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

Timothy Hughes; Ida E. Sønderby; Tatiana Polushina; Lars Hansson; Asbjørn Holmgren; Lavinia Athanasiu; Christian Melbø-Jørgensen; Sahar Hassani; Louise K. Hoeffding; Stefan Herms; Sarah E. Bergen; Robert Karlsson; Jie Song; Marcella Rietschel; Markus M. Nöthen; Andreas J. Forstner; Per Hoffmann; Christina M. Hultman; Mikael Landén; Sven Cichon; Thomas Werge; Ole A. Andreassen; Stephanie Le Hellard; Srdjan Djurovic

doi:10.1038/s41398-018-0175-x

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

Timothy Hughes^*, Ida E. Sønderby, Tatiana Polushina, Lars Hansson, Asbjørn Holmgren, Lavinia Athanasiu, Christian Melbø-Jørgensen, Sahar Hassani, Louise K. Hoeffding, Stefan Herms, Sarah E. Bergen, Robert Karlsson, Jie Song, Marcella Rietschel, Markus M. Nöthen, Andreas J. Forstner, Per Hoffmann, Christina M. Hultman, Mikael Landén, Sven CichonThomas Werge, Ole A. Andreassen, Stephanie Le Hellard, Srdjan Djurovic

^*Corresponding author for this work

Department of Clinical Medicine

7 Citations (Scopus)

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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.

Original language	English
Article number	210
Journal	Translational Psychiatry
Volume	8
Issue number	1
Pages (from-to)	1-12
ISSN	2158-3188
DOIs	https://doi.org/10.1038/s41398-018-0175-x
Publication status	Published - 2018

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Elevated expression of a minor isoform of ANK3 is a risk factor for bipolar disorderFinal published version, 2.65 MB

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Hughes, T., Sønderby, I. E., Polushina, T., Hansson, L., Holmgren, A., Athanasiu, L., Melbø-Jørgensen, C., Hassani, S., Hoeffding, L. K., Herms, S., Bergen, S. E., Karlsson, R., Song, J., Rietschel, M., Nöthen, M. M., Forstner, A. J., Hoffmann, P., Hultman, C. M., Landén, M., ... Djurovic, S. (2018). Elevated expression of a minor isoform of ANK3 is a risk factor for bipolar disorder. Translational Psychiatry, 8(1), 1-12. Article 210. https://doi.org/10.1038/s41398-018-0175-x

Hughes, T, Sønderby, IE, Polushina, T, Hansson, L, Holmgren, A, Athanasiu, L, Melbø-Jørgensen, C, Hassani, S, Hoeffding, LK, Herms, S, Bergen, SE, Karlsson, R, Song, J, Rietschel, M, Nöthen, MM, Forstner, AJ, Hoffmann, P, Hultman, CM, Landén, M, Cichon, S, Werge, T, Andreassen, OA, Le Hellard, S & Djurovic, S 2018, 'Elevated expression of a minor isoform of ANK3 is a risk factor for bipolar disorder', Translational Psychiatry, vol. 8, no. 1, 210, pp. 1-12. https://doi.org/10.1038/s41398-018-0175-x

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title = "Elevated expression of a minor isoform of ANK3 is a risk factor for bipolar disorder",

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.",

author = "Timothy Hughes and S{\o}nderby, {Ida E.} and Tatiana Polushina and Lars Hansson and Asbj{\o}rn Holmgren and Lavinia Athanasiu and Christian Melb{\o}-J{\o}rgensen and Sahar Hassani and Hoeffding, {Louise K.} and Stefan Herms and Bergen, {Sarah E.} and Robert Karlsson and Jie Song and Marcella Rietschel and N{\"o}then, {Markus M.} and Forstner, {Andreas J.} and Per Hoffmann and Hultman, {Christina M.} and Mikael Land{\'e}n and Sven Cichon and Thomas Werge and Andreassen, {Ole A.} and {Le Hellard}, Stephanie and Srdjan Djurovic",

year = "2018",

doi = "10.1038/s41398-018-0175-x",

language = "English",

volume = "8",

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journal = "Translational Psychiatry",

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TY - JOUR

T1 - Elevated expression of a minor isoform of ANK3 is a risk factor for bipolar disorder

AU - Hughes, Timothy

AU - Sønderby, Ida E.

AU - Polushina, Tatiana

AU - Hansson, Lars

AU - Holmgren, Asbjørn

AU - Athanasiu, Lavinia

AU - Melbø-Jørgensen, Christian

AU - Hassani, Sahar

AU - Hoeffding, Louise K.

AU - Herms, Stefan

AU - Bergen, Sarah E.

AU - Karlsson, Robert

AU - Song, Jie

AU - Rietschel, Marcella

AU - Nöthen, Markus M.

AU - Forstner, Andreas J.

AU - Hoffmann, Per

AU - Hultman, Christina M.

AU - Landén, Mikael

AU - Cichon, Sven

AU - Werge, Thomas

AU - Andreassen, Ole A.

AU - Le Hellard, Stephanie

AU - Djurovic, Srdjan

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

U2 - 10.1038/s41398-018-0175-x

DO - 10.1038/s41398-018-0175-x

M3 - Journal article

C2 - 30297702

AN - SCOPUS:85054573297

SN - 2158-3188

VL - 8

SP - 1

EP - 12

JO - Translational Psychiatry

JF - Translational Psychiatry

IS - 1

M1 - 210

ER -

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

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