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Editorials   |    
Schizophrenia as a Human Leukocyte Antigen-Associated Disease Revisited
Peter McGuffin, Ph.D., F.R.C.P.; Robert A. Power, M.Sc.
Am J Psychiatry 2013;170:821-823. doi:10.1176/appi.ajp.2013.13030336
View Author and Article Information

Dr. McGuffin reports long-standing research collaborations with members of the Cardiff MRC Centre for Neuropsychiatric Genetics and Genomics. Mr. Power is supported by a U.K. MRC Ph.D. studentship, and this research is supported in part by grants from the MRC and by the National Institute for Health Research Biomedical Research Centre at the South London and Maudsley National Health Service Foundation Trust and the Institute of Psychiatry, King’s College London.

From the Medical Research Council (MRC) Social, Genetic, and Developmental Psychiatry Center, King’s College London.

Address correspondence to Dr. McGuffin (peter.mcguffin@kcl.ac.uk).

Copyright © 2013 by the American Psychiatric Association

Accepted March , 2013.

The major histocompatibility complex (MHC) on chromosome 6p represents a unique region of the genome, containing genes encoding human leukocyte antigens (HLA) and many others involved in immune functioning (1). In this issue of the Journal, Walters et al. (2) provide the latest intriguing twist in the long-running tale regarding the relationship between the MHC and schizophrenia. HLA loci were among the first genetic markers to be studied in relation to schizophrenia, and more than 30 years ago one of us performed a meta-analysis of the first few HLA association studies and concluded that the results were promising (3). Such early studies were very modest in scale, and a meta-analysis 22 years later, by which time more data had accumulated, produced largely negative results (4). However, the HLA/schizophrenia story never really died, and in a subsequent meta-analysis of linkage studies, the region of chromosome 6p containing the MHC was one of the “hits” (5). More recently, the tale was fully revived with several independent genome-wide association studies (GWAS), followed by a combined analysis by the Psychiatric Genomics Consortium, showing associations between single-nucleotide polymorphisms (SNPs) in the MHC region and schizophrenia (611).

However, this finding generates a number of questions. Variants in the MHC region have been associated with numerous immunological disorders, but there is no compelling evidence of an auto-immune basis for schizophrenia. Until now, there has been only one other well-established HLA-associated disorder, hemochromatosis, which does not have an immune basis (12). There are also the unique genetic features of the MHC region that make associations difficult to pin down and increase the likelihood of false positive associations.

One of these is linkage disequilibrium (LD), the phenomenon whereby stretches of genome remain in “blocks” despite many generations of meiotic crossing over. The strong LD in the MHC (13), particularly around HLA genes, makes it difficult to identify the causal variants from markers that are merely “tags” in LD. This can be seen in disorders such as rheumatoid arthritis where the initial HLA association was established relatively easily, but it took a surprisingly long time to isolate the causal variants (14). There is also evidence for negative assortative mating affecting the region. That is, individuals tend to select mates who are dissimilar to themselves with respect to MHC genes (15), leading to greater heterogeneity at these loci in their children. Additionally, as one of the MHC’s major roles is in protecting against pathogens by recognizing “non-self,” there is almost certainly strong selection pressure that increases diversity in the region. Indeed, the HLA loci are the most polymorphic (that is, they have the largest number of common alleles) of any in the genome. Since it is highly polymorphic, the MHC region is highly sensitive to population stratification. This is the phenomenon whereby admixtures of populations that have differing marker gene frequencies can result in apparent but spurious marker-disease associations. This means careful ethnic matching of case and control subjects is needed to overcome the problem of hidden population structure when it comes to the MHC.

Despite these caveats, there is good reason for optimism that the association with schizophrenia is real. First, the statistical support is becoming more compelling in that increasing GWAS sample sizes have been associated with ever decreasing p values that make the probability of a type I error vanishingly small. Furthermore, a new Irish sample independent of the most recent Psychiatric Genomics Consortium meta-analysis supported the MHC association and, by imputation, found that the most significant result was with a classic HLA-C marker, a class I MHC molecule (16). Second, several strands of research suggest that the MHC plays an important role in neuronal function, with expression levels affecting synaptic plasticity and potentially the formation of new memories (17). Specifically, there is now evidence that class I MHC proteins regulate synaptic responses mediated by N-methyl-d-aspartic acid (NMDA) type glutamate receptors (NMDARs) in the mammalian CNS. The mechanism appears to work via tonic inhibition of NMDAR function, which in turn affects downstream NMDAR-induced AMPA receptor trafficking (18). Recent data also indicate that not only are MHC class I proteins required for normal postnatal brain development and plasticity, but they are also widely expressed in the mammalian brain prenatally during the earliest stages of neuronal differentiation (19), consistent with a possible role in neurodevelopmental disorders. Finally, the study by Walters et al. in this issue (2), which looks at structural MRI and cognitive measures in patients with schizophrenia and healthy comparison subjects, found significant associations between a SNP in the MHC, previously identified by schizophrenia GWAS, and both delayed episodic memory and decreased hippocampal volume.

In conclusion, exploring the possible role of the MHC region in schizophrenia has been a long saga. The MHC is arguably one of the most complicated and trap-laden regions of the genome, but it now seems highly probable that it contains one or more genes that confer increased susceptibility to schizophrenia. While this might warrant a reappraisal of whether immune mechanisms play a role in schizophrenia and related disorders, there is increasing evidence that the MHC plays a role in synaptic plasticity and brain development through nonimmune functions. The tale is not yet over, but perhaps we have the beginnings of the denouement.

Shiina  T;  Hosomichi  K;  Inoko  H;  Kulski  JK:  The HLA genomic loci map: expression, interaction, diversity and disease.  J Hum Genet 2009; 54:15–39
[CrossRef]
 
Walters  JTR;  Rujescu  D;  Franke  B;  Giegling  I;  Vásquez  AA;  Hargreaves  A;  Russo  G;  Morris  DW;  Hoogman  M;  Da Costa  A;  Moskvina  V;  Fernández  G;  Gill  M;  Corvin  A;  O'Donovan  MC;  Donohoe  G;  Owen  MJ:  The role of the major histocompatibility complex region in cognition and brain structure: a schizophrenia GWAS follow-up.  Am J Psychiatry  2013; 170:877–885
 
McGuffin  P:  Is schizophrenia an HLA-associated disease? Psychol Med 1979; 9:721–728
[CrossRef]
 
Wright  P;  Nimgaonkar  VL;  Donaldson  PT;  Murray  RM:  Schizophrenia and HLA: a review.  Schizophr Res 2001; 47:1–12
[CrossRef]
 
Lewis  CM;  Levinson  DF;  Wise  LH;  DeLisi  LE;  Straub  RE;  Hovatta  I;  Williams  NM;  Schwab  SG;  Pulver  AE;  Faraone  SV;  Brzustowicz  LM;  Kaufmann  CA;  Garver  DL;  Gurling  HM;  Lindholm  E;  Coon  H;  Moises  HW;  Byerley  W;  Shaw  SH;  Mesen  A;  Sherrington  R;  O’Neill  FA;  Walsh  D;  Kendler  KS;  Ekelund  J;  Paunio  T;  Lönnqvist  J;  Peltonen  L;  O’Donovan  MC;  Owen  MJ;  Wildenauer  DB;  Maier  W;  Nestadt  G;  Blouin  JL;  Antonarakis  SE;  Mowry  BJ;  Silverman  JM;  Crowe  RR;  Cloninger  CR;  Tsuang  MT;  Malaspina  D;  Harkavy-Friedman  JM;  Svrakic  DM;  Bassett  AS;  Holcomb  J;  Kalsi  G;  McQuillin  A;  Brynjolfson  J;  Sigmundsson  T;  Petursson  H;  Jazin  E;  Zoëga  T;  Helgason  T:  Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: schizophrenia.  Am J Hum Genet 2003; 73:34–48
[CrossRef]
 
Li  T;  Li  Z;  Chen  P;  Zhao  Q;  Wang  T;  Huang  K;  Li  J;  Li  Y;  Liu  J;  Zeng  Z;  Feng  G;  He  L;  Shi  Y:  Common variants in major histocompatibility complex region and TCF4 gene are significantly associated with schizophrenia in Han Chinese.  Biol Psychiatry 2010; 68:671–673
[CrossRef]
 
Purcell  SM;  Wray  NR;  Stone  JL;  Visscher  PM;  O’Donovan  MC;  Sullivan  PF;  Sklar  P; International Schizophrenia Consortium:  Common polygenic variation contributes to risk of schizophrenia and bipolar disorder.  Nature 2009; 460:748–752
 
Shi  J;  Levinson  DF;  Duan  J;  Sanders  AR;  Zheng  Y;  Pe’er  I;  Dudbridge  F;  Holmans  PA;  Whittemore  AS;  Mowry  BJ;  Olincy  A;  Amin  F;  Cloninger  CR;  Silverman  JM;  Buccola  NG;  Byerley  WF;  Black  DW;  Crowe  RR;  Oksenberg  JR;  Mirel  DB;  Kendler  KS;  Freedman  R;  Gejman  PV:  Common variants on chromosome 6p22.1 are associated with schizophrenia.  Nature 2009; 460:753–757
 
Stefansson  H;  Ophoff  RA;  Steinberg  S;  Andreassen  OA;  Cichon  S;  Rujescu  D;  Werge  T;  Pietiläinen  OP;  Mors  O;  Mortensen  PB;  Sigurdsson  E;  Gustafsson  O;  Nyegaard  M;  Tuulio-Henriksson  A;  Ingason  A;  Hansen  T;  Suvisaari  J;  Lonnqvist  J;  Paunio  T;  Børglum  AD;  Hartmann  A;  Fink-Jensen  A;  Nordentoft  M;  Hougaard  D;  Norgaard-Pedersen  B;  Böttcher  Y;  Olesen  J;  Breuer  R;  Möller  HJ;  Giegling  I;  Rasmussen  HB;  Timm  S;  Mattheisen  M;  Bitter  I;  Réthelyi  JM;  Magnusdottir  BB;  Sigmundsson  T;  Olason  P;  Masson  G;  Gulcher  JR;  Haraldsson  M;  Fossdal  R;  Thorgeirsson  TE;  Thorsteinsdottir  U;  Ruggeri  M;  Tosato  S;  Franke  B;  Strengman  E;  Kiemeney  LA;  Melle  I;  Djurovic  S;  Abramova  L;  Kaleda  V;  Sanjuan  J;  de Frutos  R;  Bramon  E;  Vassos  E;  Fraser  G;  Ettinger  U;  Picchioni  M;  Walker  N;  Toulopoulou  T;  Need  AC;  Ge  D;  Yoon  JL;  Shianna  KV;  Freimer  NB;  Cantor  RM;  Murray  R;  Kong  A;  Golimbet  V;  Carracedo  A;  Arango  C;  Costas  J;  Jönsson  EG;  Terenius  L;  Agartz  I;  Petursson  H;  Nöthen  MM;  Rietschel  M;  Matthews  PM;  Muglia  P;  Peltonen  L;  St Clair  D;  Goldstein  DB;  Stefansson  K;  Collier  DA; Genetic Risk and Outcome in Psychosis (GROUP):  Common variants conferring risk of schizophrenia.  Nature 2009; 460:744–747
 
Figueiredo  TC;  de Oliveira  JR:  Reconsidering the association between the major histocompatibility complex and bipolar disorder.  J Mol Neurosci 2012; 47:26–30
[CrossRef]
 
Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium:  Genome-wide association study identifies five new schizophrenia loci.  Nat Genet 2011; 43:969–976
[CrossRef]
 
McCune  CA;  Ravine  D;  Worwood  M;  Jackson  HA;  Evans  HM;  Hutton  D:  Screening for hereditary haemochromatosis within families and beyond.  Lancet 2003; 362:1897–1898
[CrossRef]
 
Jeffreys  AJ;  Kauppi  L;  Neumann  R:  Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex.  Nat Genet 2001; 29:217–222
[CrossRef]
 
Raychaudhuri  S;  Sandor  C;  Stahl  EA;  Freudenberg  J;  Lee  HS;  Jia  X;  Alfredsson  L;  Padyukov  L;  Klareskog  L;  Worthington  J;  Siminovitch  KA;  Bae  SC;  Plenge  RM;  Gregersen  PK;  de Bakker  PI:  Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis.  Nat Genet 2012; 44:291–296
[CrossRef]
 
Grob  B;  Knapp  LA;  Martin  RD;  Anzenberger  G:  The major histocompatibility complex and mate choice: inbreeding avoidance and selection of good genes.  Exp Clin Immunogenet 1998; 15:119–129
[CrossRef]
 
Irish Schizophrenia Genomics Consortium and the Wellcome Trust Case Control Consortium 2:  Genome-wide association study implicates HLA-C*01:02 as a risk factor at the major histocompatibility complex locus in schizophrenia.  Biol Psychiatry 2012; 72:620–628
[CrossRef]
 
Shatz  CJ:  MHC class I: an unexpected role in neuronal plasticity.  Neuron 2009; 64:40–45
[CrossRef]
 
Fourgeaud  L;  Davenport  CM;  Tyler  CM;  Cheng  TT;  Spencer  MB;  Boulanger  LM:  MHC class I modulates NMDA receptor function and AMPA receptor trafficking.  Proc Natl Acad Sci USA 2010; 107:22278–22283
[CrossRef]
 
Chacon  MA;  Boulanger  LM:  MHC class I protein is expressed by neurons and neural progenitors in mid-gestation mouse brain.  Mol Cell Neurosci 2013; 52:117–127
[CrossRef]
 
References Container
+

References

Shiina  T;  Hosomichi  K;  Inoko  H;  Kulski  JK:  The HLA genomic loci map: expression, interaction, diversity and disease.  J Hum Genet 2009; 54:15–39
[CrossRef]
 
Walters  JTR;  Rujescu  D;  Franke  B;  Giegling  I;  Vásquez  AA;  Hargreaves  A;  Russo  G;  Morris  DW;  Hoogman  M;  Da Costa  A;  Moskvina  V;  Fernández  G;  Gill  M;  Corvin  A;  O'Donovan  MC;  Donohoe  G;  Owen  MJ:  The role of the major histocompatibility complex region in cognition and brain structure: a schizophrenia GWAS follow-up.  Am J Psychiatry  2013; 170:877–885
 
McGuffin  P:  Is schizophrenia an HLA-associated disease? Psychol Med 1979; 9:721–728
[CrossRef]
 
Wright  P;  Nimgaonkar  VL;  Donaldson  PT;  Murray  RM:  Schizophrenia and HLA: a review.  Schizophr Res 2001; 47:1–12
[CrossRef]
 
Lewis  CM;  Levinson  DF;  Wise  LH;  DeLisi  LE;  Straub  RE;  Hovatta  I;  Williams  NM;  Schwab  SG;  Pulver  AE;  Faraone  SV;  Brzustowicz  LM;  Kaufmann  CA;  Garver  DL;  Gurling  HM;  Lindholm  E;  Coon  H;  Moises  HW;  Byerley  W;  Shaw  SH;  Mesen  A;  Sherrington  R;  O’Neill  FA;  Walsh  D;  Kendler  KS;  Ekelund  J;  Paunio  T;  Lönnqvist  J;  Peltonen  L;  O’Donovan  MC;  Owen  MJ;  Wildenauer  DB;  Maier  W;  Nestadt  G;  Blouin  JL;  Antonarakis  SE;  Mowry  BJ;  Silverman  JM;  Crowe  RR;  Cloninger  CR;  Tsuang  MT;  Malaspina  D;  Harkavy-Friedman  JM;  Svrakic  DM;  Bassett  AS;  Holcomb  J;  Kalsi  G;  McQuillin  A;  Brynjolfson  J;  Sigmundsson  T;  Petursson  H;  Jazin  E;  Zoëga  T;  Helgason  T:  Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: schizophrenia.  Am J Hum Genet 2003; 73:34–48
[CrossRef]
 
Li  T;  Li  Z;  Chen  P;  Zhao  Q;  Wang  T;  Huang  K;  Li  J;  Li  Y;  Liu  J;  Zeng  Z;  Feng  G;  He  L;  Shi  Y:  Common variants in major histocompatibility complex region and TCF4 gene are significantly associated with schizophrenia in Han Chinese.  Biol Psychiatry 2010; 68:671–673
[CrossRef]
 
Purcell  SM;  Wray  NR;  Stone  JL;  Visscher  PM;  O’Donovan  MC;  Sullivan  PF;  Sklar  P; International Schizophrenia Consortium:  Common polygenic variation contributes to risk of schizophrenia and bipolar disorder.  Nature 2009; 460:748–752
 
Shi  J;  Levinson  DF;  Duan  J;  Sanders  AR;  Zheng  Y;  Pe’er  I;  Dudbridge  F;  Holmans  PA;  Whittemore  AS;  Mowry  BJ;  Olincy  A;  Amin  F;  Cloninger  CR;  Silverman  JM;  Buccola  NG;  Byerley  WF;  Black  DW;  Crowe  RR;  Oksenberg  JR;  Mirel  DB;  Kendler  KS;  Freedman  R;  Gejman  PV:  Common variants on chromosome 6p22.1 are associated with schizophrenia.  Nature 2009; 460:753–757
 
Stefansson  H;  Ophoff  RA;  Steinberg  S;  Andreassen  OA;  Cichon  S;  Rujescu  D;  Werge  T;  Pietiläinen  OP;  Mors  O;  Mortensen  PB;  Sigurdsson  E;  Gustafsson  O;  Nyegaard  M;  Tuulio-Henriksson  A;  Ingason  A;  Hansen  T;  Suvisaari  J;  Lonnqvist  J;  Paunio  T;  Børglum  AD;  Hartmann  A;  Fink-Jensen  A;  Nordentoft  M;  Hougaard  D;  Norgaard-Pedersen  B;  Böttcher  Y;  Olesen  J;  Breuer  R;  Möller  HJ;  Giegling  I;  Rasmussen  HB;  Timm  S;  Mattheisen  M;  Bitter  I;  Réthelyi  JM;  Magnusdottir  BB;  Sigmundsson  T;  Olason  P;  Masson  G;  Gulcher  JR;  Haraldsson  M;  Fossdal  R;  Thorgeirsson  TE;  Thorsteinsdottir  U;  Ruggeri  M;  Tosato  S;  Franke  B;  Strengman  E;  Kiemeney  LA;  Melle  I;  Djurovic  S;  Abramova  L;  Kaleda  V;  Sanjuan  J;  de Frutos  R;  Bramon  E;  Vassos  E;  Fraser  G;  Ettinger  U;  Picchioni  M;  Walker  N;  Toulopoulou  T;  Need  AC;  Ge  D;  Yoon  JL;  Shianna  KV;  Freimer  NB;  Cantor  RM;  Murray  R;  Kong  A;  Golimbet  V;  Carracedo  A;  Arango  C;  Costas  J;  Jönsson  EG;  Terenius  L;  Agartz  I;  Petursson  H;  Nöthen  MM;  Rietschel  M;  Matthews  PM;  Muglia  P;  Peltonen  L;  St Clair  D;  Goldstein  DB;  Stefansson  K;  Collier  DA; Genetic Risk and Outcome in Psychosis (GROUP):  Common variants conferring risk of schizophrenia.  Nature 2009; 460:744–747
 
Figueiredo  TC;  de Oliveira  JR:  Reconsidering the association between the major histocompatibility complex and bipolar disorder.  J Mol Neurosci 2012; 47:26–30
[CrossRef]
 
Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium:  Genome-wide association study identifies five new schizophrenia loci.  Nat Genet 2011; 43:969–976
[CrossRef]
 
McCune  CA;  Ravine  D;  Worwood  M;  Jackson  HA;  Evans  HM;  Hutton  D:  Screening for hereditary haemochromatosis within families and beyond.  Lancet 2003; 362:1897–1898
[CrossRef]
 
Jeffreys  AJ;  Kauppi  L;  Neumann  R:  Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex.  Nat Genet 2001; 29:217–222
[CrossRef]
 
Raychaudhuri  S;  Sandor  C;  Stahl  EA;  Freudenberg  J;  Lee  HS;  Jia  X;  Alfredsson  L;  Padyukov  L;  Klareskog  L;  Worthington  J;  Siminovitch  KA;  Bae  SC;  Plenge  RM;  Gregersen  PK;  de Bakker  PI:  Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis.  Nat Genet 2012; 44:291–296
[CrossRef]
 
Grob  B;  Knapp  LA;  Martin  RD;  Anzenberger  G:  The major histocompatibility complex and mate choice: inbreeding avoidance and selection of good genes.  Exp Clin Immunogenet 1998; 15:119–129
[CrossRef]
 
Irish Schizophrenia Genomics Consortium and the Wellcome Trust Case Control Consortium 2:  Genome-wide association study implicates HLA-C*01:02 as a risk factor at the major histocompatibility complex locus in schizophrenia.  Biol Psychiatry 2012; 72:620–628
[CrossRef]
 
Shatz  CJ:  MHC class I: an unexpected role in neuronal plasticity.  Neuron 2009; 64:40–45
[CrossRef]
 
Fourgeaud  L;  Davenport  CM;  Tyler  CM;  Cheng  TT;  Spencer  MB;  Boulanger  LM:  MHC class I modulates NMDA receptor function and AMPA receptor trafficking.  Proc Natl Acad Sci USA 2010; 107:22278–22283
[CrossRef]
 
Chacon  MA;  Boulanger  LM:  MHC class I protein is expressed by neurons and neural progenitors in mid-gestation mouse brain.  Mol Cell Neurosci 2013; 52:117–127
[CrossRef]
 
References Container
+
+

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