title: A Loss-of-Function Variant in a Minor Isoform of ANK3 Protects Against Bipolar Disorder and Schizophrenia.
abstract: Ankyrin-3 (ANK3) was one of the first genes to reach significance in a bipolar disorder genome-wide association study. Many subsequent association studies confirmed this finding and implicated this gene in schizophrenia. However, the exact nature of the role of ANK3 in the pathophysiology remains elusive. In particular, the specific isoforms involved and the nature of the imbalance are unknown.
  
  
  
  We genotyped a Norwegian sample of 402 patients with bipolar disorder, 293 patients with schizophrenia, and 330 healthy control subjects genome-wide with the Illumina Human Exome BeadChip. We performed allelic association tests at the genome-wide and gene levels and found a significantly associated single nucleotide polymorphism in a splice site of ANK3. We replicated this finding in two other samples and studied the functional effect of this single nucleotide polymorphism by performing quantitative polymerase chain reaction on the affected exon junction in complementary DNA from blood total RNA.
  
  
  
  The splice site single nucleotide polymorphism (rs41283526) is located in an alternatively spliced exon of ANK3 and has a strong and significant protective effect against bipolar disorder (odds ratio = .31) and schizophrenia (odds ratio = .21). The minor allele of rs41283526 is a loss-of-function variant that disables the correct splicing of the transcript. Data from the BrainSpan human developmental transcriptome show that the exon bearing this variant is expressed only in a minor isoform of ANK3, the transcription of which is initiated in early adolescence.
  
  
  
  Our results suggest that an elevated expression of this transcript starting in adolescence may be an important factor in the pathophysiology of schizophrenia and bipolar disorder.
authors.affiliation: Department of Medical Genetics, Oslo; NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo. Electronic address: timothy.hughes@medisin.uio.no.
authors.forename: Timothy
authors.initials: T
authors.lastname: Hughes
authors.affiliation: Department of Medical Genetics, Oslo; NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo.
authors.forename: Lars
authors.initials: L
authors.lastname: Hansson
authors.affiliation: Department of Medical Genetics, Oslo; NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo.
authors.forename: Ida E
authors.initials: IE
authors.lastname: Sønderby
authors.affiliation: NORMENT, Division of Mental Health and Addiction, Oslo University Hospital, Oslo; NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo.
authors.forename: Lavinia
authors.initials: L
authors.lastname: Athanasiu
authors.affiliation: NORMENT, Division of Mental Health and Addiction, Oslo University Hospital, Oslo; NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo; Prostate Cancer Research Group, Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo.
authors.forename: Verena
authors.initials: V
authors.lastname: Zuber
authors.affiliation: NORMENT, Division of Mental Health and Addiction, Oslo University Hospital, Oslo; NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo.
authors.forename: Martin
authors.initials: M
authors.lastname: Tesli
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm.
authors.forename: Jie
authors.initials: J
authors.lastname: Song
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Hultman
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Bergen
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm; Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Landén
authors.affiliation: NORMENT, Division of Mental Health and Addiction, Oslo University Hospital, Oslo; NORMENT, KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Melle
authors.affiliation: NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo.
authors.forename: Ole Andreas
authors.initials: OA
authors.lastname: Andreassen
authors.affiliation: Department of Medical Genetics, Oslo; NORMENT, KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Srdjan
authors.initials: S
authors.lastname: Djurovic
mesh_terms: D000328:Adult; D017487:Ankyrins / Q000235:genetics*; D001714:Bipolar Disorder / Q000235:genetics*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009664:Norway; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics*
chemical_list: C490613:ANK3 protein, human; D017487:Ankyrins; D020033:Protein Isoforms
keywords: ANK3; Bipolar disorder; Genetics; Minor isoform; Schizophrenia; Splice site