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Common Sequence Variants in the Major Histocompatibility Complex Region Associate with Cerebral Ventricular Size in Schizophrenia

  • Ingrid Agartz
    Correspondence
    Address correspondence to Ingrid Agartz, M.D., Ph.D., University of Oslo, Institute of Clinical Medicine, Psychiatry Section, PO Box 85 Vinderen, 0319 Oslo, Norway
    Affiliations
    Institute of Clinical Medicine, Department of Biostatistics, University of Oslo, Oslo, Norway

    Department of Research and Development, Diakonhjemmet Hospital, Oslo University Hospital, Oslo, Norway
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  • Andrew Anand Brown
    Affiliations
    Institute of Clinical Medicine, Department of Biostatistics, University of Oslo, Oslo, Norway

    Institute of Basic Medical Sciences, Department of Biostatistics, University of Oslo, Oslo, Norway
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  • Lars M. Rimol
    Affiliations
    Institute of Clinical Medicine, Department of Biostatistics, University of Oslo, Oslo, Norway
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  • Cecilie B. Hartberg
    Affiliations
    Institute of Clinical Medicine, Department of Biostatistics, University of Oslo, Oslo, Norway
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  • Anders M. Dale
    Affiliations
    Department of Neurosciences, University of California, San Diego, La Jolla, California

    Department of Radiology, University of California, San Diego, La Jolla, California
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  • Ingrid Melle
    Affiliations
    Institute of Clinical Medicine, Department of Biostatistics, University of Oslo, Oslo, Norway

    Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
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  • Srdjan Djurovic
    Affiliations
    Institute of Clinical Medicine, Department of Biostatistics, University of Oslo, Oslo, Norway

    Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
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  • Ole A. Andreassen
    Affiliations
    Institute of Clinical Medicine, Department of Biostatistics, University of Oslo, Oslo, Norway

    Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
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      Background

      Because of evidence from genetic linkage and genome-wide association studies, as well as suggested involvement of infection, the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1 has been implicated in the development of schizophrenia.

      Methods

      Here, we investigated how gene variants across the MHC region are associated with brain structure in a large ethnically homogenous sample (n = 420), including patients with schizophrenia spectrum disorders and other severe mental illness and healthy control subjects.

      Results

      We demonstrate highly significant associations between common gene markers in the MHC region and cerebral ventricular volume specifically in schizophrenia spectrum patients (uncorrected p values between 1.16 × 10−4 and 2.00 × 10−7). One single nucleotide polymorphism, rs2596532, survives Bonferroni correction for multiple testing across all single nucleotide polymorphisms and brain structure measures (adjusted p value 5.59 × 10−4).

      Conclusions

      The results indicate that MHC variants are implicated in characteristic brain abnormalities of schizophrenia.

      Key Words

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      References

        • Lewis C.M.
        • Levinson D.F.
        • Wise L.H.
        • DeLisi L.E.
        • Straub R.E.
        • Hovatta I.
        • et al.
        Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia.
        Am J Hum Genet. 2003; 73: 34-48
        • Yolken R.H.
        • Torrey E.F.
        Are some cases of psychosis caused by microbial agents?.
        Mol Psychiatry. 2008; 13: 470-479
        • Brown A.S.
        • Derkits E.J.
        Prenatal infection and schizophrenia: A review of epidemiologic and translational studies.
        Am J Psychiatry. 2010; 167: 261-280
        • Purcell S.M.
        • Wray N.R.
        • Stone J.L.
        • Visscher P.M.
        • O'Donovan M.C.
        • et al.
        • International Schizophrenia Consortium
        Common polygenic variation contributes to risk of schizophrenia and bipolar disorder.
        Nature. 2009; 460: 748-752
        • Shi J.
        • Levinson D.F.
        • Duan J.
        • Sanders A.R.
        • Zheng Y.
        • Pe'er I.
        • et al.
        Common variants on chromosome 6p22.1 are associated with schizophrenia.
        Nature. 2009; 460: 753-757
        • Stefansson H.
        • Ophoff R.A.
        • Steinberg S.
        • Andreassen O.A.
        • Cichon S.
        • Rujescu D.
        • et al.
        Common variants conferring risk of schizophrenia.
        Nature. 2009; 460: 744-747
        • Shatz C.J.
        MHC class I: An unexpected role in neuronal plasticity.
        Neuron. 2009; 64: 40-45
        • Potvin S.
        • Stip E.
        • Sepehry A.A.
        • Gendron A.
        • Bah R.
        • Kouassi E.
        • et al.
        Inflammatory cytokine alterations in schizophrenia: A systematic quantitative review.
        Biol Psychiatry. 2008; 63: 801-808
        • Shenton M.E.
        • Dickey C.C.
        • Frumin M.
        • McCarley R.W.
        A review of MRI findings in schizophrenia.
        Schizophr Res. 2001; 49: 1-52
        • Rimol L.M.
        • Hartberg C.B.
        • Nesvåg R.
        • Fennema-Notestine C.
        • Hagler D.J.
        • Pung C.J.
        • et al.
        Cortical thickness and subcortical volumes in schizophrenia and bipolar disorder.
        Biol Psychiatry. 2010; 68: 41-50
        • Rimol L.M.
        • Agartz I.
        • Djurovic S.
        • Brown A.A.
        • Roddey J.C.
        • Kähler A.K.
        • et al.
        Sex-dependent association of common variants of microcephaly genes with brain structure.
        Proc Natl Acad Sci U S A. 2010; 107: 384-388
        • Wagner B.D.
        • Zerbe G.O.
        • Mexal S.
        • Leonard S.S.
        Permutation-based adjustments for the significance of partial regression coefficients in microarray data analysis.
        Genet Epidemiol. 2008; 32: 1-8
        • Sklar P.
        • Smoller J.W.
        • Fan J.
        • Ferreira M.A.
        • Perlis R.H.
        • Chambert K.
        • et al.
        Whole-genome association study of bipolar disorder.
        Mol Psychiatry. 2008; 13: 558-569
        • Ferreira M.A.
        • O'Donovan M.C.
        • Meng Y.A.
        • Jones I.R.
        • Ruderfer D.M.
        • Jones L.
        • et al.
        Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder.
        Nat Genet. 2008; 40: 1056-1058
        • Scott L.J.
        • Muglia P.
        • Kong X.Q.
        • Guan W.
        • Flickinger M.
        • Upmanyu R.
        • et al.
        Genome-wide association and meta-analysis of bipolar disorder in individuals of European ancestry.
        Proc Natl Acad Sci U S A. 2009; 106: 7501-7506
        • Dutt A.
        • McDonald C.
        • Dempster E.
        • Prata D.
        • Shaikh M.
        • Williams I.
        • et al.
        The effect of COMT, BDNF, 5-HTT, NRG1 and DTNBP1 genes on hippocampal and lateral ventricular volume in psychosis.
        Psychol Med. 2009; 39: 1783-1797
        • Pastinen T.
        Genome-wide allele-specific analysis: Insights into regulatory variation.
        Nat Rev Genet. 2010; 11: 533-538
        • Kubicki M.
        • McCarley R.
        • Westin C.F.
        • Park H.J.
        • Maier S.
        • Kikinis R.
        • et al.
        A review of diffusion tensor imaging studies in schizophrenia.
        J Psychiatr Res. 2007; 41: 15-30
        • Kempton M.J.
        • Stahl D.
        • Williams S.C.
        • DeLisi L.E.
        Progressive lateral ventricular enlargement in schizophrenia: A meta-analysis of longitudinal MRI studies.
        Schizophr Res. 2010; 120: 54-62
        • Koutsouleris N.
        • Gaser C.
        • Bottlender R.
        • Davatzikos C.
        • Decker P.
        • Jäger M.
        • et al.
        Use of neuroanatomical pattern regression to predict the structural brain dynamics of vulnerability and transition to psychosis.
        Schizophr Res. 2010; 123: 175-187