RBFOX1 and Working Memory: From Genome to Transcriptome Revealed Posttranscriptional Mechanism Separate From Attention-Deficit/Hyperactivity Disorder
Background: Many psychiatric disorders share a working memory (WM) impairment phenotype, yet the genetic causes remain unclear. Here, we generated genetic profiles of WM deficits using attention-deficit/hyperactivity disorder samples and validated the results in zebrafish models. Methods: We used 2 relatively large attention-deficit/hyperactivity disorder cohorts, 799 and 776 cases, respectively. WM impairment was assessed using the Rey Complex Figure Test. First, 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 identified and replicated a locus with rs75885813 as the index single nucleotide polymorphism showing significant association with WM defects but not with attention-deficit/hyperactivity disorder. Functional feature exploration found that these single nucleotide polymorphisms may regulate the expression level of RBFOX1 through chromatin interaction. Further pathway enrichment analysis of potential associated single nucleotide polymorphisms revealed the involvement of posttranscription regulation that affects messenger RNA 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 might partially lead to reduced WM learning of larval zebrafish. Conclusions: The locus with rs75885813 in RBFOX1 was identified as associated with WM. Rbfox1 regulates synaptic and long-term potentiation–related gene snap25a to adjust WM at the posttranscriptional level.
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1.Peking University Sixth Hospital,Peking University Institute of Mental Health,NHC Key Laboratory of Mental Health,National Clinical Research Center for Mental Disorders,Beijing,China
2.School of Life Science,Southern University of Science and Technology,Shenzhen,China
3.Department of Biological Science,National University of Singapore,Singapore
4.Peking-Tsinghua Center for Life Sciences,International Data Group,McGovern Institute for Brain Research at Peking University,Peking University,Beijing,China
Zhong，Yuanxin,Zhang，Na,Zhao，Feng,et al. RBFOX1 and Working Memory: From Genome to Transcriptome Revealed Posttranscriptional Mechanism Separate From Attention-Deficit/Hyperactivity Disorder[J]. Biological Psychiatry Global Open Science,2023.
Zhong，Yuanxin.,Zhang，Na.,Zhao，Feng.,Chang，Suhua.,Chen，Wei.,...&Yang，Li.(2023).RBFOX1 and Working Memory: From Genome to Transcriptome Revealed Posttranscriptional Mechanism Separate From Attention-Deficit/Hyperactivity Disorder.Biological Psychiatry Global Open Science.
Zhong，Yuanxin,et al."RBFOX1 and Working Memory: From Genome to Transcriptome Revealed Posttranscriptional Mechanism Separate From Attention-Deficit/Hyperactivity Disorder".Biological Psychiatry Global Open Science (2023).
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