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

Institute of Clinical Medicine, Department of Biostatistics, University of Oslo, Oslo, Norway.
Biological psychiatry (Impact Factor: 10.26). 04/2011; 70(7):696-8. DOI: 10.1016/j.biopsych.2011.02.034
Source: PubMed


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

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    • "We found no significant associations between SNP variation across the ZNF804A gene and cortical thickness measures in psychosis patients or healthy controls. Although the cohort we investigated is of moderate size it has previously been used to successfully identify variants associated with brain measures in other candidate gene studies of schizophrenia (K ¨ ahler et al. 2012, Agartz et al. 2011). The difficulty of replicating results from genetic association studies has led to imaging genetics studies to move towards meta analyses of tens of thousands of samples (e.g. the ENIGMA Network /http:// enigma.loni.ucla.eduS), "
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    ABSTRACT: ZNF804A SNP rs1344706 confers genome-wide risk for schizophrenia and bipolar disorder. Both disorders affect cortical thickness. To determine if single nucleotide polymorphisms (SNPs) across ZNF804A are associated with cortical thinning, we investigated 63 SNPs (including rs1344706) in 365 psychosis patients and healthy controls. Results show no significant associations.
    Full-text · Article · Apr 2013
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    • "MHC is purported to be associated with neuropsychoimmunological pathophysiology in schizophrenia [Samaroo et al., 2010; Kano et al., 2011; Singh et al., 2011]. Furthermore, considerable attention has been given to MHC candidate gene associated with schizophrenia in GWAS and especially with brain morphology [Agartz et al., 2011; Williams et al., 2011]. Previously, a case– control study using an Asian population showed an association between MHC and schizophrenia [Li et al., 2010]. "
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    ABSTRACT: Recent GWAS demonstrated an association between candidate genes located at region 6p22.1 and schizophrenia. This region has been reported to house certain candidate SNPs, which may be associated with schizophrenia at HIST1H2BJ, PRSS16, and PGBD1. These genes may presumably be associated with pathophysiology in schizophrenia, namely epigenetics and psychoneuroimmunology. A three-step study was undertaken to focus on these genes with the following aims: (1) whether these genes may be associated in Japanese patients with schizophrenia by performing a 1st stage case-control study (514 cases and 706 controls) using Japanese tagging SNPs; (2) if the genetic regions of interest for the disease from the 1st stage of analyses were found, re-sequencing was performed to search for new mutations; (3) finally, a replication study was undertaken to confirm positive findings from the 1st stage were reconfirmed using a larger number of subjects (2,583 cases and 2,903 controls) during a 2nd stage multicenter replication study in Japan. Genotyping was performed using TaqMan PCR method for the selected nine tagging SNPs. Although three SNPs situated at the 3' side of PGBD1; rs3800324, rs3800327, and rs2142730, and two-window haplotypes between rs3800327 and rs2142730 showed positive associations with schizophrenia, these associations did not have enough power to sustain significance during the 2nd stage replication study. In addition, re-sequencing for exons 5 and 6 situated at this region did not express any new mutations for schizophrenia. Taken together these results indicate that the genes HIST1H2BJ, PRSS16, and PGBD1 were not associated with Japanese patients with schizophrenia.
    Full-text · Article · Jun 2012 · American Journal of Medical Genetics Part B Neuropsychiatric Genetics
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    • "A study of 10 genes involved in synaptic plasticity and formation of perineural nets showed that common B3GAT2 variants were associated with schizophrenia risk and cortical area (Kahler et al., 2011). Consistent with GWAS data, a significant association was found in schizophrenia patients between ventricle size and a SNP in the major histocompatibility cluster (Agartz et al., 2011). In a GWAS of schizophrenia, reduced cortical thickness was associated with SNPs in the 15q12 region (Bakken et al., 2011). "
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    ABSTRACT: In June 2011, 70 researchers from the disciplines of cognitive science, genetics, psychology, psychiatry, neurobiology, and computer science gathered in Os, Norway, for the first Imaging and Cognition Genetics meeting. The aim of the conference was to discuss progress, enhance collaboration, and maximize the sharing of resources within this new field. In this Perspective, we summarize the major themes that emerged from ICG 2011. The first is the importance of defining cognitive and imaging phenotypes and endophenotypes suitable for genetic analysis. These can come from differential psychology, cognitive science, structural MRI, tractography, and functional imaging. The second theme is the emergence of new methods for the analysis of complex traits. These include advanced computational and statistical techniques for analyzing complex datasets, and new ways of interpreting data from genome-wide association studies, such as jointly evaluating the contribution of SNPs in specific genes and pathways rather than considering single SNPs in isolation. The final theme is the importance of establishing functional correlates of newly identified genetic variants.
    Full-text · Article · May 2012 · Frontiers in Neuroscience
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