1. ¹Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
2. ²Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, and Department of Psychiatry, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA
3. ³Center for Neuropsychiatric Genetics, State University of New York (SUNY), Syracuse, NY, USA
4. ⁴Department of Psychiatry, State University of New York (SUNY), Syracuse, NY, USA
5. ⁵Department of Neuroscience and Physiology, State University of New York (SUNY), Syracuse, NY, USA
6. ⁶Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA
7. ⁷Department of Psychiatry, Georgetown University, Washington DC, USA
8. ⁸Psicologia Medica, Universidade de Coimbra, Coimbra, Portugal
9. ⁹Mental State Hospital, Haar, Germany
10. ¹⁰Department of Psychiatry, University of Bonn, Bonn, Germany
11. ¹¹Department of Psychiatry, University Medical School of Pécs, Pécs, Hungary
12. ¹²Department of Psychiatry, University of Regensburg, Regensburg, Germany
13. ¹³Western Australian Institute for Medical Research and Centre for Medical Research, University of Western Australia, Crawley, WA, Australia
14. ¹⁴School of Psychiatry and Clinical Neurosciences, University of Western Australia, Crawley, WA, Australia
15. ¹⁵Veterans Administration Medical Center, Washington, DC, USA

Correspondence: Dr P Sklar, Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, 185 Cambridge Street, 6th Floor, Boston, MA 02114, USA. E-mail: sklar@psych.mgh.harvard.edu

Received 2 May 2005; Revised 11 July 2005; Accepted 19 July 2005; Published online 20 September 2005.

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 GABA_A receptor gene cluster in schizophrenia, and suggest that schizophrenia-associated haplotypes may alter expression of GABA-related genes.