GABAA receptor subunit gene polymorphisms predict symptom-based and developmental deficits in Chinese Han children and adolescents with autistic spectrum disorders

Abstract

GABAA receptor subunit genes GABRB3, GABRA5, and GABRG3 located on chromosome 15q11-q13 have been implicated in the etiology of autistic spectrum disorders (ASD). This study intended to investigate the possible role of single-nucleotide polymorphisms (SNPs) present in GABRB3 (rs2081648 and rs1426217), GABRA5 (rs35586628), and GABRG3 (rs208129) genes in ASD susceptibility and symptom-based and developmental phenotypes of ASD in Chinese Han children and adolescents. 99 ASD patients and 231 age- and gender- frequency-matched typical developing (TD) controls were tested by TaqMan® genotyping assay. Symptom-based phenotypes were evaluated by Childhood Autism Rating Scale (CARS) and Autism Behavior Checklist (ABC), and developmental phenotypes were assessed by Early Childhood Development Questionnaire (ECDQ) in ASD patients. Three haplotypes and global χ 2 test of all SNPs demonstrated significant associations between ASD and TD groups. Besides, GABRB3 rs2081648, GABRA5 rs35586628, and GABRG3 rs208129 polymorphisms were associated with symptom-based deficits in social interaction, sensorimotor and somatosensory coordination, visual response, imitation, activity level, language expression and adaptability. Developmental abnormalities in late emergences of social interaction and fine motor were detected in GABRB3 rs2081648 polymorphism. Overall results indicated that gene synergy may participate in ASD pathogenesis, and GABAA receptor gene polymorphisms can predict symptom-based and developmental deficits in ASD individuals.

Mechanisms underlying the EEG biomarker in Dup15q syndrome

“…Furthermore, polymorphisms [64–70] and abnormal expression levels [71–74] of several GABA A receptor subunit genes have also been identified in individuals with ASD. In fact, single-nucleotide polymorphisms in all three of the GABA A receptor genes that are duplicated in Dup15q syndrome were recently found to predict symptom-based and developmental deficits in a large ( n = 99) cohort of children and adolescents with ASD [75]. At the same time, EEG beta band anomalies have been linked to ASD [76–79], though arguably less so than anomalies in other frequency bands [80].…”

Sleep–behaviour relationship in children with autism spectrum disorder: methodological pitfalls and insights from cognition and sensory processing

“…A still‐speculative theory proposes that the atypical distribution of GABAergic interneurons in autism explains their deficits in global perception and their insistence on sameness . Accordingly, a recent study showed that different subunits of the GABA A receptor are associated with specific autism symptoms such as deficits in social interactions, insistence on sameness, and language impairments . Being the main inhibitory neurotransmitter in the central nervous system, GABA is involved in the inhibition of wake‐promoting cellular populations in the brainstem, the hypothalamus, and the basal forebrain.…”

“…46 Accordingly, a recent study showed that different subunits of the GABA A receptor are associated with specific autism symptoms such as deficits in social interactions, insistence on sameness, and language impairments. 47 Being the main inhibitory neurotransmitter in the central nervous system, GABA is involved in the inhibition of wake-promoting cellular populations in the brainstem, the hypothalamus, and the basal forebrain. GABA acts through GABA A , GABA B , and GABA C receptors, the first being the most well-known for its role in sleep initiation and maintenance.…”

Network-Based Integrative Analysis of Genomics, Epigenomics and Transcriptomics in Autism Spectrum Disorders

“…The list of predicted genes includes GABRA5 . It transcribes for the subunit 5 of GABA receptor alpha whose reduced expression and reduced protein level have been described in autism [44], and the SNPs of this gene are biomarkers of symptoms and developmental deficit in Han Chinese with autism [45]. The inclusion of this gene in the core list strengthens the evidences of imbalance between excitatory and inhibitory neurotransmission in ASDs and abnormalities in glutamate and GABA signaling as possible causative pathological mechanisms of ASDs.…”