CNTN4: A Possible Candidate Gene for Microbiota–Gut–Brain Axis in Autism Spectrum Disorders and Attention-Deficit/Hyperactivity Disorder

The gut microbiota plays a significant role in autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD), though findings vary substantially across studies. Using gut microbiome data from a genome-wide association study of 5,959 participants and summary statistics from 46,351 ASD and 55,374 ADHD cases, we conducted bidirectional Mendelian randomization (MR) analyses with inverse variance weighting as the primary method. Reverse MR analysis assessed potential reverse causality. We annotated single nucleotide polymorphisms (SNPs) with SNP-nexus to identify associated genes, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses to characterize their functional roles. Seventeen gut microbial taxa showed causal associations with ASD risk, while 27 were linked to ADHD. Reverse MR analysis revealed associations between aSD and species Desulfovibrio piger as well as species Bacillus U , but no reverse causality was detected for ADHD. Biological annotation identified five novel conserved genes in host-microbiome interactions shared by ASD and ADHD, with CNTN4 emerging as a common candidate gene. These findings support a potential causal relationship between gut microbiota and ASD/ADHD risk while uncovering novel conserved genes implicated in host–microbiome interactions for both disorders. Lay Abstract Distinct gut microbiota profiles were observed in individuals with ADHD and ASD. Seventeen microbial species showed significant associations with ASD, while 27 were linked to ADHD. CNTN4 emerged as a potential candidate gene shared across both neurodevelopmental conditions and host–microbiome interactions.