yet to be fully elucidated. There is a growing recognition that immune system dysfunction might play a pivotal role in the etiopathogenesis of schizophrenia, as supported by immunological, genetic and expression studies showing alterations of various immune cell subsets and components (Craddock et al., 2007, Muller et al., in press, Saetre et al., 2007, Schmitt et al., 2011). Recently, MHC [also known as HLA (human leukocyte antigen) in human, both the terms have been used interchangeably in this review] — a complex genetic locus known to influence immune regulation and host–microbe interplay has emerged as a major determinant of schizophrenia risk (de Jong et al., 2012, Papiol et al., 2011, Shi et al., 2009, Stefansson et al., 2009). The MHC is a ~ 4 Mb region on the short arm of chromosome 6 (6p21.3–22.1) which is one of the most polymorphic and gene dense regions of the immune-related genes in the human genome (as reviewed in Shiina et al., 2009, Traherne, 2008). The newly defined extended HLA system spanning about a 7.6 Mb region comprises class -I, -II and -III, extended HLA class I, and extended class II sub-regions (as reviewed in Shiina et al., 2009). According to Release 3.7.0, 12 January 2012 of IMGT/HLA database (http://www.ebi.ac.uk/imgt/hla/), the HLA region has altogether 7130 (5518 HLA class I and 1612 class II alleles) observed HLA and 139 non-HLA alleles.
The MHC molecules were primarily known to be involved in antigen processing and presentation, intercellular recognition as well as self versus non-self discrimination. The highly polymorphic HLA-A, -B and -C molecules encoded by the classical HLA class I gene cluster, play essential roles in the detection and elimination of virus-infected cells, tumor cells and transplanted allogeneic cells while the classical class II molecules are crucial in initiating cellular and humoral immune responses. However, the current understanding suggests that many of the genes of the extended HLA system code for proteins that act as ligands, receptors, interacting partners, signaling molecules, cytokines, heat shock proteins, transcription factors etc. not only play significant roles in immunity but also in non-immune processes related to development, regulation etc. (Shiina et al., 2009). In addition to this, the MHC and MHC-linked molecules are critically involved in determining the susceptibility or resistance to a myriad number of infectious agents (Blackwell et al., 2009).
Recently, the MHC region has become the subject of intense research in complex human diseases as disruption of the expression of MHC molecules and/or variation within the MHC were found to contribute to autoimmune, infectious and inflammatory conditions (Fernando et al., 2008, Gough and Simmonds, 2007, Rioux et al., 2009, Trowsdale, 2011). Some MHC genes are among the strongest risk variants for several autoimmune/inflammatory disorders, e.g. multiple sclerosis (MS), type 1 diabetes (T1D), systemic lupus erythematosus (SLE), inflammatory bowel diseases (IBD) etc. (Fernando et al., 2012, Lincoln et al., 2009, Nejentsev et al., 2007, Rioux et al., 2009). Cumulative evidence from multiple MHC association studies of these disorders implicated several genes representing classical HLA (HLA-A, -B, -C, -DRB, -DQA, -DQB, -DPA, and -DPB), TNF, TLA, LTB, TAP, MICA, MICB, the complement loci (C2, C4, CFB) etc. (Fernando et al., 2008). Although the mechanisms underlying the MHC-mediated risk of autoimmune/inflammatory disorders are not fully understood, it has been demonstrated that most of these disorders are the result of breakdown in immunological tolerance or immune-mediated destruction of autologous cells or tissues due to inappropriate interactions between predisposing genes and environmental triggers.
Many of the MHC-linked autoimmune/inflammatory disorders are found to co-occur significantly more in schizophrenia; along with infections, these conditions enhance the risk of developing schizophrenia (Benros et al., 2011, Chen et al., 2012, Eaton et al., 2006). Although these observations have provided suggestive evidence of MHC's involvement in schizophrenia, multiple genetic studies have shown association of schizophrenia with most of the above-mentioned as well as other MHC genes, such as classical HLA, TNF, MICB, NOTCH4, TAP genes, complement genes and so on (Czerski et al., 2008, Fellerhoff and Wank, 2009, Prasad et al., 2010, Shayevitz et al., 2012, Shirts et al., 2007, Wright et al., 2001, Zakharyan et al., 2011). Furthermore, recent genome wide association (GWA) studies have established MHC region as the most consistently replicated risk loci for schizophrenia (Ikeda et al., 2011, Papiol et al., 2011, Purcell et al., 2009, Ripke et al., 2011, Shi et al., 2009, Stefansson et al., 2009, Steinberg et al., 2011, Yue et al., 2011). In this review, we highlight recent advances in immunogenetic research on the MHC gene family and the evidence implicating it in the pathophysiology of schizophrenia.
Section snippets
Schizophrenia as an autoimmune–inflammatory–infectious disorder: a review of evidence
Preliminary support toward autoimmune hypothesis of schizophrenia was derived from its association with a range of autoimmune disorders (Eaton et al., 2006, Eaton et al., 2010). However, substantial evidence pointing to a role of autoimmunity in schizophrenia has come from studies showing presence of a number of autoantigens/autoantibodies to neurotransmitters, such as dopamine, serotonin, acetylcholine and other components including NMDA receptors (as reviewed in Carter, 2011, Jones et al.,
Neurobiological attributes of MHC: implications for psychopathology
Although multiple lines of evidence have already established a role of MHC molecules in autoimmunity and inflammation, the potential effect of MHC molecules on CNS functions and behavior is beginning to be understood. However, the evidence emerging from animal and in vitro studies suggests that MHC molecules can affect core functions of the CNS, as illustrated by their involvement in neurodevelopment, neuronal and synaptic plasticity, learning, memory and behavior (Boulanger, 2009, Boulanger
MHC and schizophrenia: evidence for association
The proposition that MHC confers risk to schizophrenia although debated for some time but accumulating evidence from multiple immunological, genetic, mRNA/protein expression and imaging studies argue in favor of a significant role of MHC in schizophrenia (Agartz et al., 2011, Debnath et al., 2006, Kano et al., 2011, Krause et al., 2012, Lewis et al., 2003, Saetre et al., 2007, Sequeira et al., 2012, Wright et al., 2001). The first evidence supporting HLA as a schizophrenia susceptibility locus
HLA association with schizophrenia risk factors
Epidemiological studies have linked schizophrenia susceptibility with a number of demographic, clinical and environmental variables. A number of such variables have additionally been associated with HLA reviewed here.
Relationship between HLA and schizophrenia endophenotypes
One of the important strategies for functional verification of the identified risk variants of schizophrenia has been to understand the impact of such variants on the intermediate phenotypes that are associated with disease trait. A number of studies have shown endophenotypes associated with schizophrenia risk variants (Greenwood et al., 2012, Hall and Smoller, 2010). Eye movement disturbances is an established endophenotype of schizophrenia (Gottesman and Gould, 2003) and both the eye tracking
Impact of MHC variation on brain morphology and cognitive deficits in schizophrenia
Structural brain abnormalities and disabling cognitive deficits have consistently been associated with schizophrenia (van Os and Kapur, 2009). Cognitive deficits are correlated with structural alterations and dysfunction of several cognition-related neurotransmitter systems, including dopamine and the NMDAR (Antonova et al., 2005, Javitt, 2007). Converging evidence from structural neuroimaging studies indicates increased ventricular size, smaller temporal lobes and hippocampi (Shenton et al.,
Microglia in neuroinflammation: relevance of cytokine–MHC network in schizophrenia
An increasing body of evidence suggests presence of neuroinflammation in schizophrenia (Doorduin et al., 2009, Meyer, 2011, Monji et al., 2013, Saetre et al., 2007). The activation of microglia is a well-known indicator of CNS inflammation. Though the microglia comprise about less than one-tenth of the total brain cells, they react swiftly to even minor pathological changes in the brain and may directly lead to the neuronal degeneration by producing various pro-inflammatory cytokines and free
MHC and schizophrenia: gene–environment interactions and epigenetics
Environmental factors account for a significant portion of vulnerability toward developing schizophrenia (van Os et al., 2008). These factors are suspected to interact with the maternal and offspring genomes that led to increased rates of congenital malformations and behavioral abnormalities in offspring. Adverse prenatal events due to environmental insults that led to cognitive and behavior syndromes in schizophrenia have been associated with genes (Mittal et al., 2008). Maternal infection is
Comparative immunogenetics: HLA association with comorbid conditions prevalent in schizophrenia
A number of psychiatric as well as other medical comorbidities are commonly found among schizophrenia patients. The psychiatric comorbidities include anxiety, depression, panic disorder, posttraumatic stress disorder, substance abuse disorder, obsessive–compulsive disorder etc. (Buckley et al., 2009). However, there is a significant lack of information of HLA association with these comorbid conditions. Regarding nonpsychiatric comorbid conditions, epidemiological studies over the past few
Pharmacogenetic strategies in schizophrenia and the MHC
The extraordinary diversity and the novel immune functions of the HLA molecules have contributed to their importance and relevance in health and disease. The structural and functional diversities of HLA have led to a challenging level of complexity regarding the design of genomic medicines. Accounting for an individual's genetic background and in particular with respect to HLA in the pharmacogenetics of various disorders is becoming increasingly significant (Charron, 2011). Several drugs
MHC and schizophrenia: quo vadis?
Although the involvement of the MHC gene family in schizophrenia is gaining certainty (Fig. 1), a pertinent question arises “Is MHC a major contributor to the pathogenesis of schizophrenia?”
It is noteworthy that MHC is associated with more than a hundred diseases, majority of them have immunological underpinnings while some are even unrelated to immunity. Considering the association of schizophrenia with MHC-linked autoimmune disorders, genetic variation and altered expression of MHC in
Conclusion
Recent advances in our understanding of the functional implication of MHC molecules on neurodevelopment have shed light on the role and mechanisms by which immunogenetic processes contribute to the pathogenesis of schizophrenia. Although the majority of findings implicating the MHC region are consistent within the immune dogma of schizophrenia, many identified risk variants such as HIST1H2BJ, PRSS16, PGBD1, RPP21, and NOTCH4 in the MHC region have non-immune functions. The risk variants within
Disclosure
The authors declare that they have no conflicts of interest to disclose.
Contributors
MD conceived the idea and wrote the manuscript. DMC and GV also participated in writing the manuscript and provided expert opinion.
Acknowledgments
GV is supported by the Wellcome Trust DBT India Alliance Senior Fellowship and the DBT Senior Innovative Young Biotechnologist Award.
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