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.

Association between GABA(A) receptor subunit polymorphisms and autism spectrum disorder (ASD)

“…The evidence that GABRA4, associated with ASD (Ma et al, 2005), combined with GABRG2, associated with epilepsy (Haerian and Baum, 2013), are overrepresented in our sample would support this idea. This is also sustained by previous findings where a synergistic interaction between GABRB3, which is associated with ASD (e.g., Buxbaum et al, 2002), and GABRD, associated with epilepsy (e.g., Dibbens et al, 2004), was found (Sesarini et al, 2014).…”

“…The MDR analysis replicated the original findings (Sesarini et al, 2014) where synergistic effect between the markers of genes GABRB3 (chromosome 15) and GABRD (chromosome 1) were associated with increased risk for autism suggesting a potential gene-gene interaction (epistasis) across chromosomes. There was no other genetic interaction in association with ASD observed for the rest of the genes studied (data not shown).…”

“…Previous results have suggested a synergistic interaction between GABRB3 and GABRD in ASD individuals (Sesarini et al, 2014). In the present study, we analyzed an expanded sample of Argentinean ASD population and polymorphisms.…”

“…Evidence for synergy between markers in GABA(A) receptor (GABAR) subunits β3 (chromosome 15) and δ (chromosome 1) has recently been reported suggesting genegene interaction across chromosomes associated with increased risk for autism (Sesarini et al, 2014), whereas polymorphisms in GABAR subunits have also been associated with epilepsy (Kumari et al, 2011).…”

Genetics in child and adolescent psychiatry: methodological advances and conceptual issues

“…For example, in spite of some inconsistencies, a potential interaction between the 7-repeat allele of the DRD4 and the 10-repeat allele DAT1 has been initially reported in ADHD (for review [9]). Similarly, a recent study evaluated the independent and combined contribution of single SNPs to the genetic variance of autism spectrum disorders in an Argentinian sample and revealed a potential association of a gene-gene interaction between GABAAreceptor subunit genes with an increased risk for autism spectrum disorders [130].…”