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Replication of linkage on chromosome 7q22 and association of the regional Reelin gene with working memory in schizophrenia families

Molecular Psychiatry volume 13, pages 673–684 (2008)Cite this article

Abstract

Schizophrenia is a common and complex mental disorder. Hereditary factors are important for its etiology, but despite linkage signals reported to several chromosomal regions in different populations, final identification of predisposing genes has remained a challenge. Utilizing a large family-based schizophrenia study sample from Finland, we have identified several linked loci: 1q32.2–q42, 2q, 4q31, 5q and 7q22. In this study, an independent sample of 352 nuclear schizophrenia families (n=1626) allowed replication of linkage on 7q21–32. In a sample of 245 nuclear families (n=1074) originating from the same geographical region as the families revealing the linkage, SNP and microsatellite association analyses of the four regional candidate genes, GRM3, RELN, SEMA3A and VGF, revealed no significant association to the clinical diagnosis of schizophrenia. Instead, quantifiable trait component analyses with neuropsychological endophenotypes available from 186 nuclear families (n=861) of the sample showed significant association to RELN variants for traits related to verbal (P=0.000003) and visual working memory (P=0.002), memory (P=0.002) and executive functioning (P=0.002). Trait-associated allele-positive subjects scored lower in the tests measuring working memory (P=0.0004–0.0000000004), memory (P=0.02–0.0001) and executive functioning (P=0.001). Our findings suggest that allelic variants of RELN contribute to the endophenotypes of schizophrenia.

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Acknowledgements

We acknowledge the contributions of Drs Joseph D Terwilliger, Jari Haukka, Markus Perola and Mr Tero Hiekkalinna for practical help and critical comments on the statistical analyses of this study, and Ms Minna Suvela, Ms Sisko Lietola, Mr Pekka Ellonen and Ms Minttu Jussila for laboratory work. We warmly thank all the participating patients and their families, whose supportive attitude towards our research is highly appreciated, as well as all the field workers who participated in the sample collection and the diagnostic assessment. This study was supported by the Academy of Finland (Center of Excellence in Complex Disease Genetics), and Biocentrum Helsinki. Juho Wedenoja was funded by the Helsinki Biomedical Graduate School. Anu Loukola is a post-doctoral fellow of the Academy of Finland.

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  1. Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland

    J Wedenoja, A Loukola, T Paunio, J Ekelund, K Silander, T Varilo, K Heikkilä & L Peltonen

  2. Department of Medical Genetics, University of Helsinki, Helsinki, Finland

    J Wedenoja, T Varilo, J Lönnqvist & L Peltonen

  3. Department of Mental Health and Alcohol Research, National Public Health Institute, Helsinki, Finland

    A Tuulio-Henriksson, T Paunio, J Ekelund, J Suvisaari, T Partonen & J Lönnqvist

  4. Department of Psychology, University of Helsinki, Helsinki, Finland

    A Tuulio-Henriksson

  5. Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland

    T Paunio, J Ekelund & J Lönnqvist

  6. Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA

    T Varilo & L Peltonen

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Wedenoja, J., Loukola, A., Tuulio-Henriksson, A. et al. Replication of linkage on chromosome 7q22 and association of the regional Reelin gene with working memory in schizophrenia families. Mol Psychiatry 13, 673–684 (2008). https://doi.org/10.1038/sj.mp.4002047

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