Petryshen, T. L. and Middleton, F. A. and Tahl, A. R. and Rockwell, G. N. and Purcell, S. and Aldinger, K. A. and Kirby, A. and Morley, C. P. and McGann, L. and Gentile, K. L. and Waggoner, S. G. and Medeiros, H. M. and Carvalho, C. and Macedo, A. and Albus, M. and Maier, W. and Trixler, M. and Eichhammer, P. and Schwab, S. G. and Wildenauer, D. B. and Azevedo, M. H. and Pato, M. T. and Pato, C. N. and Daly, M. J. and Sklar, P. (2005) Genetic investigation of chromosome 5q GABA(A) receptor subunit genes in schizophrenia. MOLECULAR PSYCHIATRY, 10 (12). pp. 1074-1088. ISSN 1359-4184, 1476-5578
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | GENOME-WIDE SCAN; FAMILY-BASED ASSOCIATION; AT-RISK HAPLOTYPE; SUSCEPTIBILITY LOCI; PREFRONTAL CORTEX; BIPOLAR DISORDER; MESSENGER-RNAS; LINKAGE ANALYSIS; POPULATION STRATIFICATION; MICROARRAY ANALYSIS; linkage disequilibrium; haplotypes; single nucleotide polymorphisms; oligonucleotide array sequence analysis; gene expression |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Psychiatrie und Psychotherapie |
| Depositing User: | Petra Gürster |
| Date Deposited: | 22 Jun 2022 12:23 |
| Last Modified: | 22 Jun 2022 12:23 |
| URI: | https://pred.uni-regensburg.de/id/eprint/35381 |
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