Investigation of autism and GABA receptor subunit genes in multiple ethnic groups

Abstract

Autism is a neurodevelopmental disorder of complex genetics, characterized by impairment in social interaction and communication, as well as repetitive behavior. Multiple lines of evidence, including alterations in levels of GABA and GABA receptors in autistic patients, indicate that the GABAergic system, which is responsible for synaptic inhibition in the adult brain, may be involved in autism. Previous studies in our lab indicated association of noncoding single nucleotide polymorphisms (SNPs) within a GABA receptor subunit gene on chromosome 4, GABRA4, and interaction between SNPs in GABRA4 and GABRB1 (also on chromosome 4), within Caucasian autism patients. Studies of genetic variation in African-American autism families are rare. Analysis of 557 Caucasian and an independent population of 54 AfricanAmerican families with 35 SNPs within GABRB1 and GABRA4 strengthened the evidence for involvement of GABRA4 in autism risk in Caucasians (rs17599165, p=0.0015; rs1912960, p=0.0073; and rs17599416, p=0.0040) and gave evidence of significant association in African-Americans (rs2280073, p=0.0287 and rs168 59788, p=0.0253). The GABRA4 and GABRB1 interaction was also confirmed in the Caucasian dataset (most significant pair, rs1912960 and rs2351299; p=0.004). Analysis of the subset of families with a positive history of seizure activity in at least one autism patient revealed no association to GABRA4; however, three SNPs within GABRB1 showed significant allelic association; rs2351 299 (p=0.0163), rs4482737 (p=0.0339), and rs3832300 (p=0.0253). These results confirmed our earlier findings, indicating GABRA4 and GABRB1 as genes contributing to autism susceptibility, extending the effect to multiple ethnic groups and suggesting seizures as a stratifying phenotype.

A preliminary transcranial magnetic stimulation study of cortical inhibition and excitability in high‐functioning autism and Asperger disorder

“…14,15 Widespread abnormalities in GABA A receptor activity was recently demonstrated in postmortem brain tissue samples from individuals with autism, with affected regions including parietal and frontal cortices and the cerebellum. 22 These findings are also consistent with neural connectivity studies suggesting a reduction of inhibitory cells in autism, 23,24 which operate as 'GABA-gated pacemakers for neocortical oscillatory activity' (Wilson et al 24 …”

“…Indeed, there is some evidence for GABAergic abnormalities in autism. 14,15 It is unclear, however, whether in vivo GABA impairments exist in autism and, if so, whether these impairments also extend to Asperger disorder (which is often considered a milder form of autistic disorder).…”

Disparities in Diagnoses Received Prior to a Diagnosis of Autism Spectrum Disorder

“…Cuccaro et al (2005) report that African-American children with autism may have more impaired language development than white children, while oral communication with Lord (2005, oral communication) suggested no such differences. In their study of the involvement of GABA receptor subunit genes in autism, Collins et al (2006) report invariance across white and a small group of African-American children, but note that different single nucleotide polymorphisms were associated in each ethnic group. Much further research is required to determine whether ethnic genotypic differences exist, and whether they are associated with different clinical presentation.…”

Common Genetic Etiologies and Biological Pathways Shared Between Autism Spectrum Disorders and Intellectual Disabilities

“…GABRα2, GABRβ1, GABRγ1 and GABRα4 on 4p14 (Ma et al, 2005;Vincent et al, 2006;Kakinuma et al, 2008) have also been implicated in autism. Molecular work specific to some of these GABA receptors supports their role in autism (Ma et al, 2005;Collins et al, 2006;Fatemi et al, 2010). It is also of note that GABA neurotransmission is strongly implicated in fragile X syndrome, and knockout of the fmr1 gene in mice has a hugely disruptive effect on the GABAergic system, and is a potential target for the treatment of symptoms for both Fragile-X syndrome and autism (Hagerman et al, 2005).…”