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  • Lilly-Molecular Psychiatry Award Honorable Mention
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Lilly-Molecular Psychiatry Award Honorable Mention

Genetic investigation of chromosome 5q GABAA receptor subunit genes in schizophrenia

Molecular Psychiatry volume 10, pages 1074–1088 (2005)Cite this article

Abstract

We previously performed a genome-wide linkage scan in Portuguese schizophrenia families that identified a risk locus on chromosome 5q31–q35. This finding was supported by meta-analysis of 20 other schizophrenia genome-wide scans that identified 5q23.2–q34 as the second most compelling susceptibility locus in the genome. In the present report, we took a two-stage candidate gene association approach to investigate a group of gamma-aminobutyric acid (GABA) A receptor subunit genes (GABRA1, GABRA6, GABRB2, GABRG2, and GABRP) within our linkage peak. These genes are plausible candidates based on prior evidence for GABA system involvement in schizophrenia. In the first stage, associations were detected in a Portuguese patient sample with single nucleotide polymorphisms (SNPs) and haplotypes in GABRA1 (P=0.00062–0.048), GABRP (P=0.0024–0.042), and GABRA6 (P=0.0065–0.0088). The GABRA1 and GABRP findings were replicated in the second stage in an independent German family-based sample (P=0.0015–0.043). Supportive evidence for association was also obtained for a previously reported GABRB2 risk haplotype. Exploratory analyses of the effects of associated GABRA1 haplotypes on transcript levels found altered expression of GABRA6 and coexpressed genes of GABRA1 and GABRB2. Comparison of transcript levels in schizophrenia patients and unaffected siblings found lower patient expression of GABRA6 and coexpressed genes of GABRA1. Interestingly, the GABRA1 coexpressed genes include synaptic and vesicle-associated genes previously found altered in schizophrenia prefrontal cortex. Taken together, these results support the involvement of the chromosome 5q GABAA receptor gene cluster in schizophrenia, and suggest that schizophrenia-associated haplotypes may alter expression of GABA-related genes.

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Acknowledgements

We gratefully acknowledge the families and individuals who participated in this study. We thank Ana Dourado, Jose Valente, Carlos Paz Ferreira, Isabel Coelho, and MJ Soares for patient collection, Sinead O'Leary for analytical assistance, and Eric Lander, Ed Skolnick, Nick Patterson, and Vamsi Mootha for helpful discussions of the manuscript. We acknowledge the Stanley Medical Research Foundation, and Michael Knable, DO, Serge Weis, MD, Fuller Torrey, MD, Maree Webster, PhD, and Robert Yolken, MD for donating postmortem brain tissue. This research was supported by NIMH Grants MH52618 and MH058693 to CNP, and NARSAD Young Investigator awards to TLP and CNP. MJD was a Pfizer Fellow in Computational Biology.

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Authors and Affiliations

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

    T L Petryshen, A R Tahl, G N Rockwell, K A Aldinger, S G Waggoner, M J Daly & P Sklar

  2. Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, and Department of Psychiatry, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA

    T L Petryshen, S Purcell & P Sklar

  3. Center for Neuropsychiatric Genetics, State University of New York (SUNY), Syracuse, NY, USA

    F A Middleton, C P Morley, H M Medeiros, C Carvalho, A Macedo, M T Pato & C N Pato

  4. Department of Psychiatry, State University of New York (SUNY), Syracuse, NY, USA

    F A Middleton, C P Morley, M T Pato & C N Pato

  5. Department of Neuroscience and Physiology, State University of New York (SUNY), Syracuse, NY, USA

    F A Middleton, L McGann & K L Gentile

  6. Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA

    A Kirby & M J Daly

  7. Department of Psychiatry, Georgetown University, Washington, DC, USA

    H M Medeiros, M T Pato & C N Pato

  8. Psicologia Medica, Universidade de Coimbra, Coimbra, Portugal

    M H Azevedo

  9. Mental State Hospital, Haar, Germany

    M Albus

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

    W Maier

  11. Department of Psychiatry, University Medical School of Pécs, Pécs, Hungary

    M Trixler

  12. Department of Psychiatry, University of Regensburg, Regensburg, Germany

    P Eichhammer

  13. Western Australian Institute for Medical Research and Centre for Medical Research, University of Western Australia, Crawley, WA, Australia

    S G Schwab

  14. School of Psychiatry and Clinical Neurosciences, University of Western Australia, Crawley, WA, Australia

    S G Schwab & D B Wildenauer

  15. Veterans Administration Medical Center, Washington, DC, USA

    M T Pato & C N Pato

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  1. T L Petryshen
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Correspondence to P Sklar.

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

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Petryshen, T., Middleton, F., Tahl, A. et al. Genetic investigation of chromosome 5q GABAA receptor subunit genes in schizophrenia. Mol Psychiatry 10, 1074–1088 (2005). https://doi.org/10.1038/sj.mp.4001739

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  • DOI: https://doi.org/10.1038/sj.mp.4001739

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