title: Genetic variation in the miR-708 gene and its binding targets in bipolar disorder.
abstract: rs12576775 was found to be associated with bipolar disorder (BD) in a genome-wide association study (GWAS). The GWAS signal implicates genes for the microRNAs miR-708 and miR-5579 and the first exon of the Odd Oz/ten-m homolog 4 gene (ODZ4). In the present study, miR-708, its surrounding region, and its targets were analyzed for potential BD-associated functional variants.
  
  
  
  The miR-708 gene and surrounding regions were screened for variation using high-resolution melting (HRM) analysis in 1099 cases of BD, followed by genotyping of rare variants in an enlarged sample of 2078 subjects with BD, 1303 subjects with schizophrenia, and 1355 healthy controls. Whole-genome sequencing data from 99 subjects with BD were analyzed for variation in potential miR-708 binding sites. The minor allele frequencies (MAFs) of these variants were compared with those reported in reference individuals.
  
  
  
  Three variants detected by HRM were selected to be genotyped. rs754333774 was detected in three cases of BD, two cases of schizophrenia, and no controls. This variant is located 260 base pairs upstream from miR-708 and may play a role in controlling the expression of the miR. Four variants were identified in miR-708 targets binding sites. The MAFs of each of these variants were similar in BD and reference samples.
  
  
  
  We report a single recurrent variant located near the miR-708 gene that may have a role in BD and schizophrenia susceptibility. These findings await replication in independent cohorts, as do functional analyses of the potential consequences of this variant.
authors.affiliation: UCL Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, UK.|UCL Institute of Ophthalmology, University College London, London, UK.
authors.forename: Alessia
authors.initials: A
authors.lastname: Fiorentino
authors.affiliation: UCL Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, UK.
authors.forename: Niamh Louise
authors.initials: NL
authors.lastname: O'Brien
authors.affiliation: UCL Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, UK.
authors.forename: Sally Isabel
authors.initials: SI
authors.lastname: Sharp
authors.affiliation: UCL Genetics Institute, University College London, London, UK.|Centre for Psychiatry, Barts and the London School of Medicine and Dentistry, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Curtis
authors.affiliation: UCL Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, UK.
authors.forename: Nicholas James
authors.initials: NJ
authors.lastname: Bass
authors.affiliation: UCL Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, UK.
authors.forename: Andrew
authors.identifier: 0000-0003-1567-2240
authors.initials: A
authors.lastname: McQuillin
mesh_terms: D000328:Adult; D001714:Bipolar Disorder / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000235:genetics*
chemical_list: C568528:MIRN708 microRNA, human; D035683:MicroRNAs
keywords: bipolar disorder; miR-708; microRNA; sequencing; susceptibility; variation