TL;DR
Although no statistically significant genetic associations were identified in the present cohort, the bioinformatics findings suggest that these loci remain biologically relevant within Wnt-related pathways.
Abstract Objectives Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with a significant genetic component, often linked to disruptions in the serotonergic system. The HTR2A gene, specifically the rs6313 (102T>C) polymorphism, is a primary candidate for investigating ASD susceptibility. The aim of this study is to investigate the association of rs6313 polymorphism with susceptibility to ASD in the Jordanian population. Methods In this case-control study, 99 Jordanian children with ASD and 109 neurotypical controls were genotyped using PCR-RFLP. Genotype and allele frequencies were analyzed under multiple genetic models. Results No statistically significant differences were found between cases and controls regarding genotype (p=0.54) or allele frequencies (p=0.3284). The distribution adhered to Hardy-Weinberg equilibrium in both groups. Conclusions Our findings suggest no significant association between the HTR2A rs6313 and ASD susceptibility in the Jordanian population. These results emphasize the need for larger, multi-marker studies to account for regional genetic diversity.
Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition arising from interactions between genetic susceptibility and environmental factors, including vitamin D status. This study investigated the associations of serum vitamin D levels and vitamin D receptor (VDR) gene variants with ASD in Indonesian children. This exploratory case-control study included 80 children aged 24-59 months from Surabaya, Indonesia, comprising 40 children with ASD and 40 typically developing controls. Serum 25-hydroxyvitamin D3 (25[OH]D3) concentrations were measured using an enzyme-linked immunosorbent assay, while the VDR region containing rs731236 was amplified by polymerase chain reaction and analyzed using bidirectional Sanger sequencing. Sequencing additionally identified rs11574113, rs7975232, and the rare missense variant rs1338135647 (p.Gly375Asp). Children with ASD had lower serum 25(OH)D3 concentrations than controls (median, 46.13 vs 69.27 ng/mL; p = 0.027), and the difference remained significant after adjustment for age and sex (adjusted median difference, -24.86 ng/mL; 95% confidence interval [CI], -42.42 to -7.30; p = 0.007). The rs1338135647 AG genotype was more frequent in children with ASD than in controls (22.5% vs 2.5%) and remained associated with ASD after adjustment for age and sex using Firth penalized logistic regression (odds ratio, 6.44; 95% CI, 1.21-67.64; p = 0.028). No significant associations were observed for the other VDR variants. Lower vitamin D levels and the rare rs1338135647 variant may independently co-occur with ASD in Indonesian children; however, these hypothesis-generating findings require replication and functional validation in larger independent cohorts.
ObjectiveTo investigate the association between Wnt signaling pathway genes and non-syndromic orofacial cleft (NSOC) in the Han Chinese population.DesignBased on a previously published genome-wide association study (GWAS), we performed a discovery phase analysis on 635 QC-passed SNPs (out of 7054 initially extracted from 59 Wnt pathway genes). Significant loci were then validated in an independent replication cohort.SettingA specialized craniofacial surgery center within a tertiary care institution.Patients/ParticipantsIn the discovery phase, we extracted the genotype data of 2512 NSOC cases and 2255 controls from two previous published GWASs. The independent replication cohort included 2724 patients with NSOC and 1263 healthy controls, all of Han Chinese descent.InterventionsNo clinical interventions were applied; the study involved genetic data analysis only.Main Outcome MeasuresSNPs associated with NSOC and its subtypes were identified through allelic and genotypic association analyses, with odds ratios (ORs), 95% confidence intervals (CIs), and P-values calculated.ResultsIn the independent replication cohort, rs4821611 in RAC2 was significantly associated with NSOC (P = 5.8 × 10-7, OR = 0.77, 95% CI: 0.70-0.85), NSCL/P (P = 4.4 × 10-11, OR = 0.68, 95%CI: 0.61-0.77), and NSCLO (P = 3.27 × 10-15, OR = 0.6, 95% CI: 0.53-0.68). Genotypic analysis confirmed these associations. rs757190 in WNT3 was also associated with NSCLP (P = 0.00056, OR = 0.78, 95% CI: 0.67-0.90).Conclusionsrs4821611 in RAC2 and rs757190 in WNT3 are associated with NSOC and its subtypes in the Han Chinese population, supporting a role for Wnt signaling in cleft pathogenesis.
Autism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental condition with complex genetic and molecular mechanism. Identifying reliable molecular biomarkers remains a critical challenge. In this study, we integrated mRNA expression profiles from five post-mortem brain tissue GEO datasets to identify ASD-associated genes. Following batch effect correction, differentially expressed genes (DEGs) were analysed and Weighted Gene Co-expression Network Analysis (WGCNA) was performed to screen genes correlated with ASD. Then, five machine learning algorithms - Random Forest, LASSO, Boruta, CatBoost, and LightGBM - were applied to screen hub genes. Lastly, alterations of the hub gene(s) were investigated with a maternal immune activation (MIA) rat model using poly I:C by measuring mRNA expression of the hub genes in the rat nucleus accumbens (NAc) and caudate putamen (CPu). A total of 30 DEGs and 54 WGCNA module genes were identified, yielding 29 key candidates by intersecting these two gene sets. EIF4A1 (Eukaryotic Translation Initiation Factor 4A1) was the sole gene consistently ranked among the top five by all five machine learning algorithms. Analysis of the integrated dataset confirmed that EIF4A1 mRNA expression was significantly elevated in ASD subjects. Finally, using the MIA rat model of ASD, we found that EIF4A1 mRNA expression was significantly down-regulated in the NAc and CPu, and this deficit was rescued by treatment with the antipsychotics olanzapine or risperidone. In conclusion, the present study positions EIF4A1 as a promising candidate molecular indicator with potential implications for understanding disease mechanisms and developing targeted interventions of ASD.
Background: Although genetic-environmental interactions are established in autism spectrum disorder (ASD), how environmental toxicants confer susceptibility remains unclear. This study aimed to investigate potential relationship between genetically predicted cerebrospinal fluid (CSF), metabolite levels and ASD liability, and to prioritize regulatory genes, key pathways, and candidate environmental toxicants. Methods: Using two ASD GWAS datasets (exploration data: 18,381 ASD cases/27,969 controls; validation data: 18,235 ASD cases/36,741 controls), we applied multi-omics approaches to prioritize ASD-associated CSF metabolites, regulatory SNPs, and genes. Enrichment analysis and protein–protein interaction (PPI) network analysis were performed on these metabolite-related genes to explore the potential mechanisms linking CSF metabolic disturbances to ASD. Finally, candidate environmental neurotoxicants were screened through protein-chemical interaction analysis, with binding relationships assessed via molecular docking prediction. Results: Two-sample Mendelian randomization (MR) analysis prioritized adenine and proline as candidate CSF metabolites with potential risk associations with ASD. Summary-data-based MR (SMR) prioritized 39 brain-specific quantitative trait loci (QTL) involving 35 candidate regulatory genes, including dual-metabolite modulator GRM8. Functional enrichment analyses suggested potential associations with mitochondrial dysfunction, Hippo signaling pathway, and microtubule dynamics impairment, with protein–protein interaction networks highlighting KATNA1/KATNAL2 as hubs. Protein-chemical interaction screening nominated 14 candidate environmental toxicants, including established chemicals (acetaminophen, valproic acid, estradiol) and novel candidates (SB-431542, K 7174, benzo[a]pyrene), with docking affinity assessed computationally. Conclusions: Our study provides suggestive evidence that elevated adenine and proline may be potential risk factors for ASD and suggests possible involvement of the mitochondrial–Hippo–microtubule pathway. We also propose benzo[a]pyrene as a candidate environmental toxicant that may perturb CSF metabolism. However, given the limited statistical significance, these findings require further validation.
The biological plausibility of LNX2 as a candidate gene for neurodevelopmental disorders is supported, highlighting its preferential association with neuronal projection-cell networks, synaptic vesicle trafficking pathways, and neuron-specific regulatory programs.