Study Report

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Basic Info

Reference	Ohnishi, T., 2007 PMID: 17251911
Citation	Ohnishi, T., K. Yamada, et al. (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 32(8): 1727-1737.
Disease Type	Bipolar I Disorder & Schizophrenia
Study Design	case-control
Study Type	Candidate-gene association study
Sample Size	496 patients with bipolar disorder and 543 control subjects, 570 schizophrenics and 570 controls
SNP/Region/Marker Size	26 SNPs
Predominant Ethnicity	Mongloid
Population	Japanese
Gender	BD patients: 242 men and 254 women; controls: 259 men and 284 women
Age Group	adults : The mean age of patients was 49.9 (SD=14.6) years, and that of controls was 49.9 (SD=11.7) years.

Detail Info

Sample Diagnosis	DSM-IV
Sample Status	A group of unrelated Japanese bipolar patients (242 men and 254 women) consisting of both bipolar I (162 men and 170 women) and bipolar II (80 men and 84 women) were recruited through the COSMO (Collaborative Study of Mood Disorders) consortium in Japan. Included in the analysis were 570 schizophrenics and none of them had additional Axis-I disorders as defined by DSM-IV.
Technique	genotyping using TaqMan, direct sequencing using the BigDye Terminator Cycle Sequencing FS Ready Reaction kit and the ABI PRISM 3730 Genetic Analyzer and Real-Time Quantitative RT-PCR
Statistical Method	Allelic and genotypic frequencies of markers between patients and controls were assessed using Fisher's exact test; Haplotype frequencies were computed using the expectation-maximization algorithm implemented in COCAPHASE ver2.35; Haplotype distributions were also evaluated using the COCAPHASE program.
Result Summary	They 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.

Genetic factors reported by this study for BD

SNPs reported by this study for BD (count: 13)

SNP	Related Gene(s)	Allele Change	Statistical Values	Author Comments	Result Category
rs594235	IMPA2	T/C	Fisher's exact test, allelic P-value = 0.591, genotypic P-value = 0.51		Negative
rs607200	IMPA2	T/C	Fisher's exact test, allelic P-value = 0.508, genotypic P-value = 0.756		Negative
rs3786284	IMPA2	A/G	Fisher's exact test, allelic P-value = 0.63, genotypic P-value = 0.6		Negative
rs3786291	IMPA2	T/C	Fisher's exact test, allelic P-value = 0.519, genotypic P-value = 0.347		Negative
rs2075825	IMPA2	T/C	Fisher's exact test, allelic P-value = 1, genotypic P-value = 0.049	displayed marginally significant genotypic association with ...... displayed marginally significant genotypic association with bipolar disorder. More...	Positive
rs3786282	IMPA2	A/C	Fisher's exact test, allelic P-value = 0.615, genotypic P-value = 0.865		Negative
rs11545506	IMPA2	T/C	Fisher's exact test, allelic P-value = 0.713, genotypic P-value = 0.263		Negative
rs2075824	IMPA2	T/C	Fisher's exact test, allelic P-value = 0.042, genotypic P-value = 0.118	allelic distributions differed significantly, albeit modest,...... allelic distributions differed significantly, albeit modest, between bipolar patients and controls More...	Positive
rs640088	IMPA2	T/C	Fisher's exact test, allelic P-value = 0.627, genotypic P-value = 0.493		Negative
rs613993	IMPA2	A/G	Fisher's exact test, allelic P-value = 0.523, genotypic P-value = 0.348		Negative
rs971362	IMPA2	T/G	Fisher's exact test, allelic P-value = 0.143, genotypic P-value = 0.304		Negative
rs644710	IMPA2	T/C	Fisher's exact test, allelic P-value = 0.965, genotypic P-value = 0.503		Negative
rs971363	IMPA2	T/G	Fisher's exact test, allelic P-value = 0.479, genotypic P-value = 0.447		Negative

Haplotypes reported by this study for BD (count: 9)

Markers	Haplotype	Related Gene(s)/Region(s)	Statistical Values	Author Comments	Result Category
IMPA2_-708G>A - rs2075824		IMPA2	P-value = 0.017	displayed evidence of association with bipolar illness displayed evidence of association with bipolar illness	Positive
rs971362 - IMPA2_-708G>A - rs2075824 - IMPA2_-207T>C - IMPA2_-185A>G	G-G-C-T-A	IMPA2	COCAPHASE P-value = 0.209, OR=1.126, X<sup>2</sup>=1.576	There were no promoter haplotypes spanning SNP02-SNP06 that ...... There were no promoter haplotypes spanning SNP02-SNP06 that were significantly associated with bipolar disorder More...	Negative
rs971362 - IMPA2_-708G>A - rs2075824 - IMPA2_-207T>C - IMPA2_-185A>G	G-G-C-T-G	IMPA2	COCAPHASE P-value = 0.725, OR=1.045, X<sup>2</sup>=0.124	There were no promoter haplotypes spanning SNP02-SNP06 that ...... There were no promoter haplotypes spanning SNP02-SNP06 that were significantly associated with bipolar disorder More...	Negative
rs971362 - IMPA2_-708G>A - rs2075824 - IMPA2_-207T>C - IMPA2_-185A>G	T-G-T-C-G	IMPA2	COCAPHASE P-value = 0.497, OR=0.936, X<sup>2</sup>=0.462	There were no promoter haplotypes spanning SNP02-SNP06 that ...... There were no promoter haplotypes spanning SNP02-SNP06 that were significantly associated with bipolar disorder More...	Negative
rs971362 - IMPA2_-708G>A - rs2075824 - IMPA2_-207T>C - IMPA2_-185A>G	T-A-T-C-G	IMPA2	COCAPHASE P-value = 0.239, OR=0.859, X<sup>2</sup>=1.386	There were no promoter haplotypes spanning SNP02-SNP06 that ...... There were no promoter haplotypes spanning SNP02-SNP06 that were significantly associated with bipolar disorder More...	Negative
rs971362 - IMPA2_-708G>A - rs2075824		IMPA2	P-value = 0.03	obtained a significant empirical p-value for the three-locus...... obtained a significant empirical p-value for the three-locus window More...	Positive
rs971362 - IMPA2_-708G>A		IMPA2	P-value = 0.022	displayed evidence of association with bipolar illness displayed evidence of association with bipolar illness	Positive
rs2075824 - IMPA2_-207T>C		IMPA2	P-value = 0.033	displayed evidence of association with bipolar illness displayed evidence of association with bipolar illness	Positive
IMPA2_-708G>A - rs2075824 - IMPA2_-207T>C		IMPA2	P-value = 0.015	obtained a significant empirical p-value for the three-locus...... obtained a significant empirical p-value for the three-locus window More...	Positive

Other variants reported by this study for BD (count: 5)

Variant Name	Related Gene	Type	Allele Change	Statistical Values	Author Comments	Result Category
IMPA2 -708G>A	IMPA2	point mutation	A/G	Fisher's exact test, allelic P-value = 0.462, genotypic P-value = 0.511		Negative
IMPA2 IVS1-15G>A	IMPA2	point mutation	A/G	Fisher's exact test, allelic P-value = 0.157, genotypic P-value = 0.339		Negative
IMPA2 IVS5+13-14InsA	IMPA2	insertion/deletion	Ins/Del	Fisher's exact test, allelic P-value = 0.394, genotypic P-value = 0.407		Negative
IMPA2 -207T>C	IMPA2	point mutation	T/C	Fisher's exact test, allelic P-value = 0.046, genotypic P-value = 0.114	allelic distributions differed significantly, albeit modest,...... allelic distributions differed significantly, albeit modest, between bipolar patients and controls More...	Positive
IMPA2 -185A>G	IMPA2	point mutation	G/A	Fisher's exact test, allelic P-value = 0.197, genotypic P-value = 0.184		Negative

Genes reported by this study for BD (count: 1)

Gene	Statistical Values/Author Comments	Result Category
IMPA2	We observed association of IMPA2 promoter single nucleotide polymorphisms (SNPs) (-461C and -207T) w...... We observed association of IMPA2 promoter single nucleotide polymorphisms (SNPs) (-461C and -207T) with bipolar disorder; 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. More...	Positive

Genetic factors reported by this study for SZ and/or MDD

SNPs reported by this study for SZ/MDD

Disease	SNP	Related Gene(s)	Statistical Values	Result Category
SZ	rs971363	IMPA2	Fisher's exact test, allelic P-value = 0.36, genotypic P-value = 0.175	Negative
SZ	rs971362	IMPA2	Fisher's exact test, allelic P-value = 0.238, genotypic P-value = 0.361	Negative
SZ	rs644710	IMPA2	Fisher's exact test, allelic P-value = 0.933, genotypic P-value = 0.95	Negative
SZ	rs640088	IMPA2	Fisher's exact test, allelic P-value = 0.926, genotypic P-value = 0.596	Negative
SZ	rs613993	IMPA2	Fisher's exact test, allelic P-value = 0.54, genotypic P-value = 0.628	Negative
SZ	rs607200	IMPA2	Fisher's exact test, allelic P-value = 0.447, genotypic P-value = 0.692	Negative
SZ	rs594235	IMPA2	Fisher's exact test, allelic P-value = 0.67, genotypic P-value = 0.475	Negative
SZ	rs3786291	IMPA2	Fisher's exact test, allelic P-value = 0.903, genotypic P-value = 0.922	Negative
SZ	rs3786284	IMPA2	Fisher's exact test, allelic P-value = 0.267, genotypic P-value = 0.521	Negative
SZ	rs11545506	IMPA2	Fisher's exact test, allelic P-value = 0.882, genotypic P-value = 0.983	Negative
SZ	rs2075824	IMPA2	Fisher's exact test, allelic P-value = 0.13, genotypic P-value = 0.24	Negative
SZ	rs2075825	IMPA2	Fisher's exact test, allelic P-value = 1, genotypic P-value = 1	Negative
SZ	rs3786282	IMPA2	Fisher's exact test, allelic P-value = 0.965, genotypic P-value = 1	Negative

Other variants reported by this study for SZ/MDD

Disease	Variant Name	Related Gene	Type	Statistical Values	Description	Result Category
SZ	IMPA2 -207T>C	IMPA2	point mutation	Fisher's exact test, allelic P-value = 0.207, genotypic P-value = 0.294		Negative
SZ	IMPA2 -185A>G	IMPA2	point mutation	Fisher's exact test, allelic P-value = 0.507, genotypic P-value = 0.797		Negative
SZ	IMPA2 -708G>A	IMPA2	point mutation	Fisher's exact test, allelic P-value = 0.659, genotypic P-value = 0.204		Negative
SZ	IMPA2 IVS1-15G>A	IMPA2	point mutation	Fisher's exact test, allelic P-value = 0.297, genotypic P-value = 0.038	Modest nominal genotypic association of with schizophrenia was detected.	Positive
SZ	IMPA2 IVS5+13-14InsA	IMPA2	insertion/deletion	Fisher's exact test, allelic P-value = 0.183, genotypic P-value = 0.365		Negative

Genes reported by this study for SZ/MDD

Disease	Gene	Description	Result Category
SZ	IMPA2	Modest nominal genotypic association of SNP10 with schizophrenia was detected.	Positive