Study Report

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Basic Info

Reference	Kim, S. H., 2012 (a) PMID: 22155192
Citation	Kim, S. H., S. Y. Shin, et al. (2012). "The genetic association of DUSP6 with bipolar disorder and its effect on ERK activity." Prog Neuropsychopharmacol Biol Psychiatry 37(1): 41-49.
Disease Type	Bipolar Disorder & Schizophrenia
Study Design	case-control
Study Type	Candidate-gene association study
Sample Size	354 patients with BD, 248 patients with SPR and 350 controls
SNP/Region/Marker Size	6 SNPs
Predominant Ethnicity	Mongloid
Population	Korean
Gender	150 men and 204 women with BD, 150 men and 98 women with SZ, 174 men and 176 women controls
Age Group	adults : mean age=33.5 (SD=12.0) years of BD patients, mean age=32.7 (SD=7.8) years of SZ patients, mean age=25.9 (SD=6.5) years of controls

Detail Info

Sample Diagnosis	DSM-IV
Sample Status	The patients were individually interviewed by trained researchers using the Korean version of the Diagnostic Interview for Genetic Studies (DIGS). Meetings with more than two psychiatrists were held regularly to arrive at consensual decisions about the participants' final diagnoses and to eliminate subjects with organic brain disease, alcohol or drug problems, or other general medical conditions possibly manifesting as psychiatric symptoms.
Technique	genotyping using the TaqMan method
Statistical Method	Contingency chi-square tests were performed to compare the allele frequencies of patients and controls. Correction for multiple testing was performed using a correction with 10,000 permutations with UNPHASED Ver3.1.2 software. Haplotype frequencies and the significance of haplotype associations were calculated with HAPLOVIEW software Ver. 4.2.
Result Summary	Among the examined DUSP6 SNPs, five (rs769700, rs704076, rs770087, rs808820, and rs2279574) showed positive allelic associations, with the frequency of minor alleles (C, T, G, G, and G) in each SNP significantly increased in women with BD. Consequently, the 'C-T-G-G-G' haplotype was significantly over-represented (P=0.016; OR=3.242), whereas the 'T-G-T-A-T' haplotype was significantly under-represented (P=0.014; OR=0.697). We found no significant associations with DUSP6 SNPs in men with bipolar disorder or schizophrenia. We also investigated the functions of the functional SNPs' positive associations and found that Leu114Val (rs2279574; T/G) and Ser144Ala (rs770087; T/G) mutations in DUSP6 proteins reduced lithium-induced ERK1/2 phosphorylation in vitro, implicating the dominant active functions. Thus, DUSP6 may not only play important roles in the pathogenesis of bipolar disorder, particularly in women, but also affect the therapeutic response to lithium through modulating lithium's effects on intracellular signaling.

Genetic factors reported by this study for BD

SNPs reported by this study for BD (count: 6)

SNP	Related Gene(s)	Allele Change	Statistical Values	Author Comments	Result Category
rs770087	DUSP6	T/G	chi-square P-value = 0.006, Permutation P-value = 0.0227, X²=7.5649, OR=2.219; chi-square P-value = 0.0007, Permutation P-value = 0.0015, X²=11.3843, OR=4.162 for female subjects, chi-square P-value = 0.9623, Permutation P-value = 1, X²=0.0022, OR=1.021 for male subjects	showed nominally significant association with BD, and the em...... showed nominally significant association with BD, and the empirical P-value with 10, 000 permutations for each SNP was also significant. showed nominally significant allelic associations with BD, but not with SPR, in female patients. More...	Positive
rs808820	DUSP6	A/G	chi-square P-value = 0.0517, Permutation P-value = 0.1731, X²=3.7846, OR=1.911; chi-square P-value = 0.0068, Permutation P-value = 0.0217, X²=7.3133, OR=3.633 for female subjects, chi-square P-value = 0.6973, Permutation P-value = 0.9947, X²=0.1513, OR=0.813 for male subjects	showed nominally significant allelic associations with BD, b...... showed nominally significant allelic associations with BD, but not with SPR, in female patients More...	Positive
rs704076	DUSP6	G/T	chi-square P-value = 0.0088, Permutation P-value = 0.0287, X²=6.8557, OR=2.153; chi-square P-value = 0.0004, Permutation P-value = 0.0007, X²=12.6608, OR=4.436 for female subjects, chi-square P-value = 0.5159, Permutation P-value = 0.9253, X²=0.422, OR=0.7282 for male subjects	showed nominally significant association with BD, and the em...... showed nominally significant association with BD, and the empirical P-value with 10, 000 permutations for each SNP was also significant. showed nominally significant allelic associations with BD, but not with SPR, in female patients. More...	Positive
rs769700	DUSP6	T/C	chi-square P-value = 0.006, Permutation P-value = 0.0227, X²=7.5649, OR=2.219; chi-square P-value = 0.0007, Permutation P-value = 0.0015, X²=11.3843, OR=4.162 for female subjects, chi-square P-value = 0.9623, Permutation P-value = 1, X²=0.0022, OR=1.021 for male subjects	showed nominally significant association with BD, and the em...... showed nominally significant association with BD, and the empirical P-value with 10, 000 permutations for each SNP was also significant. showed nominally significant allelic associations with BD, but not with SPR, in female patients. More...	Positive
rs2279574	DUSP6	T/G	chi-square P-value = 0.0813, Permutation P-value = 0.2472, X²=3.0382, OR=1.21; chi-square P-value = 0.015, Permutation P-value = 0.0469, X²=5.9218, OR=1.442 for female subjects, chi-square P-value = 0.9545, Permutation P-value = 1, X²=0.0033, OR=0.9909 for male subjects	showed nominally significant allelic associations with BD, b...... showed nominally significant allelic associations with BD, but not with SPR, in female patients More...	Positive
rs704073	DUSP6	C/T	chi-square P-value = 0.0624, Permutation P-value = 0.2083, X²=3.472, OR=2.105; chi-square P-value = 0.038, Permutation P-value = 0.1229, X²=4.3044, OR=3.091 for female subjects, chi-square P-value = 0.8272, Permutation P-value = 0.9992, X²=0.0476, OR=1.149 for male subjects	showed nominally significant allelic associations with BD, b...... showed nominally significant allelic associations with BD, but not with SPR, in female patients More...	Positive

Haplotypes reported by this study for BD (count: 3)

Markers	Haplotype	Related Gene(s)/Region(s)	Statistical Values	Author Comments	Result Category
rs769700 - rs704076 - rs770087 - rs808820 - rs2279574	T-G-T-A-G	DUSP6	P-value = 0.4260, X<sup>2</sup>=0.6340, OR=1.1240	no significant association was reported in this study no significant association was reported in this study	Negative
rs769700 - rs704076 - rs770087 - rs808820 - rs2279574	T-G-T-A-T	DUSP6	P-value = 0.0139, X<sup>2</sup>=6.0530, OR=0.6971	the T-G-T-A-T haplotype was significantly under-represented ...... the T-G-T-A-T haplotype was significantly under-represented in female patients with BD, but did not show positive associations with BD among men. More...	Positive
rs769700 - rs704076 - rs770087 - rs808820 - rs2279574	C-T-G-G-G	DUSP6	P-value = 0.0157, X<sup>2</sup>=5.8330, OR=3.2415	the C-T-G-G-G haplotype of DUSP6 was significantly over-repr...... the C-T-G-G-G haplotype of DUSP6 was significantly over-represented in female patients with BD, but did not show positive associations with BD among men. More...	Positive

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

Gene	Statistical Values/Author Comments	Result Category
DUSP6	DUSP6 may not only play important roles in the pathogenesis of bipolar disorder, particularly in wom...... DUSP6 may not only play important roles in the pathogenesis of bipolar disorder, particularly in women, but also affect the therapeutic response to lithium through modulating lithium's effects on intracellular signaling. 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	Description	Result Category
SZ	rs704076	DUSP6	chi-square P-value = 0.6096, Permutation P-value = 0.9485, X²=0.2607, OR=1.205; chi-square P-value = 0.4105, Permutation P-value = 0.8111, X²=0.6775, OR=1.648 for female subjects, chi-square P-value = 0.8973, Permutation P-value = 1, X²=0.0167, OR=0.9427 for male subjects	showed nominally significant allelic associations with BD, but not with SPR, in female patients	Negative
SZ	rs704073	DUSP6	chi-square P-value = 0.5978, Permutation P-value = 0.9424, X²=0.2783, OR=1.294; chi-square P-value = 0.6115, Permutation P-value = 0.9859, X²=0.2579, OR=1.475 for female subjects, chi-square P-value = 0.8272, Permutation P-value = 0.9993, X²=0.0476, OR=1.149 for male subjects	showed nominally significant allelic associations with BD, but not with SPR, in female patients	Negative
SZ	rs2279574	DUSP6	chi-square P-value = 0.9205, Permutation P-value = 0.9992, X²=0.01, OR=1.012; chi-square P-value = 0.8087, Permutation P-value = 1, X²=0.0586, OR=1.047 for female subjects, chi-square P-value = 0.7677, Permutation P-value = 0.93, X²=0.0872, OR=0.954 for male subjects	showed nominally significant allelic associations with BD, but not with SPR, in female patients	Negative
SZ	rs808820	DUSP6	chi-square P-value = 0.9126, Permutation P-value = 0.9994, X²=0.0121, OR=1.047; chi-square P-value = 0.4866, Permutation P-value = 0.9137, X²=0.4841, OR=1.595 for female subjects, chi-square P-value = 0.6207, Permutation P-value = 0.9726, X²=0.2448, OR=0.7687 for male subjects	showed nominally significant allelic associations with BD, but not with SPR, in female patients	Negative
SZ	rs770087	DUSP6	chi-square P-value = 0.9919, Permutation P-value = 1, X²=0.0001, OR=0.9961; chi-square P-value = 0.4652, Permutation P-value = 0.8983, X²=0.5333, OR=1.559 for female subjects, chi-square P-value = 0.4958, Permutation P-value = 0.9196, X²=0.464, OR=0.7172 for male subjects	showed nominally significant allelic associations with BD, but not with SPR, in female patients	Negative
SZ	rs769700	DUSP6	chi-square P-value = 0.9919, Permutation P-value = 1, X²=0.0001, OR=0.9961; chi-square P-value = 0.4652, Permutation P-value = 0.8983, X²=0.5333, OR=1.559 for female subjects, chi-square P-value = 0.4958, Permutation P-value = 0.9196, X²=0.464, OR=0.7172 for male subjects	showed nominally significant allelic associations with BD, but not with SPR, in female patients	Negative

Genes reported by this study for SZ/MDD

Disease	Gene	Description	Result Category
SZ	DUSP6	No significant association was reported in this study.	Negative