Study Report

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Basic Info

Reference	Szczepankiewicz, A., 2013 PMID: 23962971
Citation	Szczepankiewicz, A., A. Leszczynska-Rodziewicz, et al. (2013). "Epistatic interaction between CRHR1 and AVPR1b variants as a predictor of major depressive disorder." Psychiatr Genet.
Disease Type	bipolar disorder & major depressive disorder
Study Design	case-control
Study Type	Candidate-gene association study
Sample Size	486 patients with bipolar disorder and 215 patients with MDD, 712 healthy participants
SNP/Region/Marker Size	13 SNPs
Predominant Ethnicity	ethnically homogenous
Gender	42.8% male patients for bipolar, 25.4% male patients for MDD, 42.5% male controls
Age Group	adults : mean age=45.2, SD=13.5 years of bipolar patients, mean age= 44.9, SD=13.8 years of MDD patients, mean age=39.9, SD=12.7 years of controls

Detail Info

Sample Diagnosis	DSM-IV
Sample Status	Patients were recruited from among inpatients from the Wielkopolska region, considered as ethnically homogenous, treated at the Department of Psychiatry, University of Medical Sciences, Poznan. Phenotyping was based on clinical interviews, medical records, and family history, and consensus diagnosis was made according to Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria, using the Structured Clinical Interview for DSM Disorders. Age at onset of bipolar patients is 31.6, s.d. 11.5 years, age at onset of MDD patients is 38.8, s.d. 13.5 years.
Technique	Genotyping of CRHR1 and AVPR1b polymorphisms was performed using TaqMan single nucleotide polymorphism genotyping assays.
Statistical Method	The two-tailed Pearson's X2-test and Fisher's exact test were used to test differences in the genotypic and allelic distributions, respectively, between the groups of patients and controls. In addition, two-tailed power analysis was carried out using Quanto software, which includes minor allele frequency as well as prevalence of disease in its calculations. Odds ratios were calculated with 2*2 contingency tables using Fisher's exact test on a demo version of GraphPad InStat 3 software. Correction for multiple testing was performed for multiple comparisons in haplotype analysis, by 10 000 permutations. Higher-order gene-gene interactions among tested SNPs were analyzed using the nonparametric and genetic model-free multifactor dimensionality reduction (MDR) approach (v.2.0 beta 8.3).
Result Summary	By single marker analysis we have found an association of rs28536160 of AVPR1b and rs4076452 and rs16940655 of CRHR1 with mood disorders (P=0.036, 0.0013, and 0.003, respectively). We observed strong linkage disequilibrium between seven CRHR1 polymorphisms grouped in two haplotype blocks; however, none of them showed an association with MDD or bipolar disorder. Similarly, no association was found for three of four strongly linked AVPR1b polymorphisms. Gene-gene interaction analysis revealed a significant epistatic interaction between AVPR1b and CRHR1 genes in susceptibility to MDD (P=0.017). Polymorphisms of CRHR1 and AVPR1b may modify susceptibility to mood disorders.

Genetic factors reported by this study for BD

SNPs reported by this study for BD (count: 12)

SNP	Related Gene(s)	Allele Change	Statistical Values	Author Comments	Result Category
rs28536160	AVPR1B	C/T	allelic P-value=0.149, genotypic P-value=0.036, OR=0.804, 95% CI=0.607-1.067 for affective disorder; allelic P-value=0.062, genotypic P-value=0.056, OR=1.388, 95% CI=0.999-1.888 for BD	In the single marker association analysis of AVPR1b gene we ...... In the single marker association analysis of AVPR1b gene we observed an association of rs28536160 with mood disorders (P=0.036); this was not observed in the bipolar disorder and MDD patients separately. More...	Negative
rs28373064	AVPR1B	A/G	allelic P-value=0.454, genotypic P-value=0.706, OR=0.926, 95% CI=0.766-1.119 for affective disorder; allelic P-value=0.19, genotypic P-value=0.332, OR=0.859, 95% CI=0.702-1.067 for BD	No significant association was observed. No significant association was observed.	Negative
rs35369693	AVPR1B	C/G	allelic P-value=0.729, genotypic P-value=0.907, OR=0.934, 95% CI=0.682-1.279 for affective disorder; allelic P-value=0.778, genotypic P-value=0.907, OR=0.935, 95% CI=0.662-1.310 for BD	No significant association was observed. No significant association was observed.	Negative
rs28632197	AVPR1B	A/G	allelic P-value=0.883, genotypic P-value=0.824, OR=0.974, 95% CI=0.763-1.244 for affective disorder; allelic P-value=0.631, genotypic P-value=0.556, OR=1.088, 95% CI=0.780-1.336 for BD	No significant association was observed. No significant association was observed.	Negative
rs4076452	CRHR1	C/G	allelic P-value=0.196, genotypic P-value=0.013, OR=1.142, 95% CI=0.940-1.386 for affective disorder; allelic P-value=0.321, genotypic P-value=0.099, OR=1.123, 95% CI=0.892-1.372 for BD	For the CRHR1 gene, we observed an association of rs4076452 ...... For the CRHR1 gene, we observed an association of rs4076452 with mood disorders. This was not observed in the bipolar disorder. More...	Negative
rs4792887	CRHR1 MAPT-AS1	C/T	allelic P-value=0.201, genotypic P-value=0.266, OR=1.631, 95% CI=0.665-1.080 for affective disorder; allelic P-value=0.244, genotypic P-value=0.371, OR=0.841, 95% CI=0.644-1.108 for BD	No significant association was observed. No significant association was observed.	Negative
rs110402	CRHR1 MAPT-AS1	A/G	allelic P-value=0.079, genotypic P-value=0.166, OR=0.874, 95% CI=0.755-1.013 for affective disorder; allelic P-value=0.16, genotypic P-value=0.343, OR=0.885, 95% CI=0.751-1.041 for BD	No significant association was observed. No significant association was observed.	Negative
rs16940655	CRHR1 MAPT-AS1	C/T	allelic P-value=0.228, genotypic P-value=0.003, OR=1.137, 95% CI=0.930-1.389 for affective disorder; allelic P-value=0.157, genotypic P-value=0.007, OR=1.181, 95% CI=0.959-1.489 for BD	For the CRHR1 gene, we observed an association of rs16940655...... For the CRHR1 gene, we observed an association of rs16940655 with mood disorders. The association of rs16940655 was also observed in patients with bipolar disorder. More...	Positive
rs12936511	CRHR1 MAPT-AS1	C/T	allelic P-value=0.362, genotypic P-value=0.269, OR=0.828, 95% CI=0.603-1.180 for affective disorder; allelic P-value=0.301, genotypic P-value=0.151, OR=0.801, 95% CI=0.544-1.166 for BD	No significant association was observed. No significant association was observed.	Negative
rs242950	CRHR1 MAPT-AS1	C/T	allelic P-value=0.407, genotypic P-value=0.671, OR=0.901, 95% CI=0.716-1.134 for affective disorder; allelic P-value=0.832, genotypic P-value=0.615, OR=0.877, 95% CI=0.678-1.135 for BD	No significant association was observed. No significant association was observed.	Negative
rs173365	CRHR1 MAPT-AS1	A/G	allelic P-value=0.845, genotypic P-value=0.834, OR=1.018, 95% CI=0.877-1.180 for affective disorder; allelic P-value=0.888, genotypic P-value=0.972, OR=0.984, 95% CI=0.835-1.161 for BD	No significant association was observed. No significant association was observed.	Negative
rs878886	CRHR1 MAPT-AS1	C/G	allelic P-value=0.113, genotypic P-value=0.258, OR=1.176, 95% CI=0.967-1.430 for affective disorder; allelic P-value=0.066, genotypic P-value=0.161, OR=1.231, 95% CI=0.997-1.533 for BD	No significant association was observed. No significant association was observed.	Negative

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

Markers	Haplotype	Related Gene(s)/Region(s)	Statistical Values	Author Comments	Result Category
rs12936511 - rs16940655 - rs173365 - rs242950 - rs878886	C-C-G-C-C	CRHR1	P-value=0.75, X<sup>2</sup>=0.101	For the MDD and bipolar disorder patients, we have not obser...... For the MDD and bipolar disorder patients, we have not observed any significant differences in haplotype frequencies. More...	Negative
rs12936511 - rs16940655 - rs173365 - rs242950 - rs878886	C-T-A-C-G	CRHR1	P-value=0.297, X<sup>2</sup>=1.086	For the MDD and bipolar disorder patients, we have not obser...... For the MDD and bipolar disorder patients, we have not observed any significant differences in haplotype frequencies. More...	Negative
rs4792887 - rs110402	C-G	CRHR1	P-value=0.288, X<sup>2</sup>=1.129	For the MDD and bipolar disorder patients, we have not obser...... For the MDD and bipolar disorder patients, we have not observed any significant differences in haplotype frequencies. More...	Negative
rs4792887 - rs110402	T-G	CRHR1	P-value=0.211, X<sup>2</sup>=1.559	For the MDD and bipolar disorder patients, we have not obser...... For the MDD and bipolar disorder patients, we have not observed any significant differences in haplotype frequencies. More...	Negative
rs28536160 - rs28373064 - rs35369693	G-G-A	AVPR1B	P-value=0.36, X<sup>2</sup>=0.837	For the MDD and bipolar disorder patients, we have not obser...... For the MDD and bipolar disorder patients, we have not observed any significant differences in haplotype frequencies. More...	Negative
rs4792887 - rs110402	C-A	CRHR1	P-value=0.071, X<sup>2</sup>=3.251	For the MDD and bipolar disorder patients, we have not obser...... For the MDD and bipolar disorder patients, we have not observed any significant differences in haplotype frequencies. More...	Negative
rs28536160 - rs28373064 - rs35369693	G-G-G	AVPR1B	P-value=0.352, X<sup>2</sup>=0.865	For the MDD and bipolar disorder patients, we have not obser...... For the MDD and bipolar disorder patients, we have not observed any significant differences in haplotype frequencies. More...	Negative
rs28536160 - rs28373064 - rs35369693	G-C-A	AVPR1B	P-value=0.561, X<sup>2</sup>=0.337	For the MDD and bipolar disorder patients, we have not obser...... For the MDD and bipolar disorder patients, we have not observed any significant differences in haplotype frequencies. More...	Negative
rs12936511 - rs16940655 - rs173365 - rs242950 - rs878886	T-C-A-C-C	CRHR1	P-value=0.278, X<sup>2</sup>=1.175	For the MDD and bipolar disorder patients, we have not obser...... For the MDD and bipolar disorder patients, we have not observed any significant differences in haplotype frequencies. More...	Negative
rs12936511 - rs16940655 - rs173365 - rs242950 - rs878886	C-C-A-C-G	CRHR1	P-value=0.031, X<sup>2</sup>=4.626	For the MDD and bipolar disorder patients, we have not obser...... For the MDD and bipolar disorder patients, we have not observed any significant differences in haplotype frequencies. We observed that the CCACG haplotype in the second haplotype block was significantly more frequent in the patients with mood disorders than in healthy individuals (P=0.031); however, the difference was not observed after multiple testing correction (after 10 000 permutations, P=0.208). More...	Negative
rs12936511 - rs16940655 - rs173365 - rs242950 - rs878886	C-C-A-T-C	CRHR1	P-value=0.306, X<sup>2</sup>=1.048	For the MDD and bipolar disorder patients, we have not obser...... For the MDD and bipolar disorder patients, we have not observed any significant differences in haplotype frequencies. More...	Negative
rs12936511 - rs16940655 - rs173365 - rs242950 - rs878886	C-C-A-C-C	CRHR1	P-value=0.454, X<sup>2</sup>=0.557	For the MDD and bipolar disorder patients, we have not obser...... For the MDD and bipolar disorder patients, we have not observed any significant differences in haplotype frequencies. More...	Negative
rs28536160 - rs28373064 - rs35369693	A-G-G	AVPR1B	P-value=0.556, X<sup>2</sup>=0.345	For the MDD and bipolar disorder patients, we have not obser...... For the MDD and bipolar disorder patients, we have not observed any significant differences in haplotype frequencies. More...	Negative

Genes reported by this study for BD (count: 2)

Gene	Statistical Values/Author Comments	Result Category
CRHR1	Polymorphisms of CRHR1 and AVPR1b may modify susceptibility to mood disorders. Polymorphisms of CRHR1 and AVPR1b may modify susceptibility to mood disorders.	Positive
AVPR1B	Polymorphisms of CRHR1 and AVPR1b may modify susceptibility to mood disorders. Polymorphisms of CRHR1 and AVPR1b may modify susceptibility to mood disorders.	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
MDD	rs110402	CRHR1 MAPT-AS1	allelic P-value=0.079, genotypic P-value=0.166, OR=0.874, 95% CI=0.755-1.013 for affective disorder; allelic P-value=0.144, genotypic P-value=0.238, OR=0.852, 95% CI=0.689-1.054 for MDD	No significant association was observed.	Negative
MDD	rs12936511	CRHR1 MAPT-AS1	allelic P-value=0.362, genotypic P-value=0.269, OR=0.828, 95% CI=0.603-1.180 for affective disorder; allelic P-value=0.904, genotypic P-value=0.962, OR=0.947, 95% CI=0.587-1.526 for MDD	No significant association was observed.	Negative
MDD	rs16940655	CRHR1 MAPT-AS1	allelic P-value=0.228, genotypic P-value=0.003, OR=1.137, 95% CI=0.930-1.389 for affective disorder; allelic P-value=0.94, genotypic P-value=0.277, OR=1.014, 95% CI=0.755-1.362 for MDD	No significant association was observed.	Negative
MDD	rs173365	CRHR1 MAPT-AS1	allelic P-value=0.845, genotypic P-value=0.834, OR=1.018, 95% CI=0.877-1.180 for affective disorder; allelic P-value=0.476, genotypic P-value=0.469, OR=1.088, 95% CI=0.876-1.350 for MDD	No significant association was observed.	Negative
MDD	rs35369693	AVPR1B	allelic P-value=0.729, genotypic P-value=0.907, OR=0.934, 95% CI=0.682-1.279 for affective disorder; allelic P-value=0.71, genotypic P-value=0.797, OR=0.925, 95% CI=0.573-1.492 for MDD	No significant association was observed.	Negative
MDD	rs28632197	AVPR1B	allelic P-value=0.883, genotypic P-value=0.824, OR=0.974, 95% CI=0.763-1.244 for affective disorder; allelic P-value=0.397, genotypic P-value=0.353, OR=0.853, 95% CI=0.597-1.219 for MDD	No significant association was observed.	Negative
MDD	rs4076452	CRHR1	allelic P-value=0.196, genotypic P-value=0.013, OR=1.142, 95% CI=0.940-1.386 for affective disorder; allelic P-value=0.177, genotypic P-value=0.02, OR=1.225, 95% CI=0.917-1.635 for MDD	We found that rs4076452 was significantly associated with an increased risk for MDD in our group.	Positive
MDD	rs4792887	CRHR1 MAPT-AS1	allelic P-value=0.201, genotypic P-value=0.266, OR=1.631, 95% CI=0.665-1.080 for affective disorder; allelic P-value=0.431, genotypic P-value=0.443, OR=0.853, 95% CI=0.598-1.218 for MDD	No significant association was observed.	Negative
MDD	rs28536160	AVPR1B	allelic P-value=0.149, genotypic P-value=0.036, OR=0.804, 95% CI=0.607-1.067 for affective disorder; allelic P-value=1, genotypic P-value=0.387, OR=1.001, 95% CI=0.662-1.514 for MDD	In the single marker association analysis of AVPR1b gene we observed an association of rs28536160 with mood disorders (P=0.036); this was not observed in the bipolar disorder and MDD patients separately.	Negative
MDD	rs28373064	AVPR1B	allelic P-value=0.454, genotypic P-value=0.706, OR=0.926, 95% CI=0.766-1.119 for affective disorder; allelic P-value=0.514, genotypic P-value=0.399, OR=1.099, 95% CI=0.830-1.454 for MDD	No significant association was observed.	Negative
MDD	rs878886	CRHR1 MAPT-AS1	allelic P-value=0.113, genotypic P-value=0.258, OR=1.176, 95% CI=0.967-1.430 for affective disorder; allelic P-value=0.768, genotypic P-value=0.941, OR=1.047, 95% CI=0.785-1.394 for MDD	No significant association was observed.	Negative
MDD	rs242950	CRHR1 MAPT-AS1	allelic P-value=0.407, genotypic P-value=0.671, OR=0.901, 95% CI=0.716-1.134 for affective disorder; allelic P-value=0.867, genotypic P-value=0.958, OR=0.954, 95% CI=0.686-1.327 for MDD	No significant association was observed.	Negative

Haplotypes reported by this study for SZ/MDD

Disease	Markers	Haplotype	Related Gene(s)/Region(s)	Statistical Values	Description	Result Category
MDD	rs12936511 - rs16940655 - rs173365 - rs242950 - rs878886	C-T-A-C-G	CRHR1	P-value=0.297, X<sup>2</sup>=1.086	For the MDD and bipolar disorder patients, we have not observed any significant differences in haplotype frequencies.	Negative
MDD	rs12936511 - rs16940655 - rs173365 - rs242950 - rs878886	C-C-G-C-C	CRHR1	P-value=0.75, X<sup>2</sup>=0.101	For the MDD and bipolar disorder patients, we have not observed any significant differences in haplotype frequencies.	Negative
MDD	rs12936511 - rs16940655 - rs173365 - rs242950 - rs878886	C-C-A-C-C	CRHR1	P-value=0.454, X<sup>2</sup>=0.557	For the MDD and bipolar disorder patients, we have not observed any significant differences in haplotype frequencies.	Negative
MDD	rs12936511 - rs16940655 - rs173365 - rs242950 - rs878886	C-C-A-T-C	CRHR1	P-value=0.306, X<sup>2</sup>=1.048	For the MDD and bipolar disorder patients, we have not observed any significant differences in haplotype frequencies.	Negative
MDD	rs12936511 - rs16940655 - rs173365 - rs242950 - rs878886	C-C-A-C-G	CRHR1	P-value=0.031, X<sup>2</sup>=4.626	For the MDD and bipolar disorder patients, we have not observed any significant differences in haplotype frequencies. We observed that the CCACG haplotype in the second haplotype block was significantly more frequent in the patients with mood disorders than in healthy individuals (P=0.031); however, the difference was not observed after multiple testing correction (after 10 000 permutations, P=0.208).	Negative
MDD	rs12936511 - rs16940655 - rs173365 - rs242950 - rs878886	T-C-A-C-C	CRHR1	P-value=0.278, X<sup>2</sup>=1.175	For the MDD and bipolar disorder patients, we have not observed any significant differences in haplotype frequencies.	Negative
MDD	rs28536160 - rs28373064 - rs35369693	A-G-G	AVPR1B	P-value=0.556, X<sup>2</sup>=0.345	For the MDD and bipolar disorder patients, we have not observed any significant differences in haplotype frequencies.	Negative
MDD	rs28536160 - rs28373064 - rs35369693	G-C-A	AVPR1B	P-value=0.561, X<sup>2</sup>=0.337	For the MDD and bipolar disorder patients, we have not observed any significant differences in haplotype frequencies.	Negative
MDD	rs28536160 - rs28373064 - rs35369693	G-G-G	AVPR1B	P-value=0.352, X<sup>2</sup>=0.865	For the MDD and bipolar disorder patients, we have not observed any significant differences in haplotype frequencies.	Negative
MDD	rs4792887 - rs110402	C-A	CRHR1	P-value=0.071, X<sup>2</sup>=3.251	For the MDD and bipolar disorder patients, we have not observed any significant differences in haplotype frequencies.	Negative
MDD	rs28536160 - rs28373064 - rs35369693	G-G-A	AVPR1B	P-value=0.36, X<sup>2</sup>=0.837	For the MDD and bipolar disorder patients, we have not observed any significant differences in haplotype frequencies.	Negative
MDD	rs4792887 - rs110402	T-G	CRHR1	P-value=0.211, X<sup>2</sup>=1.559	For the MDD and bipolar disorder patients, we have not observed any significant differences in haplotype frequencies.	Negative
MDD	rs4792887 - rs110402	C-G	CRHR1	P-value=0.288, X<sup>2</sup>=1.129	For the MDD and bipolar disorder patients, we have not observed any significant differences in haplotype frequencies.	Negative

Genes reported by this study for SZ/MDD

Disease	Gene	Description	Result Category
MDD	AVPR1B	Polymorphisms of CRHR1 and AVPR1b may modify susceptibility to mood disorders. Gene-gene interaction analysis revealed a significant epistatic interaction between AVPR1b and CRHR1 genes in susceptibility to MDD.	Positive
MDD	CRHR1	Polymorphisms of CRHR1 and AVPR1b may modify susceptibility to mood disorders. Gene-gene interaction analysis revealed a significant epistatic interaction between AVPR1b and CRHR1 genes in susceptibility to MDD.	Positive