title: Evidence for interaction between markers in GABA(A) receptor subunit genes in an Argentinean autism spectrum disorder population.
abstract: Autism spectrum disorders (ASD) can be conceptualized as a genetic dysfunction that disrupts development and function of brain circuits mediating social cognition and language. At least some forms of ASD may be associated with high level of excitation in neural circuits, and gamma-aminobutyric acid (GABA) has been implicated in its etiology. Single-nucleotide polymorphisms (SNP) located within the GABA receptor (GABAR) subunit genes GABRA1, GABRG2, GABRB3, and GABRD were screened. A hundred and thirty-six Argentinean ASD patients and 150 controls were studied, and the contribution of the SNPs in the etiology of ASD was evaluated independently and/or through gene-gene interaction using multifactor dimensionality reduction (MDR) method. From the 18 SNP studied, 11 were not present in our Argentinean population (patients and controls) and 1 SNP had minor allele frequency < 0.1%. For the remaining six SNPs, none provided statistical significant association with ASD when considering allelic or genotypic frequencies. Non-significant association with ASD was found for the haplotype analysis. MDR identified evidence for synergy between markers in GABRB3 (chromosome 15) and GABRD (chromosome 1), suggesting potential gene-gene interaction across chromosomes associated with increased risk for autism (testing balanced accuracy: 0.6081 and cross-validation consistency: 10/10, P < 0.001). Considering our Argentinean ASD sample, it can be inferred that GABRB3 would be involved in the etiology of autism through interaction with GABRD. These results support the hypothesis that GABAR subunit genes are involved in autism, most likely via complex gene-gene interactions.
authors.affiliation: Instituto de Ciencias Básicas y Medicina Experimental (ICBME), CABA, Argentina.
authors.forename: Carla V
authors.initials: CV
authors.lastname: Sesarini
authors.forename: Lucas
authors.initials: L
authors.lastname: Costa
authors.forename: Muriel
authors.initials: M
authors.lastname: Naymark
authors.forename: Nora
authors.initials: N
authors.lastname: Grañana
authors.forename: Andrea R
authors.initials: AR
authors.lastname: Cajal
authors.forename: Miguel
authors.initials: M
authors.lastname: García Coto
authors.forename: Roberto C
authors.initials: RC
authors.lastname: Pallia
authors.forename: Pablo F
authors.initials: PF
authors.lastname: Argibay
mesh_terms: D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics*; D004843:Epistasis, Genetic / Q000235:genetics; D005787:Gene Frequency; D005819:Genetic Markers / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D058011:Multifactor Dimensionality Reduction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D021122:Protein Subunits / Q000235:genetics*; D011963:Receptors, GABA-A / Q000235:genetics*; D012016:Reference Values
chemical_list: D005819:Genetic Markers; D021122:Protein Subunits; D011963:Receptors, GABA-A
keywords: Argentinean population; GABA(A) receptor subunits polymorphisms; autism spectrum disorder (ASD); multifactor dimensionality reduction method