A promoter haplotype of the inositol monophosphatase 2 gene (IMPA2) at 18p11.2 confers a possible risk for bipolar disorder by enhancing transcription

Tetsuo Ohnishi, Kazuo Yamada, Hisako Ohba, Yoshimi Iwayama, Tomoko Toyota, Eiji Hattori, Toshiya Inada, Hiroshi Kunugi, Masahiko Tatsumi, Norio Ozaki, Nakao Iwata, Kaoru Sakamoto, Yoshimi Iijima, Yasuhide Iwata, Kenji J. Tsuchiya, Genichi Sugihara, Shinichiro Nanko, Noriko Osumi, Sevilla D. Detera-Wadleigh, Tadafumi Kato & 1 others Takeo Yoshikawa

Research output: Contribution to journalArticle

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Abstract

Lithium is an effective mood stabilizer for bipolar disorder patients and its therapeutic effect may involve inhibition of inositol monophosphatase activity. In humans, the enzyme is encoded by two genes, IMPA1 and IMPA2. IMPA2 maps to 18p11.2, a genomic interval for which evidence of linkage to bipolar disorder has been supported by several reports. We performed a genetic association study in Japanese cohorts (496 patients with bipolar disorder and 543 control subjects). Interestingly, we observed association of IMPA2 promoter single nucleotide polymorphisms (SNPs) (-461C and -207T) with bipolar disorder, the identical SNPs reported previously in a different population. In vitro promoter assay and genetic haplotype analysis showed that the combination of (-461C)-(-207T)-(-185A) drove enhanced transcription and the haplotypes containing (-461C)-(-207T)-(-185A) contributed to risk for bipolar disorder. Expression study on post-mortem brains revealed increased transcription from the IMPA2 allele that harbored (-461C)-(-207T)-(-185A) in the frontal cortex of bipolar disorder patients. The examination of allele-specific expressions in post-mortem brains did not support genomic imprinting of IMPA2, which was suggested nearby genomic locus. Contrasting to a prior report, therapeutic concentrations of lithium could not suppress the transcription of IMPA2 mRNA, and the mood-stabilizing effect of lithium is, if IMPA2 was one of the targets of lithium, deemed to be generated via inhibition of enzymatic reaction rather than transcriptional suppression. In conclusion, the present study suggests that a promoter haplotype of IMPA2 possibly contributes to risk for bipolar disorder by elevating IMPA2 levels in the brain, albeit the genetic effect varies among populations.

Original languageEnglish
Pages (from-to)1727-1737
Number of pages11
JournalNeuropsychopharmacology
Volume32
Issue number8
DOIs
Publication statusPublished - 01-08-2007

Fingerprint

Bipolar Disorder
Haplotypes
Genes
Lithium
Single Nucleotide Polymorphism
Brain
Alleles
myo-inositol-1 (or 4)-monophosphatase
Genomic Imprinting
Genetic Association Studies
Frontal Lobe
Therapeutic Uses
Genetic Promoter Regions
Population
Messenger RNA
Enzymes

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Psychiatry and Mental health

Cite this

Ohnishi, Tetsuo ; Yamada, Kazuo ; Ohba, Hisako ; Iwayama, Yoshimi ; Toyota, Tomoko ; Hattori, Eiji ; Inada, Toshiya ; Kunugi, Hiroshi ; Tatsumi, Masahiko ; Ozaki, Norio ; Iwata, Nakao ; Sakamoto, Kaoru ; Iijima, Yoshimi ; Iwata, Yasuhide ; Tsuchiya, Kenji J. ; Sugihara, Genichi ; Nanko, Shinichiro ; Osumi, Noriko ; Detera-Wadleigh, Sevilla D. ; Kato, Tadafumi ; Yoshikawa, Takeo. / A promoter haplotype of the inositol monophosphatase 2 gene (IMPA2) at 18p11.2 confers a possible risk for bipolar disorder by enhancing transcription. In: Neuropsychopharmacology. 2007 ; Vol. 32, No. 8. pp. 1727-1737.
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abstract = "Lithium is an effective mood stabilizer for bipolar disorder patients and its therapeutic effect may involve inhibition of inositol monophosphatase activity. In humans, the enzyme is encoded by two genes, IMPA1 and IMPA2. IMPA2 maps to 18p11.2, a genomic interval for which evidence of linkage to bipolar disorder has been supported by several reports. We performed a genetic association study in Japanese cohorts (496 patients with bipolar disorder and 543 control subjects). Interestingly, we observed association of IMPA2 promoter single nucleotide polymorphisms (SNPs) (-461C and -207T) with bipolar disorder, the identical SNPs reported previously in a different population. In vitro promoter assay and genetic haplotype analysis showed that the combination of (-461C)-(-207T)-(-185A) drove enhanced transcription and the haplotypes containing (-461C)-(-207T)-(-185A) contributed to risk for bipolar disorder. Expression study on post-mortem brains revealed increased transcription from the IMPA2 allele that harbored (-461C)-(-207T)-(-185A) in the frontal cortex of bipolar disorder patients. The examination of allele-specific expressions in post-mortem brains did not support genomic imprinting of IMPA2, which was suggested nearby genomic locus. Contrasting to a prior report, therapeutic concentrations of lithium could not suppress the transcription of IMPA2 mRNA, and the mood-stabilizing effect of lithium is, if IMPA2 was one of the targets of lithium, deemed to be generated via inhibition of enzymatic reaction rather than transcriptional suppression. In conclusion, the present study suggests that a promoter haplotype of IMPA2 possibly contributes to risk for bipolar disorder by elevating IMPA2 levels in the brain, albeit the genetic effect varies among populations.",
author = "Tetsuo Ohnishi and Kazuo Yamada and Hisako Ohba and Yoshimi Iwayama and Tomoko Toyota and Eiji Hattori and Toshiya Inada and Hiroshi Kunugi and Masahiko Tatsumi and Norio Ozaki and Nakao Iwata and Kaoru Sakamoto and Yoshimi Iijima and Yasuhide Iwata and Tsuchiya, {Kenji J.} and Genichi Sugihara and Shinichiro Nanko and Noriko Osumi and Detera-Wadleigh, {Sevilla D.} and Tadafumi Kato and Takeo Yoshikawa",
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Ohnishi, T, Yamada, K, Ohba, H, Iwayama, Y, Toyota, T, Hattori, E, Inada, T, Kunugi, H, Tatsumi, M, Ozaki, N, Iwata, N, Sakamoto, K, Iijima, Y, Iwata, Y, Tsuchiya, KJ, Sugihara, G, Nanko, S, Osumi, N, Detera-Wadleigh, SD, Kato, T & Yoshikawa, T 2007, 'A promoter haplotype of the inositol monophosphatase 2 gene (IMPA2) at 18p11.2 confers a possible risk for bipolar disorder by enhancing transcription', Neuropsychopharmacology, vol. 32, no. 8, pp. 1727-1737. https://doi.org/10.1038/sj.npp.1301307

A promoter haplotype of the inositol monophosphatase 2 gene (IMPA2) at 18p11.2 confers a possible risk for bipolar disorder by enhancing transcription. / Ohnishi, Tetsuo; Yamada, Kazuo; Ohba, Hisako; Iwayama, Yoshimi; Toyota, Tomoko; Hattori, Eiji; Inada, Toshiya; Kunugi, Hiroshi; Tatsumi, Masahiko; Ozaki, Norio; Iwata, Nakao; Sakamoto, Kaoru; Iijima, Yoshimi; Iwata, Yasuhide; Tsuchiya, Kenji J.; Sugihara, Genichi; Nanko, Shinichiro; Osumi, Noriko; Detera-Wadleigh, Sevilla D.; Kato, Tadafumi; Yoshikawa, Takeo.

In: Neuropsychopharmacology, Vol. 32, No. 8, 01.08.2007, p. 1727-1737.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A promoter haplotype of the inositol monophosphatase 2 gene (IMPA2) at 18p11.2 confers a possible risk for bipolar disorder by enhancing transcription

AU - Ohnishi, Tetsuo

AU - Yamada, Kazuo

AU - Ohba, Hisako

AU - Iwayama, Yoshimi

AU - Toyota, Tomoko

AU - Hattori, Eiji

AU - Inada, Toshiya

AU - Kunugi, Hiroshi

AU - Tatsumi, Masahiko

AU - Ozaki, Norio

AU - Iwata, Nakao

AU - Sakamoto, Kaoru

AU - Iijima, Yoshimi

AU - Iwata, Yasuhide

AU - Tsuchiya, Kenji J.

AU - Sugihara, Genichi

AU - Nanko, Shinichiro

AU - Osumi, Noriko

AU - Detera-Wadleigh, Sevilla D.

AU - Kato, Tadafumi

AU - Yoshikawa, Takeo

PY - 2007/8/1

Y1 - 2007/8/1

N2 - Lithium is an effective mood stabilizer for bipolar disorder patients and its therapeutic effect may involve inhibition of inositol monophosphatase activity. In humans, the enzyme is encoded by two genes, IMPA1 and IMPA2. IMPA2 maps to 18p11.2, a genomic interval for which evidence of linkage to bipolar disorder has been supported by several reports. We performed a genetic association study in Japanese cohorts (496 patients with bipolar disorder and 543 control subjects). Interestingly, we observed association of IMPA2 promoter single nucleotide polymorphisms (SNPs) (-461C and -207T) with bipolar disorder, the identical SNPs reported previously in a different population. In vitro promoter assay and genetic haplotype analysis showed that the combination of (-461C)-(-207T)-(-185A) drove enhanced transcription and the haplotypes containing (-461C)-(-207T)-(-185A) contributed to risk for bipolar disorder. Expression study on post-mortem brains revealed increased transcription from the IMPA2 allele that harbored (-461C)-(-207T)-(-185A) in the frontal cortex of bipolar disorder patients. The examination of allele-specific expressions in post-mortem brains did not support genomic imprinting of IMPA2, which was suggested nearby genomic locus. Contrasting to a prior report, therapeutic concentrations of lithium could not suppress the transcription of IMPA2 mRNA, and the mood-stabilizing effect of lithium is, if IMPA2 was one of the targets of lithium, deemed to be generated via inhibition of enzymatic reaction rather than transcriptional suppression. In conclusion, the present study suggests that a promoter haplotype of IMPA2 possibly contributes to risk for bipolar disorder by elevating IMPA2 levels in the brain, albeit the genetic effect varies among populations.

AB - Lithium is an effective mood stabilizer for bipolar disorder patients and its therapeutic effect may involve inhibition of inositol monophosphatase activity. In humans, the enzyme is encoded by two genes, IMPA1 and IMPA2. IMPA2 maps to 18p11.2, a genomic interval for which evidence of linkage to bipolar disorder has been supported by several reports. We performed a genetic association study in Japanese cohorts (496 patients with bipolar disorder and 543 control subjects). Interestingly, we observed association of IMPA2 promoter single nucleotide polymorphisms (SNPs) (-461C and -207T) with bipolar disorder, the identical SNPs reported previously in a different population. In vitro promoter assay and genetic haplotype analysis showed that the combination of (-461C)-(-207T)-(-185A) drove enhanced transcription and the haplotypes containing (-461C)-(-207T)-(-185A) contributed to risk for bipolar disorder. Expression study on post-mortem brains revealed increased transcription from the IMPA2 allele that harbored (-461C)-(-207T)-(-185A) in the frontal cortex of bipolar disorder patients. The examination of allele-specific expressions in post-mortem brains did not support genomic imprinting of IMPA2, which was suggested nearby genomic locus. Contrasting to a prior report, therapeutic concentrations of lithium could not suppress the transcription of IMPA2 mRNA, and the mood-stabilizing effect of lithium is, if IMPA2 was one of the targets of lithium, deemed to be generated via inhibition of enzymatic reaction rather than transcriptional suppression. In conclusion, the present study suggests that a promoter haplotype of IMPA2 possibly contributes to risk for bipolar disorder by elevating IMPA2 levels in the brain, albeit the genetic effect varies among populations.

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