title: Evidence for genetic regulation of mRNA expression of the dosage-sensitive gene retinoic acid induced-1 (RAI1) in human brain.
abstract: RAI1 (retinoic acid induced-1) is a dosage-sensitive gene that causes Smith-Magenis syndrome (SMS) when mutated or deleted and Potocki-Lupski Syndrome (PTLS) when duplicated, with psychiatric features commonly observed in both syndromes. How common genetic variants regulate this gene, however, is unknown. In this study, we found that RAI1 mRNA expression in Chinese prefrontal and temporal cortex correlate with genotypes of common single nucleotide polymorphisms (SNPs) located in the RAI1 5'-upstream region. Using genotype imputation, "R(2)-Δ(2)" analysis, and data from the RegulomeDB database, we identified SNPs rs4925102 and rs9907986 as possible regulatory variants, accounting for approximately 30-40% of the variance in RAI1 mRNA expression in both brain regions. Specifically, rs4925102 and rs9907986 are predicted to disrupt the binding of retinoic acid RXR-RAR receptors and the transcription factor DEAF1 (Deformed epidermal autoregulatory factor-1), respectively. Consistent with these predictions, we observed binding of RXRα and RARα to the predicted RAI1 target in chromatin immunoprecipitation assays. Retinoic acid is crucial for early development of the central neural system, and DEAF1 is associated with intellectual disability. The observation that a significant portion of RAI1 mRNA expression is genetically controlled raises the possibility that common RAI1 5'-region regulatory variants contribute more generally to psychiatric disorders.
authors.affiliation: Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Tao
authors.affiliation: Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Song
authors.affiliation: Institutes of Brain Science, Fudan University, Shanghai, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Shanghai Ocean University, Shanghai, Ministry of Education, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China.|Institutes of Brain Science, Fudan University, Shanghai, China.|State Key Laboratory for Medical Neurobiology, Fudan University, Shanghai, China.
authors.forename: David
authors.initials: D
authors.lastname: Saffen
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D045744:Cell Line, Tumor; D025063:Chromosome Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D058674:Chromosome Duplication / Q000235:genetics*; D004268:DNA-Binding Proteins; D018628:Gene Dosage; D005786:Gene Expression Regulation; D005838:Genotype; D060005:Genotyping Techniques; D006801:Humans; D009154:Mutation; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D047488:Retinoid X Receptors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D058496:Smith-Magenis Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013702:Temporal Lobe / Q000378:metabolism / Q000473:pathology; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: C116013:DEAF1 protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C431552:RAI1 protein, human; D012333:RNA, Messenger; D047488:Retinoid X Receptors; D015534:Trans-Activators; D014157:Transcription Factors