Study Report

Comment on Study

View All Comments on Study

Basic Info

Reference	Shi, J., 2007 PMID: 17373692
Citation	Shi, J., E. Hattori, et al. (2007). "No evidence for association between 19 cholinergic genes and bipolar disorder." Am J Med Genet B Neuropsychiatr Genet 144B(6): 715-723.
Disease Type	Bipolar Disorder
Study Design	family-based
Study Type	Candidate-gene association study
Sample Size	83 samples from 22 multiplex families of CNG pedigrees and 474 samples from 152 families of NIMH collections
SNP/Region/Marker Size	93 SNPs
Predominant Ethnicity	Caucasian
Population	NIMH collections and the CNG pedigrees
Gender	Of 201 affected children, 109 were females and 92 were males

Detail Info

Sample Diagnosis	Diagnostic Instrument for Genetic Studies (DIGS) and the Family Interview for Genetic Studies (FIGS)
Sample Status	The nuclear trio- and quad-families in these two series included 201 affected children. Of them, 156 met DSM-III-R criteria for bipolar I disorder, 30 for bipolar II disorder, and 15 for schizoaffective disorder bipolar type.
Technique	genotyping using the TaqMan; PCR amplication and allelic discrimination analysis on the Prism 7900HT Fast Real-Time PCR system
Statistical Method	The transmission disequilibrium test (TDT) was used to test for individual SNP transmission distortion. The sib_tdt program from the ASPEX 2.3 analysis package was used to analyze all affected sibs with significance for the individual SNP estimated by permutation. TDT analyses of individual SNPs and haplotype blocks were performed using Haploview software. Nominal P-values were estimated from the chi-square (1 df) and the P-values for SNPs would not necessarily agree with those from ASPEX/sib_tdt. P-values were corrected for multiple testing of all the SNPs and haplotypes within a gene through 1,000 permutations to obtain a 'gene-wide' P-value. To evaluate interactions between genes without significant main effects, they used the 'focused interaction testing framework' method (FITF). All SNPs and haplotypes were compared between the alcohol and non-alcohol dependence group using chi-square tests to see if there was a significant difference in the proportion of alleles/haplotypes transmitted between the two groups.
Result Summary	Sib-transmission/disequilibrium test (sib_TDT) analysis showed nominally significant transmission bias for four SNPs (CHRNA2: rs7017417, P=0.024; CHRNA5: rs514743, P=0.031; CHRNB1: rs2302762, P=0.049; CHRNB4: rs1948, P=0.031). Haploview analyses showed nominally significant transmission bias of several haplotypes in CHRNA2, CHRNA7, CHRNB1, and CHRNB4, respectively. However, none of these associations reached gene-wide significance after correction by permutation. Alcohol dependence (including alcohol abuse) was not a significant covariate in the present genetic association analysis. Thus, it is unlikely that these 19 cholinergic genes play a major role in the pre-disposition to BD in these pedigrees.

SNPs reported by this study for BD (count: 93)

SNP	Related Gene(s)	Allele Change	Statistical Values	Author Comments	Result Category
rs4275821	PSMA4 CHRNA5	G/A	TDT P-value = 0.19 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs4475425	CHRM2	A/G	TDT P-value = 0.94 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs4779656	AVEN CHRM5	A/G	TDT P-value = 0.52 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs4779971	CHRNA7	A/G	TDT P-value = 0.49 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs3793791	CHAT	C/T	TDT P-value = 1 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs3853818	CHRNB1 FGF11	C/T	TDT P-value = 0.3 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs4151120	FGF11 TMEM102 CHRNB1	A/T	TDT P-value = 0.19 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs4264869	CHRNA9	C/T	TDT P-value = 0.13 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs528011	CHRM3	G/T	TDT P-value = 0.32 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs543307	CHRM3	C/T	TDT P-value = 0.28 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs615470	CHRNA3 CHRNA5	C/T	TDT P-value = 0.092 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs621060	CHRM3	A/G	TDT P-value = 0.42 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs4861065	CHRNA9	C/T	TDT P-value = 0.4 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs4963323	CHRM1	C/G	TDT P-value = 0.62 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs499167	CHRM5	A/C	TDT P-value = 1 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs514743	CHRNA3 CHRNA5	A/T	TDT P-value = 0.031 of Allelic Association With Bipolar Disorder in the Combined Sample	the SNP showed nominally significant association with BD, bu...... the SNP showed nominally significant association with BD, but the association failed to maintain significance after correction for multiple testing by permutation More...	Positive
rs6700643	CHRM3	C/T	TDT P-value = 0.64 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs6688537	CHRM3	A/C	TDT P-value = 1 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs6732758	CHRNA1	A/G	TDT P-value = 0.32 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs6708544	CHRNA1	G/A	TDT P-value = 0.47 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs6537546	CHAT	A/T	TDT P-value = 0.68 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs6495309	CHRNA3 CHRNB4	G/A	TDT P-value = 0.2 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs658842	CHRM3	A/T	TDT P-value = 0.75 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs6578411	CHRNA10 NUP98	A/G	TDT P-value = 0.33 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs7004381	CHRNB3	A/G	TDT P-value = 0.43 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs6957496	CHRM2	A/G	TDT P-value = 0.27 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs7017612	CHRNB3	A/C	TDT P-value = 0.5 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs7017417	EPHX2 CHRNA2	A/G	TDT P-value = 0.024 of Allelic Association With Bipolar Disorder in the Combined Sample	the SNP showed nominally significant association with BD, bu...... the SNP showed nominally significant association with BD, but the association failed to maintain significance after correction for multiple testing by permutation More...	Positive
rs6819483	CHRNA9	C/G	TDT P-value = 1 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs680244	CHRNA5	C/T	TDT P-value = 0.073 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs684513	CHRNA5	C/G	TDT P-value = 0.25 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs6823439	CHRNA9	T/A	TDT P-value = 0.22 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs1913456	CHRNA7	A/T	TDT P-value = 0.48 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs1917810	CHAT	A/G	TDT P-value = 0.82 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs1500946	CHRNA7	A/G	TDT P-value = 0.3 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs1824024	CHRM2	A/C	TDT P-value = 0.19 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs1364409	CHRM2	T/A	TDT P-value = 0.41 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs1455858	CHRM2	C/T	TDT P-value = 0.33 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs13329490	CHRNA7	G/T	TDT P-value = 1 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs1355920	CHRNA7	G/A	TDT P-value = 0.34 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs2271583	CHRNA10 ART1	A/G	TDT P-value = 0.086 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs2273502	CHRNA4	C/T	TDT P-value = 0.28 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs2061174	CHRM2	A/G	TDT P-value = 0.26 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs2072660	CHRNB2	T/C	TDT P-value = 1 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs1948	CHRNA3 CHRNB4	A/G	TDT P-value = 0.031 of Allelic Association With Bipolar Disorder in the Combined Sample	the SNP showed nominally significant association with BD, bu...... the SNP showed nominally significant association with BD, but the association failed to maintain significance after correction for multiple testing by permutation More...	Positive
rs2036527	CHRNA5	A/G	TDT P-value = 0.93 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs1917813	CHAT	C/T	TDT P-value = 0.61 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs1938677	CHRM1	A/G	TDT P-value = 0.71 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs2684941	AVEN CHRM5	A/G	TDT P-value = 1 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs2672213	CHRNA10 NUP98	C/T	TDT P-value = 0.56 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs2507821	CHRM1	G/T	TDT P-value = 0.95 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs2350786	CHRM2	A/G	TDT P-value = 0.95 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs2337980	CHRNA7	A/G	TDT P-value = 0.66 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs2302765	CHRNB1 FGF11	C/T	TDT P-value = 0.29 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs2302762	CHRNB1 ZBTB4	C/T	TDT P-value = 0.049 of Allelic Association With Bipolar Disorder in the Combined Sample	the SNP showed nominally significant association with BD, bu...... the SNP showed nominally significant association with BD, but the association failed to maintain significance after correction for multiple testing by permutation More...	Positive
rs2279465	MDK DGKZ MIR4688 CHRM4	A/G	TDT P-value = 0.15 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs3755486	CHRNA1	C/T	TDT P-value = 0.43 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs324650	CHRM2	A/T	TDT P-value = 1 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs324614	CHRM2	G/C	TDT P-value = 0.25 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs2741862	CHRNA10 ART1 NUP98	A/G	TDT P-value = 1 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs2741339	CHRNA2	A/G	TDT P-value = 1 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs2741335	CHRNA2	A/C	TDT P-value = 0.47 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs2702285	AVEN CHRM5	C/T	TDT P-value = 0.74 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs2684953	AVEN CHRM5	C/T	TDT P-value = 0.86 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs10805117	CHRNA9	A/T	TDT P-value = 0.28 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs1127317	ADAR CHRNB2	T/G	TDT P-value = 1 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs1019882	CHRM3	C/T	TDT P-value = 0.73 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs10495447	CHRM3	A/G	TDT P-value = 0.66 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs11783289	CHRNB3	G/A	TDT P-value = 0.6 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs1316971	CHRNB4	A/G	TDT P-value = 0.43 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs11633223	CHRNB4	A/G	TDT P-value = 0.67 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs11637630	CHRNA3	A/G	TDT P-value = 0.23 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs10082479	CHAT	A/T	TDT P-value = 0.76 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs10107450	CHRNA6	G/A	TDT P-value = 0.35 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs7178270	CHRNB4	G/C	TDT P-value = 0.46 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs7179733	CHRNA7	G/A	TDT P-value = 0.5 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs7094248	CHAT	C/G	TDT P-value = 0.63 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs7123164	ART1 CHRNA10	A/G	TDT P-value = 0.38 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs7782965	CHRM2 KRT8P51	C/T	TDT P-value = 0.56 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs7810473	CHRM2	A/G	TDT P-value = 0.35 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs7520974	CHRM3 CHRM3-AS1	A/G	TDT P-value = 0.77 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs755203	CHRNA4	A/G	TDT P-value = 0.69 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs885834	CHAT SLC18A3	A/G	TDT P-value = 0.89 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs891397	CHRNA2	A/C	TDT P-value = 0.66 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs8035668	CHRNA7	C/T	TDT P-value = 0.27 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs8191992	CHRM2	A/T	TDT P-value = 0.82 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs9314347	PTK2B CHRNA2	A/G	TDT P-value = 0.52 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs935863	CHRNA1	A/G	TDT P-value = 0.83 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs904951	CHRNA7	C/T	TDT P-value = 0.39 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs9217	CHRNB1 ZBTB4	C/T	TDT P-value = 0.3 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs978437	CHRM2	C/T	TDT P-value = 0.42 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs965435	CHRNA7	C/T	TDT P-value = 0.47 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative
rs951266	CHRNA5	A/G	TDT P-value = 0.36 of Allelic Association With Bipolar Disorder in the Combined Sample		Negative

Haplotypes reported by this study for BD (count: 4)

Markers	Haplotype	Related Gene(s)/Region(s)	Statistical Values	Author Comments	Result Category
rs1948 - rs7178270 - rs1316971 - rs11633223	G-C-G-G	CHRNB4	Uncorrected P-value = 0.017, Gene-wide Permutation P-value = 0.382	The haplotype showed nominally significant association with ...... The haplotype showed nominally significant association with BD by Haploview analyses but the significance did not remain after permutation testing More...	Positive
rs8035668 - rs1500946	C-A	CHRNA7	Uncorrected P-value = 0.03, Gene-wide Permutation P-value = 0.554	The haplotype showed nominally significant association with ...... The haplotype showed nominally significant association with BD by Haploview analyses but the significance did not remain after permutation testing More...	Positive
rs4151120 - rs3853818 - rs2302765 - rs2302762 - rs9217	T-T-T-T-T	CHRNB1	Uncorrected P-value = 0.011, Gene-wide Permutation P-value = 0.249	The haplotype showed nominally significant association with ...... The haplotype showed nominally significant association with BD by Haploview analyses but the significance did not remain after permutation testing More...	Positive
rs9314347 - rs891397	G-C	CHRNA2	Uncorrected P-value = 0.029, Gene-wide Permutation P-value = 0.349	The haplotype showed nominally significant association with ...... The haplotype showed nominally significant association with BD by Haploview analyses but the significance did not remain after permutation testing More...	Positive

Genes reported by this study for BD (count: 19)

Gene	Statistical Values/Author Comments	Result Category
CHAT	no evidence of interaction among these 19 cholinergic genes was found by Allelic Association, Haplov...... no evidence of interaction among these 19 cholinergic genes was found by Allelic Association, Haploview Tests, FITF analysis and FDR correction More...	Negative
CHRNA4	rs1948 showed nominally significant transmission bias; haploview analyses showed nominally signific...... rs1948 showed nominally significant transmission bias; haploview analyses showed nominally significant transmission bias of rs1948-rs7178270-rs1316971-rs11633223; no evidence of interaction among these 19 cholinergic genes by FITF analysis and FDR correction was found More...	Positive
CHRNA6	no evidence of interaction among these 19 cholinergic genes was found by Allelic Association, Haplov...... no evidence of interaction among these 19 cholinergic genes was found by Allelic Association, Haploview Tests, FITF analysis and FDR correction More...	Negative
CHRNA3	no evidence of interaction among these 19 cholinergic genes was found by Allelic Association, Haplov...... no evidence of interaction among these 19 cholinergic genes was found by Allelic Association, Haploview Tests, FITF analysis and FDR correction More...	Negative
CHRNA5	rs514743 showed nominally significant transmission bias; no evidence of interaction among these 19 ...... rs514743 showed nominally significant transmission bias; no evidence of interaction among these 19 cholinergic genes by FITF analysis and FDR correction was found More...	Positive
CHRNA2	no evidence of interaction among these 19 cholinergic genes was found by Allelic Association, Haplov...... no evidence of interaction among these 19 cholinergic genes was found by Allelic Association, Haploview Tests, FITF analysis and FDR correction More...	Negative
CHRNA7	haploview analyses showed nominally significant transmission bias of rs8035668-rs1500946; no eviden...... haploview analyses showed nominally significant transmission bias of rs8035668-rs1500946; no evidence of interaction among these 19 cholinergic genes by FITF analysis and FDR correction was found More...	Positive
CHRNB2	rs7017417 showed nominally significant transmission bias; haploview analyses showed nominally signi...... rs7017417 showed nominally significant transmission bias; haploview analyses showed nominally significant transmission bias of rs9314347-rs891397; no evidence of interaction among these 19 cholinergic genes by FITF analysis and FDR correction was found More...	Positive
CHRNA1	no evidence of interaction among these 19 cholinergic genes was found by Allelic Association, Haplov...... no evidence of interaction among these 19 cholinergic genes was found by Allelic Association, Haploview Tests, FITF analysis and FDR correction More...	Negative
CHRNA10	no evidence of interaction among these 19 cholinergic genes was found by Allelic Association, Haplov...... no evidence of interaction among these 19 cholinergic genes was found by Allelic Association, Haploview Tests, FITF analysis and FDR correction More...	Negative
CHRNA9	no evidence of interaction among these 19 cholinergic genes was found by Allelic Association, Haplov...... no evidence of interaction among these 19 cholinergic genes was found by Allelic Association, Haploview Tests, FITF analysis and FDR correction More...	Negative
CHRM4	no evidence of interaction among these 19 cholinergic genes was found by Allelic Association, Haplov...... no evidence of interaction among these 19 cholinergic genes was found by Allelic Association, Haploview Tests, FITF analysis and FDR correction More...	Negative
CHRNB1	rs2302762 showed nominally significant transmission bias; haploview analyses showed nominally signi...... rs2302762 showed nominally significant transmission bias; haploview analyses showed nominally significant transmission bias of rs4151120-rs3853818-rs2302765-rs2302762-rs9217; no evidence of interaction among these 19 cholinergic genes by FITF analysis and FDR correction was found More...	Positive
CHRM5	no evidence of interaction among these 19 cholinergic genes was found by Allelic Association, Haplov...... no evidence of interaction among these 19 cholinergic genes was found by Allelic Association, Haploview Tests, FITF analysis and FDR correction More...	Negative
CHRNB4	no evidence of interaction among these 19 cholinergic genes was found by Allelic Association, Haplov...... no evidence of interaction among these 19 cholinergic genes was found by Allelic Association, Haploview Tests, FITF analysis and FDR correction More...	Negative
CHRM2	no evidence of interaction among these 19 cholinergic genes was found by Allelic Association, Haplov...... no evidence of interaction among these 19 cholinergic genes was found by Allelic Association, Haploview Tests, FITF analysis and FDR correction More...	Negative
CHRM3	no evidence of interaction among these 19 cholinergic genes was found by Allelic Association, Haplov...... no evidence of interaction among these 19 cholinergic genes was found by Allelic Association, Haploview Tests, FITF analysis and FDR correction More...	Negative
CHRNB3	no evidence of interaction among these 19 cholinergic genes was found by Allelic Association, Haplov...... no evidence of interaction among these 19 cholinergic genes was found by Allelic Association, Haploview Tests, FITF analysis and FDR correction More...	Negative
CHRM1	no evidence of interaction among these 19 cholinergic genes was found by Allelic Association, Haplov...... no evidence of interaction among these 19 cholinergic genes was found by Allelic Association, Haploview Tests, FITF analysis and FDR correction More...	Negative