Genetic variants in NEF2L2 rs35652124 and GABRB3 rs2081648 genes: association with autism spectrum disorder in Iraqi children.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder of complex etiology with substantial genetic contribution. Oxidative stress and GABAergic dysregulation are implicated in the pathophysiology of ASD. Both genetic variations in NEF2L2 (Nuclear factor (erythroid-derived 2)-like 2, an antioxidant regulator) and GABRB3 (GABRB3 encodes the GABA-A receptor β3 subunit) may increase susceptibility to ASD. This is the first study of the two genes in this field in the context of the Iraqi children. Because the NEF2L2 control genotype distribution deviated significantly from Hardy-Weinberg equilibrium (χ2 = 50.05, P < 0.0001), the NEF2L2 CT-genotype association below is reported as provisional pending independent genotyping verification; stratified subgroup findings are reported after Benjamini-Hochberg false-discovery-rate correction.This case-control study engaged 90 Iraqi children. Both GABRB3 rs2081648 and NEF2L2 rs35652124 polymorphisms were genotyped using Tetra-ARMS-PCR. GABA and NRF2 were also evaluated both using serum and protein, involved in elements of the oxidative stress, and biomarkers were analyzed. This study also conducted both a haplotype and an epistatic analysis. In exploratory analysis, the NEF2L2 rs35652124 CT genotype showed an apparent association with increased ASD risk; however, because the NEF2L2 control genotype distribution deviated severely from Hardy-Weinberg equilibrium, this association is provisional and is not treated as a confirmed finding of this study. The GABRB3 rs2081648 CT genotype presented robust evidence of protection. The ASD group was found to have a significant decrease in both GABRB3 (43.8%) and NRF2 (43.7%) proteins. The combined biomarker panel for the ASD population was AUC = 0.834. The T-C haplotype presented the most pronounced risk (OR = 2.84, P = 0.003; FDR q = 0.012). The two-locus epistatic interaction (P = 0.028, based on 1,000 permutations) is preliminary pending a confirmatory 10,000-permutation analysis. The GABRB3 polymorphism and serum GABRB3/NRF2 biomarkers are associated with GABA-mediated impairments in ASD in Iraqi children; the NEF2L2 CT-genotype association remains exploratory pending independent genotyping verification.