RBFOX1 and working memory: from genome to transcriptome revealed post-transcriptional mechanism separate from ADHD

BACKGROUND: Many psychiatric disorders share working memory (WM) impairment phenotype, yet the genetic causes remain unclear. Here, we generate the genetic profiles of WM deficits using attention-deficit/hyperactivity disorder (ADHD) samples and validate the results in the zebrafish models. METHODS: We have employed two relatively large ADHD cohorts, 799 and 776 samples, respectively. WM impairment was characterized by the Rey Complex Figure Test. Firstly, association analyses were conducted at single variant, gene-based, and gene-set levels. Deeper insights into the biological mechanism were gained from further functional exploration by bioinformatic analyses and zebrafish models. RESULTS: Genomic analyses have identified and replicated a locus with rs75885813 as the index SNP to be significantly associated with WM defects but not with ADHD. Functional feature exploration found these SNPs may regulate the expression level of RBFOX1 through the chromatin interaction. Further pathway enrichment analysis of potential associated SNPs revealed the involvement of post-transcription regulation that affects mRNA stability and/or alternative splicing. Zebrafish with functionally knocked-down or genome-edited rbfox1 exhibited WM impairment but no hyperactivity. Transcriptome profiling of rbfox1 defective zebrafish indicated that alternative exon usages of snap25a and exon-skipping of grin1 genes separately yet partially lead to reduced WM learning of larval zebrafish. CONCLUSION: The locus with rs75885813 of RBFXO1 was identified to be associated with working memory. Rbfox1 regulates synaptic and long-term potentiation related genes to adjust WM at the post-transcriptional level.