Study Report

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Basic Info

Reference	Shi, J., 2008 (b) PMID: 18444252
Citation	Shi, J., J. A. Badner, et al. (2008). "Neurotransmission and bipolar disorder: a systematic family-based association study." Am J Med Genet B Neuropsychiatr Genet 147B(7): 1270-1277.
Disease Type	Bipolar Disorder
Study Design	family-based
Study Type	Candidate-gene association study
Sample Size	The sample was composed of 1,115 individuals in 101 trios and 203 quads from Caucasian bipolar families.
SNP/Region/Marker Size	1005 SNPs
Predominant Ethnicity	Caucasian
Population	CNG, NIMH and the CHIP collections

Detail Info

Sample Diagnosis	DSM-III-R or DSM-IV
Technique	genotyping
Statistical Method	Pairwise LD, using the standard LD coefficient D', was estimated between every pair of markers in each gene using Haploview (version 4.0). Haplotype blocks were identified using the solid spine of LD method implemented in Haploview. Allelic and haplotypic transmission disequilibrium tests (TDTs) were carried out for the disease trait. Permutations correcting for multiple testing were performed for individual SNPs and for all the SNPs and haplotypes in each gene, for each neurotransmission system, and for the five systems as a whole. We used two different approaches to test potential effects of sub-phenotypes including alcoholism, psychosis, substance abuse and suicide attempts, on the SNP associations. The first method was the logistic regression analysis, using the subphenotypes as covariates. The second method was the heterogeneity test. We also performed epistasis analysis to detect potential gene-gene interactions.
Result Summary	Nominally significant allelic and haplotypic associations were found for genes from each neurotransmission system, with several reaching gene-wide significance (allelic: GRIA1, GRIN2D, and QDPR; haplotypic: GRIN2C, QDPR, and SLC6A3). However, none of these associations survived correction for multiple testing in an individual system, or in all systems considered together. Significant single nucleotide polymorphism associations were not found with sub-phenotypes (alcoholism, psychosis, substance abuse, and suicide attempts) or significant gene-gene interactions.

SNPs reported by this study for BD (count: 38)

SNP	Related Gene(s)	Allele Change	Risk Allele	Statistical Values	Author Comments	Result Category
rs967771	GABRB2	A/G	A	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.0278, Gene-wide P-value = 0.2058 (P values were based on permutation for all SNPs in each gene).		Positive
rs9450594	HTR1E	A/C	A	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.0248, Gene-wide P-value = 0.0579 (P values were based on permutation for all SNPs in each gene).		Positive
rs9456	TMEM186 ABAT	A/T	A	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.0049, Gene-wide P-value = 0.0859 (P values were based on permutation for all SNPs in each gene).		Positive
rs744731	QDPR	A/G	G	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.0055, Gene-wide P-value = 0.014 (P values were based on permutation for all SNPs in each gene).	rs744731 in the QDPR gene reached gene-wide association. Non...... rs744731 in the QDPR gene reached gene-wide association. None of these associations survived multiple testing for its own system (e.g., glutamatergic or serotoninergic) or all the five systems taken together. More...	Positive
rs915841	ABCG1	A/G	G	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.0494, Gene-wide P-value = 0.5205 (P values were based on permutation for all SNPs in each gene).		Positive
rs6580038	GRIA1 RN7SL177P	A/G	G	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.0264, Gene-wide P-value = 0.3586 (P values were based on permutation for all SNPs in each gene).		Positive
rs733457	GRM4	A/C	C	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.0249, Gene-wide P-value = 0.1399 (P values were based on permutation for all SNPs in each gene).		Positive
rs623580	TPH1	A/T	T	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.0413, Gene-wide P-value = 0.0809 (P values were based on permutation for all SNPs in each gene).		Positive
rs6443074	GRM7	A/G	G	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.03, Gene-wide P-value = 0.5674 (P values were based on permutation for all SNPs in each gene).		Positive
rs5925155	GABRA3	A/G	G	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.0359, Gene-wide P-value = 0.2428 (P values were based on permutation for all SNPs in each gene).		Positive
rs592807	GRIA3	A/G	G	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.0267, Gene-wide P-value = 0.4036 (P values were based on permutation for all SNPs in each gene).		Positive
rs5028114	HTR4	A/G	A	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.0432, Gene-wide P-value = 0.2378 (P values were based on permutation for all SNPs in each gene).		Positive
rs592403	GABRB2	A/C	C	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.0198, Gene-wide P-value = 0.2517 (P values were based on permutation for all SNPs in each gene).		Positive
rs37022	SLC6A3	A/T	A	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.0371, Gene-wide P-value = 0.2108 (P values were based on permutation for all SNPs in each gene).		Positive
rs362853	GRM1	A/C	A	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.0443, Gene-wide P-value = 0.3766 (P values were based on permutation for all SNPs in each gene).		Positive
rs4790694	ARRB2	A/C	A	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.0251, Gene-wide P-value = 0.0669 (P values were based on permutation for all SNPs in each gene).		Positive
rs3818275	SLC1A2	A/G	G	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.0325, Gene-wide P-value = 0.3556 (P values were based on permutation for all SNPs in each gene).		Positive
rs2926835	GRIA1	A/T	T	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.0036, Gene-wide P-value = 0.029 (P values were based on permutation for all SNPs in each gene).	rs2926835 in the GRIA1 gene reached gene-wide association. N...... rs2926835 in the GRIA1 gene reached gene-wide association. None of these associations survived multiple testing for its own system (e.g., glutamatergic or serotoninergic) or all the five systems taken together. More...	Positive
rs2731877	SLC1A3	A/G	G	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.0224, Gene-wide P-value = 0.1948 (P values were based on permutation for all SNPs in each gene).		Positive
rs329037	GRM7	A/C	A	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.0059, Gene-wide P-value = 0.3766 (P values were based on permutation for all SNPs in each gene).		Positive
rs2926837	GRIA1	C/G	C	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.0294, Gene-wide P-value = 0.3127 (P values were based on permutation for all SNPs in each gene).		Positive
rs2268115	GRIN2B	A/C	C	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.0352, Gene-wide P-value = 0.6743 (P values were based on permutation for all SNPs in each gene).		Positive
rs220592	GRIN2B	A/C	C	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.0449, Gene-wide P-value = 0.7223 (P values were based on permutation for all SNPs in each gene).		Positive
rs252952	GABRB2	A/C	C	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.0066, Gene-wide P-value = 0.1039 (P values were based on permutation for all SNPs in each gene).		Positive
rs2453737	DRD1	A/G	G	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.0233, Gene-wide P-value = 0.0989 (P values were based on permutation for all SNPs in each gene).		Positive
rs1799281	GRIN2D GRWD1	A/G	G	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.0029, Gene-wide P-value = 0.026 (P values were based on permutation for all SNPs in each gene).	rs1799281 in the GRIN2D gene reached gene-wide association. ...... rs1799281 in the GRIN2D gene reached gene-wide association. None of these associations survived multiple testing for its own system (e.g., glutamatergic or serotoninergic) or all the five systems taken together. More...	Positive
rs1645660	SLC1A3	A/G	A	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.0292, Gene-wide P-value = 0.2927 (P values were based on permutation for all SNPs in each gene).		Positive
rs2168631	DRD1	A/G	A	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.0475, Gene-wide P-value = 0.1898 (P values were based on permutation for all SNPs in each gene).		Positive
rs2036109	ADRA1A	A/C	A	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.0268, Gene-wide P-value = 0.1728 (P values were based on permutation for all SNPs in each gene).		Positive
rs1273394	ABAT	A/C	A	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.0345, Gene-wide P-value = 0.6224 (P values were based on permutation for all SNPs in each gene).		Positive
rs12754	ADCY1 SEPT7P2	A/C	C	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.007, Gene-wide P-value = 0.1099 (P values were based on permutation for all SNPs in each gene).		Positive
rs1461225	GRIA1	A/C	C	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.0056, Gene-wide P-value = 0.0769 (P values were based on permutation for all SNPs in each gene).		Positive
rs162724	GRM7	A/G	G	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.0205, Gene-wide P-value = 0.3037 (P values were based on permutation for all SNPs in each gene).		Positive
rs1042009	ADCY1	A/G	G	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.0122, Gene-wide P-value = 0.0829 (P values were based on permutation for all SNPs in each gene).		Positive
rs1048101	ADRA1A	A/G	G	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.0306, Gene-wide P-value = 0.1888 (P values were based on permutation for all SNPs in each gene).		Positive
rs10515827	GABRB2	A/G	A	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.0206, Gene-wide P-value = 0.1409 (P values were based on permutation for all SNPs in each gene).		Positive
rs10743152	TH MIR4686	A/G	A	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.049, Gene-wide P-value = 0.2058 (P values were based on permutation for all SNPs in each gene).		Positive
rs10102186	ADRA1A	A/G	A	Allelic association of neurotransmission systems genes with bipolar disorder: TDT P-value = 0.0139, Gene-wide P-value = 0.1728 (P values were based on permutation for all SNPs in each gene).		Positive

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

Markers	Haplotype	Related Gene(s)/Region(s)	Statistical Values	Author Comments	Result Category
rs1568447 - rs690533 - rs516035	GGA	GRIN2C	Gene-wide significant haplotypic association with bipolar disorder: TDT P-value = 0.0110, Gene-wide P-value = 0.0410	Gene-wide significant haplotypic associations with BP, none ...... Gene-wide significant haplotypic associations with BP, none of these associations survived correction for multiple testing More...	Positive
rs2597758 - rs1031326 - rs744731 - rs2597778	AGGA	QDPR	Gene-wide significant haplotypic association with bipolar disorder: TDT P-value = 0.0064, Gene-wide P-value = 0.0499	Gene-wide significant haplotypic associations with BP, none ...... Gene-wide significant haplotypic associations with BP, none of these associations survived correction for multiple testing More...	Positive
rs37022 - rs2042449	TG	SLC6A3	Gene-wide significant haplotypic association with bipolar disorder: TDT P-value = 0.0068, Gene-wide P-value = 0.0340	Gene-wide significant haplotypic associations with BP, none ...... Gene-wide significant haplotypic associations with BP, none of these associations survived correction for multiple testing More...	Positive

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

Gene	Statistical Values/Author Comments	Result Category
ARRB2	Significant associations of this gene were found in BPD patients. Significant associations of this gene were found in BPD patients.	Positive
GRIN2D	rs1799281 in the GRIN2D gene reached gene-wide association (permutation P<0.05 for all SNPs of each gene). . None of these associations survived multiple testing for its own system (e.g., glutamatergic or sero...... None of these associations survived multiple testing for its own system (e.g., glutamatergic or serotoninergic) or all the five systems taken together (permutation adjusted P>0.05)ã€‚ More...	Positive
QDPR	rs744731 in the QDPR reached gene-wide association (permutation P<0.05 for all SNPs of each gene). . None of these associations survived multiple testing for its own system (e.g., glutamatergic or sero...... None of these associations survived multiple testing for its own system (e.g., glutamatergic or serotoninergic) or all the five systems taken together (permutation adjusted P>0.05)ã€‚ More...	Positive
GRIA1	rs2926835 in the GRIA1 gene reached gene-wide association (permutation P<0.05 for all SNPs of each gene). . None of these associations survived multiple testing for its own system (e.g., glutamatergic or sero...... None of these associations survived multiple testing for its own system (e.g., glutamatergic or serotoninergic) or all the five systems taken together (permutation adjusted P>0.05)ã€‚ More...	Positive