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  • Original Research Article
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Haplotypic association spanning the 22q11.21 genes COMT and ARVCF with schizophrenia

Molecular Psychiatry volume 10, pages 353–365 (2005)Cite this article

Abstract

Catechol-O-methyltransferase (COMT) has been implicated in schizophrenia by its function through its roles in monoamine neurotransmitter metabolism and its impact on prefrontal cognition, and also by its position through linkage scans and a strong cytogenetic association. Further support comes from association studies, especially family-based ones examining the COMT variant, Val108/158Met. We have studied eight markers spanning COMT and including portions of the two immediately adjacent genes, thioredoxin reductase 2 and armadillo repeat deleted in velocardiofacial syndrome (ARVCF), using association testing in 136 schizophrenia families. We found nominal evidence for association of illness to rs165849 (P=0.051) in ARVCF, and a stronger signal (global P=0.0019–0.0036) from three-marker haplotypes spanning the 3′ portions of COMT and ARVCF, including Val108/158Met with Val108/158 being the overtransmitted allele, consistent with previous studies. We also find Val108/158Met to be in linkage disequilibrium with the markers in ARVCF. These findings support previous association signals of schizophrenia to COMT markers, and suggest that ARVCF might contribute to this signal. ARVCF, a member of the catenin family, besides being a positional candidate, is also one due to its function, that is, its potential role in neurodevelopment, which is implicated in schizophrenia pathogenesis by several lines of evidence.

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Acknowledgements

We thank the patients and families for their participation. We thank DF Levinson (University of Pennsylvania School of Medicine, Philadelphia, PA, USA) for providing the age of onset information for the NIMH families. Regarding the National Institute of Mental Health (NIMH) Schizophrenia Genetics Initiative families, data and biomaterials were collected in three projects. From 1991 to 1997, the Principal Investigators and Coinvestigators were: Harvard University, Boston, MA, USA (Grant U01 MH46318) (MT Tsuang, S Faraone, and J Pepple); Washington University, St Louis, MO, USA (Grant U01 MH46276) (CR Cloninger, T Reich, and D Svrakic); and Columbia University, New York, NY, USA (Grant U01 MH46289) (C Kaufmann, D Malaspina, and J Harkavy Friedman). This work was supported by NIMH Grant R01 MH62276 to DF Levinson (ARS, SGS, DBW, PVG), by a Research Career Development Award (ARS) at the Evanston Northwestern Healthcare Research Institute, Evanston, IL, USA, and by a Howard Hughes Medical Institute Undergraduate Summer Research Fellowship (IR) at the University of Chicago, Chicago, IL, USA.

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Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Evanston Northwestern Healthcare Research Institute, Center for Psychiatric Genetics, Northwestern University, Evanston, IL, USA

    A R Sanders, I Rusu, J Duan, C Hou & P V Gejman

  2. Department of Human Genetics, University of Chicago, Chicago, IL, USA

    J E Vander Molen

  3. School of Psychiatry and Clinical Neurosciences, University of Western Australia (UWA), Perth, Australia

    S G Schwab & D B Wildenauer

  4. Centre for Medical Research, UWA, Perth, Australia

    S G Schwab

  5. Department of Psychiatry, University of Bonn, Bonn, Germany

    S G Schwab

  6. Centre for Clinical Research in Neurosciences, UWA, Perth, Australia

    D B Wildenauer

  7. Méthodologie Statistique et Epidémiologie Génétique des Maladies Multifactorielles, Institut National de la Recherche et de la Santé Médicale, Evry, France

    M Martinez

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  1. A R Sanders
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  2. I Rusu
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  9. P V Gejman
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Correspondence to A R Sanders.

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Supplementary information accompanies the paper on Molecular Psychiatry website (http://www.nature.com/mp)

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Sanders, A., Rusu, I., Duan, J. et al. Haplotypic association spanning the 22q11.21 genes COMT and ARVCF with schizophrenia. Mol Psychiatry 10, 353–365 (2005). https://doi.org/10.1038/sj.mp.4001586

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  • DOI: https://doi.org/10.1038/sj.mp.4001586

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