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A promoter variant of SHANK1 affects auditory working memory in schizophrenia patients and in subjects clinically at risk for psychosis

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Abstract

Mutations in postsynaptic scaffolding genes contribute to autism, thus suggesting a role in pathological processes in neurodevelopment. Recently, two de novo mutations in SHANK3 were described in schizophrenia patients. In most cases, abnormal SHANK3 genotype was also accompanied by cognitive disruptions. The present study queries whether common SHANK variants may also contribute to neuropsychological dysfunctions in schizophrenia. We genotyped five common coding or promoter variants located in SHANK1, SHANK2 and SHANK3. A comprehensive test battery was used to assess neuropsychological functions in 199 schizophrenia patients and 206 healthy control subjects. In addition, an independent sample of 77 subjects at risk for psychosis was analyzed for replication of significant findings. We found the T allele of the SHANK1 promoter variant rs3810280 to lead to significantly impaired auditory working memory as assessed with digit span (12.5 ± 3.6 vs. 14.8 ± 4.1, P < .001) in schizophrenia cases, applying strict Bonferroni correction for multiple testing. This finding was replicated for forward digit span in the at-risk sample (7.1 ± 2.0 vs. 8.3 ± 2.0, P = .044). Previously, altered memory functions and reduced dendritic spines and postsynaptic density of excitatory synapses were reported in SHANK1 knock-out mice. Moreover, the atypical neuroleptic clozapine was found to increase SHANK1 density in rats. Our findings suggest a role of SHANK1 in working memory deficits in schizophrenia, which may arise from neurodevelopmental changes to prefrontal cortical areas.

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Acknowledgments

This study was part of the German Research Network on Schizophrenia and was funded by the German Federal Ministry for Education and Research BMBF (grants 01GI0501, 01GI0232, 01GI0234 and 01GV0907), the German Research Foundation DFG (grants Wa 731/6 and Wa 731/4), and by the 7th framework program of the European Union (ADAMS project, HEALTH-F4-2009-242257). We thank V. Guttenthaler, A. Petruschke and C. Hanses for expert technical assistance. The authors thank all clinicians, psychiatrists, psychologists and study nurses involved in the study.

Conflicts of interest

The authors report no biomedical financial interests or potential conflicts of interest.

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Authors and Affiliations

  1. Department of Psychiatry and Psychotherapy, University of Bonn, Sigmund-Freud-Straße 25, 53105, Bonn, Germany

    Leonhard Lennertz, Michael Wagner, Anna Schuhmacher, Ingo Frommann, Julia Berning, Svenja Schulze-Rauschenbach, Martin W. Landsberg, Anja Steinbrecher, Wolfgang Maier & Rainald Mössner

  2. Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany

    Michael Alexander

  3. Institute of Human Genetics, University of Bonn, Bonn, Germany

    Michael Alexander

  4. Department of Psychiatry and Psychotherapy, University of Düsseldorf, Düsseldorf, Germany

    Wolfgang Wölwer, Petra E. Franke & Wolfgang Gaebel

  5. Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany

    Ralf Pukrop, Stephan Ruhrmann, Andreas Bechdolf & Joachim Klosterkötter

  6. Central Institute of Mental Health, Mannheim, Germany

    Heinz Häfner

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  1. Leonhard Lennertz
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Correspondence to Rainald Mössner.

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Lennertz, L., Wagner, M., Wölwer, W. et al. A promoter variant of SHANK1 affects auditory working memory in schizophrenia patients and in subjects clinically at risk for psychosis. Eur Arch Psychiatry Clin Neurosci 262, 117–124 (2012). https://doi.org/10.1007/s00406-011-0233-3

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