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Transl Psychiatry. 2018 Oct 8;8(1):210. doi: 10.1038/s41398-018-0175-x.

Elevated expression of a minor isoform of ANK3 is a risk factor for bipolar disorder.

Author information

1
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway. timothy.hughes@medisin.uio.no.
2
NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. timothy.hughes@medisin.uio.no.
3
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
4
NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
5
Department of Clinical Science, NORMENT, KG Jebsen Centre for Psychosis Research, University of Bergen, Bergen, Norway.
6
Dr Einar Martens Research Group for Biological Psychiatry, Centre for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
7
Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, Roskilde, Denmark.
8
iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark.
9
Department of Biomedicine, Human Genomics Research Group, University of Basel, Basel, Switzerland.
10
Institute of Human Genetics, University of Bonn, Bonn, Germany.
11
Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
12
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
13
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
14
Department of Psychiatry (UPK), University of Basel, Basel, Switzerland.
15
Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
16
Institute of Neuroscience and Physiology, The Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden.
17
Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany.
18
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
19
NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.

Abstract

Ankyrin-3 (ANK3) is one of the few genes that have been consistently identified as associated with bipolar disorder by multiple genome-wide association studies. However, the exact molecular basis of the association remains unknown. A rare loss-of-function splice-site SNP (rs41283526*G) in a minor isoform of ANK3 (incorporating exon ENSE00001786716) was recently identified as protective of bipolar disorder and schizophrenia. This suggests that an elevated expression of this isoform may be involved in the etiology of the disorders. In this study, we used novel approaches and data sets to test this hypothesis. First, we strengthen the statistical evidence supporting the allelic association by replicating the protective effect of the minor allele of rs41283526 in three additional large independent samples (meta-analysis p-values: 6.8E-05 for bipolar disorder and 8.2E-04 for schizophrenia). Second, we confirm the hypothesis that both bipolar and schizophrenia patients have a significantly higher expression of this isoform than controls (p-values: 3.3E-05 for schizophrenia and 9.8E-04 for bipolar type I). Third, we determine the transcription start site for this minor isoform by Pacific Biosciences sequencing of full-length cDNA and show that it is primarily expressed in the corpus callosum. Finally, we combine genotype and expression data from a large Norwegian sample of psychiatric patients and controls, and show that the risk alleles in ANK3 identified by bipolar disorder GWAS are located near the transcription start site of this isoform and are significantly associated with its elevated expression. Together, these results point to the likely molecular mechanism underlying ANK3´s association with bipolar disorder.

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