title: Multiple regulatory variants modulate expression of 5-hydroxytryptamine 2A receptors in human cortex.
abstract: BACKGROUND
  The 5-hydroxytryptamine 2A receptor, encoded by HTR2A, is a major postsynaptic target for serotonin in the human brain and a therapeutic drug target. Despite hundreds of genetic associations investigating HTR2A polymorphisms in neuropsychiatric disorders and therapies, the role of genetic HTR2A variability in health and disease remains uncertain.
  
  
  METHODS
  To discover and characterize regulatory HTR2A variants, we sequenced whole transcriptomes from 10 human brain regions with massively parallel RNA sequencing and measured allelic expression of multiple HTR2A messenger (m)RNA transcript variants. Following discovery of functional variants, we further characterized their impact on genetic expression in vitro.
  
  
  RESULTS
  Three polymorphisms modulate the use of novel alternative exons and untranslated regions (UTRs), changing expression of RNA and protein. The frequent promoter variant rs6311, widely implicated in human neuropsychiatric disorders, decreases usage of an upstream transcription start site encoding a longer 5'UTR with greater translation efficiency. rs76665058, located in an extended 3'UTR and unique to individuals of African descent, modulates allelic HTR2A mRNA expression. The third single nucleotide polymorphism, unannotated and present in only a single subject, directs alternative splicing of exon 2. Targeted analysis of HTR2A in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study reveals associations between functional variants and depression severity or citalopram response.
  
  
  CONCLUSIONS
  Regulatory polymorphisms modulate HTR2A mRNA expression in an isoform-specific manner, directing the usage of novel untranslated regions and alternative exons. These results provide a foundation for delineating the role of HTR2A and serotonin signaling in central nervous system disorders.
authors.affiliation: Department of Pharmacology, Program in Pharmacogenomics, College of Medicine, The Ohio State University, Columbus, OH, USA. Ryan.Smith2@osumc.edu
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Smith
authors.forename: Audrey C
authors.initials: AC
authors.lastname: Papp
authors.forename: Amy
authors.initials: A
authors.lastname: Webb
authors.forename: Cara L
authors.initials: CL
authors.lastname: Ruble
authors.forename: Leanne M
authors.initials: LM
authors.lastname: Munsie
authors.forename: Laura K
authors.initials: LK
authors.lastname: Nisenbaum
authors.forename: Joel E
authors.initials: JE
authors.lastname: Kleinman
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Lipska
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sadee
mesh_terms: D000483:Alleles; D002540:Cerebral Cortex / Q000378:metabolism*; D002986:Clinical Trials as Topic; D003863:Depression / Q000188:drug therapy / Q000235:genetics; D005091:Exons / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008745:Methylation; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D020033:Protein Isoforms / Q000096:biosynthesis; D044402:Receptor, Serotonin, 5-HT2A / Q000096:biosynthesis*; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use; D059467:Transcriptome / Q000235:genetics; D020506:Untranslated Regions / Q000235:genetics
chemical_list: D020033:Protein Isoforms; D044402:Receptor, Serotonin, 5-HT2A; D017367:Selective Serotonin Reuptake Inhibitors; D020506:Untranslated Regions