title: A promoter haplotype of the inositol monophosphatase 2 gene (IMPA2) at 18p11.2 confers a possible risk for bipolar disorder by enhancing transcription.
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.
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ohnishi
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yamada
authors.forename: Hisako
authors.initials: H
authors.lastname: Ohba
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Iwayama
authors.forename: Tomoko
authors.initials: T
authors.lastname: Toyota
authors.forename: Eiji
authors.initials: E
authors.lastname: Hattori
authors.forename: Toshiya
authors.initials: T
authors.lastname: Inada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kunugi
authors.forename: Masahiko
authors.initials: M
authors.lastname: Tatsumi
authors.forename: Norio
authors.initials: N
authors.lastname: Ozaki
authors.forename: Nakao
authors.initials: N
authors.lastname: Iwata
authors.forename: Kaoru
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Iijima
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Iwata
authors.forename: Kenji J
authors.initials: KJ
authors.lastname: Tsuchiya
authors.forename: Genichi
authors.initials: G
authors.lastname: Sugihara
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Nanko
authors.forename: Noriko
authors.initials: N
authors.lastname: Osumi
authors.forename: Sevilla D
authors.initials: SD
authors.lastname: Detera-Wadleigh
authors.forename: Tadafumi
authors.initials: T
authors.lastname: Kato
authors.forename: Takeo
authors.initials: T
authors.lastname: Yoshikawa
mesh_terms: D000328:Adult; D001714:Bipolar Disorder / Q000235:genetics*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002887:Chromosomes, Human, Pair 18; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009447:Neuroblastoma; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012306:Risk; D014158:Transcription, Genetic / Q000502:physiology; D014162:Transfection
chemical_list: D010744:Phosphoric Monoester Hydrolases; C021822:myo-inositol-1 (or 4)-monophosphatase; D018021:Lithium Chloride