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Articles   |    
The Role of the Major Histocompatibility Complex Region in Cognition and Brain Structure: A Schizophrenia GWAS Follow-Up
James T.R. Walters, M.R.C.Psych., Ph.D.; Dan Rujescu, M.D.; Barbara Franke, Ph.D.; Ina Giegling, Ph.D.; Alejandro Arias Vásquez, Ph.D.; April Hargreaves, M.Sc.; Giancarlo Russo, Ph.D.; Derek W. Morris, Ph.D.; Martine Hoogman, M.Sc.; Andrea Da Costa, Ph.D.; Valentina Moskvina, Ph.D.; Guillén Fernández, M.D., Ph.D.; Michael Gill, M.R.C.Psych., Ph.D.; Aiden Corvin, M.R.C.Psych., Ph.D.; Michael C. O’Donovan, F.R.C.Psych., Ph.D.; Gary Donohoe, Ph.D.; Michael J. Owen, F.R.C.Psych., Ph.D.
Am J Psychiatry 2013;170:877-885. doi:10.1176/appi.ajp.2013.12020226
View Author and Article Information

The authors report no financial relationships with commercial interests.

Genotyping of the German sample was funded by grants from the MRC and Wellcome Trust. Recruitment and genotyping of the Irish sample was supported by the Wellcome Trust and Science Foundation Ireland. Recruitment of the patients from Munich, Germany, was partially supported by GlaxoSmithKline.

From the Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, Wales; Molecular and Clinical Neurobiology and Department of Psychiatry, Ludwig-Maximilians University, Munich; the Departments of Human Genetics, Psychiatry, and Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behavior, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands; Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine and Trinity Institute of Neuroscience, Trinity College, Dublin; Functional Genomics Center Zurich, University of Zurich, Switzerland; and the Department of Language and Genetics, Max Planck Institute for Psycholinguistics, Nijmegen.

Address correspondence to Prof. O’Donovan (odonovanmc@cf.ac.uk).

Copyright © 2013 by the American Psychiatric Association

Received February 16, 2012; Revised October 16, 2012; January 08, 2013; Accepted January 14, 2013.

Abstract

Objective  The authors investigated the effects of recently identified genome-wide significant schizophrenia genetic risk variants on cognition and brain structure.

Method  A panel of six single-nucleotide polymorphisms (SNPs) was selected to represent genome-wide significant loci from three recent genome-wide association studies (GWAS) for schizophrenia and was tested for association with cognitive measures in 346 patients with schizophrenia and 2,342 healthy comparison subjects. Nominally significant results were evaluated for replication in an independent case-control sample. For SNPs showing evidence of association with cognition, associations with brain structural volumes were investigated in a large independent healthy comparison sample.

Results  Five of the six SNPs showed no significant association with any cognitive measure. One marker in the major histocompatibility complex (MHC) region, rs6904071, showed independent, replicated evidence of association with delayed episodic memory and was significant when both samples were combined. In the combined sample of up to 3,100 individuals, this SNP was associated with widespread effects across cognitive domains, although these additional associations were no longer significant after adjusting for delayed episodic memory. In the large independent structural imaging sample, the same SNP was also associated with decreased hippocampal volume.

Conclusions  The authors identified a SNP in the MHC region that was associated with cognitive performance in patients with schizophrenia and healthy comparison subjects. This SNP, rs6904071, showed a replicated association with episodic memory and hippocampal volume. These findings implicate the MHC region in hippocampal structure and functioning, consistent with the role of MHC proteins in synaptic development and function. Follow-up of these results has the potential to provide insights into the pathophysiology of schizophrenia and cognition.

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FIGURE 1. Delayed Episodic Memory Scores in German and Irish Patients With Schizophrenia and Healthy Comparison Subjects, by rs6904071 Genotypea

a WMS-R= German Wechsler Memory Scale–Revised; WMS-III=Wechsler Adult Intelligence Scale, 3rd edition.

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TABLE 1.Results of Linear Regression of Genome-Wide Significant Single-Nucleotide Polymorphism (SNP) Associations With Cognitive Domainsa
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a Positive regression coefficient indicates schizophrenia risk allele associated with worse performance on cognitive test. Nominally significant p values were taken forward for replication.

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b For loci with minor allele frequencies <0.1, the analysis was redone by grouping together minor allele and heterozygote genotype groups. The results remained unchanged and none were significant.

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TABLE 2.Detailed Results for rs6904071 in the German Sample in a Study of Single-Nucleotide Polymorphism Associations With Cognitive Domains
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a WAIS=Wechsler Adult Intelligence Scale; CPT-IP=Continuous Performance Test, Identical Pairs Version; WMS-R=German Wechsler Memory Scale–Revised. Raw scores are provided for WMS-R tests; all other scores are scaled.

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b B coefficient with respect to schizophrenia risk allele (G) adjusted for age and sex as appropriate.

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c Nominally significant association results taken forward for replication in Irish sample.

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TABLE 3.Results for rs6904071 in the Irish Replication Sample in a Study of Single-Nucleotide Polymorphism Associations With Cognitive Domains
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a Scaled test scores. WMS-III=Wechsler Memory Scale, 3rd edition; CPT-IP=Continuous Performance Test, Identical Pairs Version.

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b B coefficient with respect to schizophrenia risk allele (G) adjusted for age and sex as appropriate.

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c One-sided p value of regression.

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TABLE 4.Association of rs6904071 With z Scores of Cognitive Domains in Combined German and Irish Samples
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a Adjusted for diagnostic status.

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b Full-scale IQ in German sample and abbreviated IQ in Irish sample.

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c Wechsler Adult Intelligence Scale digit span in German sample and letter-number sequencing in Irish sample.

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d Wechsler Memory Scale spatial span in German sample and Cambridge Neuropsychological Test Automated Battery spatial working memory in Irish sample.

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e Immediate logical memory in both samples.

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f Delayed logical memory in both samples.

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g 3–7 version of the Continuous Performance Test used in German sample and three-letter version of the Continuous Performance Test, Identical Pairs Version, used in Irish sample.

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The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition > Chapter 3.  >
Gabbard's Treatments of Psychiatric Disorders, 4th Edition > Chapter 20.  >
The American Psychiatric Publishing Textbook of Geriatric Psychiatry, 4th Edition > Chapter 6.  >
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