title: Genetic investigation of chromosome 5q GABAA receptor subunit genes in schizophrenia.
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.
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: T L
authors.initials: TL
authors.lastname: Petryshen
authors.forename: F A
authors.initials: FA
authors.lastname: Middleton
authors.forename: A R
authors.initials: AR
authors.lastname: Tahl
authors.forename: G N
authors.initials: GN
authors.lastname: Rockwell
authors.forename: S
authors.initials: S
authors.lastname: Purcell
authors.forename: K A
authors.initials: KA
authors.lastname: Aldinger
authors.forename: A
authors.initials: A
authors.lastname: Kirby
authors.forename: C P
authors.initials: CP
authors.lastname: Morley
authors.forename: L
authors.initials: L
authors.lastname: McGann
authors.forename: K L
authors.initials: KL
authors.lastname: Gentile
authors.forename: S G
authors.initials: SG
authors.lastname: Waggoner
authors.forename: H M
authors.initials: HM
authors.lastname: Medeiros
authors.forename: C
authors.initials: C
authors.lastname: Carvalho
authors.forename: A
authors.initials: A
authors.lastname: Macedo
authors.forename: M
authors.initials: M
authors.lastname: Albus
authors.forename: W
authors.initials: W
authors.lastname: Maier
authors.forename: M
authors.initials: M
authors.lastname: Trixler
authors.forename: P
authors.initials: P
authors.lastname: Eichhammer
authors.forename: S G
authors.initials: SG
authors.lastname: Schwab
authors.forename: D B
authors.initials: DB
authors.lastname: Wildenauer
authors.forename: M H
authors.initials: MH
authors.lastname: Azevedo
authors.forename: M T
authors.initials: MT
authors.lastname: Pato
authors.forename: C N
authors.initials: CN
authors.lastname: Pato
authors.forename: M J
authors.initials: MJ
authors.lastname: Daly
authors.forename: P
authors.initials: P
authors.lastname: Sklar
mesh_terms: D002874:Chromosome Mapping; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005858:Germany; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011174:Portugal; D011963:Receptors, GABA-A / Q000235:genetics*; D012016:Reference Values; D012559:Schizophrenia / Q000235:genetics*
chemical_list: D011963:Receptors, GABA-A