Study Report

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Basic Info

Reference	Greenwood, T. A., 2006 PMID: 16261167
Citation	Greenwood, T. A., N. J. Schork, et al. (2006). "Identification of additional variants within the human dopamine transporter gene provides further evidence for an association with bipolar disorder in two independent samples." Mol Psychiatry 11(2): 125-133, 115.
Disease Type	Bipolar Disorder
Study Design	family-based
Study Type	Mutation study and candidate-gene association study
Sample Size	120 trios
SNP/Region/Marker Size	22 SNPs
Predominant Ethnicity	Caucasian
Population	UCSD sample and NIMH sample

Detail Info

Sample Diagnosis	Structured Clinical Interview for DSM-III-R (SCID, UCSD sample) or the Diagnostic Interview for Genetic Studies (DIGS, NIMH sample)
Sample Status	Two independent samples of parent-proband trios, each consisting of a proband with bipolar disorder (bipolar I or bipolar II) and both parents, were assembled from different sources. In each case, one triad was chosen per family for a combined sample of 120 trios deriving from 120 separate families. When available, an affected sibling of the proband was also included as an adjunct to the triad to form a sibpair family.
Technique	Mutation screening, SNP genotyping and haplotype construction
Statistical Method	They used an extended version of the transmission/disequilibrium test (ETDT) that accommodates both biallelic and multiallele marker loci and provides for the analysis of parent-offspring data under two different models, allelewise and genotypewise. The empirical significance of each ETDT statistic was evaluated using the Monte Carlo approach (MCETDT) with 1000-10 000 replicates. They used the method of Nyholt to determine the effective number of independent SNPs and the appropriate correction factor for these analyses. Using this method they determined that there were 19 independent SNPs and a P-value of 0.003 needed to be reached to keep the type I error rate at 5%. Parental gametic haplotypes were used for calculations of LD between the 22 SNPs and the 3' VNTR.
Result Summary	Two of the eight new SNPs, one in intron 8 and one in intron 13, were found to be moderately associated with bipolar disorder, each in one of the two independent samples. Analysis of haplotypes comprised of all 22 SNPs in sliding windows of five adjacent SNPs revealed an association to the region near introns 7 and 8 in both samples (empirical P-values 0.002 and 0.001, respectively, for the same window). The haplotype block structure observed in the gene in their previous study was confirmed in this sample with greater resolution allowing for discrimination of a third haplotype block in the middle of the gene. Together, these data are consistent with the presence of multiple variants in DAT1 that convey susceptibility to bipolar disorder.

Haplotypes reported by this study for BD (count: 31)

Markers	Haplotype	Related Gene(s)/Region(s)	Statistical Values	Author Comments	Result Category
DAT1_I9+102 - DAT1_I9 - 21 - DAT1_I10+117 - DAT1_I11+2078 - DAT1_I12+268	T-G-G-C-G	LMO3	allelic P-value = 0.133, genotypic P-value = 0.117 in the UCSD sample, allelic P-value = 0.525, genotypic P-value = 0.374 in the NIMH sample, allelic P-value = 0.029, genotypic P-value = 0.022 in the linked sample; P-value = 0.015 in the linked sample		Positive
DAT1_I8+2086 - DAT1_E9+59 - DAT1_I9+102 - DAT1_I9 - 21 - DAT1_I10+117	G-G-G-A-G	LMO3	allelic P-value = 0.305, genotypic P-value = 0.052 in the UCSD sample, allelic P-value = 0.152, genotypic P-value = 0.156 in the NIMH sample, allelic P-value = 0.024, genotypic P-value = 0.055 in the linked sample; P-value = 0.037 in the linked sample		Positive
DAT1_I8+2086 - DAT1_E9+59 - DAT1_I9+102 - DAT1_I9 - 21 - DAT1_I10+117	A-G-T-G-G	LMO3	allelic P-value = 0.305, genotypic P-value = 0.052 in the UCSD sample, allelic P-value = 0.152, genotypic P-value = 0.156 in the NIMH sample, allelic P-value = 0.024, genotypic P-value = 0.055 in the linked sample; P-value = 0.013 in the linked sample		Positive
DAT1_I7+922 - DAT1_I8+2086 - DAT1_E9+59 - DAT1_I9+102 - DAT1_I9 - 21	C-G-G-G-A	LMO3	allelic P-value = 0.277, genotypic P-value = 0.04 in the UCSD sample, allelic P-value = 0.057, genotypic P-value = 0.003 in the NIMH sample, allelic P-value = 0.0001, genotypic P-value = 0.0003 in the linked sample; P-value = 0.014 in the linked sample	TDT analysis of the sliding window haplotypes in the NIMH sa...... TDT analysis of the sliding window haplotypes in the NIMH sample revealed empirical P-values<=0.003 for windows 5, 8, 9, and 10 under the genotypewise model. Analysis of the sliding windows in the Linked sample revealed empirical P-values<=0.003 for windows 5, 6, 8, 10, 12, 16, 17, and 19 under the genotypewise model. Similar results were obtained using the allelewise model with empirical P-values of<=0.003 observed for windows 8, 9, 10, 12, and 19. More...	Positive
DAT1_I9 - 21 - DAT1_I10+117 - DAT1_I11+2078 - DAT1_I12+268 - DAT1_I13 - 481	G-A-T-T-A	LMO3	allelic P-value = 0.058, genotypic P-value = 0.176 in the UCSD sample, allelic P-value = 0.63, genotypic P-value = 0.172 in the NIMH sample, allelic P-value = 0.039, genotypic P-value = 0.043 in the linked sample; P-value = in the linked sample		Positive
DAT1_I9 - 21 - DAT1_I10+117 - DAT1_I11+2078 - DAT1_I12+268 - DAT1_I13 - 481	A-G-C-G-A	LMO3	allelic P-value = 0.058, genotypic P-value = 0.176 in the UCSD sample, allelic P-value = 0.63, genotypic P-value = 0.172 in the NIMH sample, allelic P-value = 0.039, genotypic P-value = 0.043 in the linked sample; P-value = 0.037 in the linked sample		Positive
DAT1_I9 - 21 - DAT1_I10+117 - DAT1_I11+2078 - DAT1_I12+268 - DAT1_I13 - 481	G-G-C-G-G	LMO3	allelic P-value = 0.058, genotypic P-value = 0.176 in the UCSD sample, allelic P-value = 0.63, genotypic P-value = 0.172 in the NIMH sample, allelic P-value = 0.039, genotypic P-value = 0.043 in the linked sample; P-value = 0.002 in the linked sample		Positive
DAT1_I9+102 - DAT1_I9 - 21 - DAT1_I10+117 - DAT1_I11+2078 - DAT1_I12+268	G-A-G-C-G	LMO3	allelic P-value = 0.133, genotypic P-value = 0.117 in the UCSD sample, allelic P-value = 0.525, genotypic P-value = 0.374 in the NIMH sample, allelic P-value = 0.029, genotypic P-value = 0.022 in the linked sample; P-value = 0.037 in the linked sample		Positive
DAT1_P215 - DAT1_P+2459 - DAT1_I1+1036 - DAT1_I1+1735 - DAT1_I1+1859		LMO3	allelic P-value = 0.187, genotypic P-value = 0.227 in the UCSD sample, allelic P-value = 0.381, genotypic P-value = 0.408 in the NIMH sample, allelic P-value = 0.039, genotypic P-value = 0.045 in the linked sample		Positive
DAT1_P+2459 - DAT1_I1+1036 - DAT1_I1+1735 - DAT1_I1+1859 - DAT1_I1+1860		LMO3	allelic P-value = 0.261, genotypic P-value = 0.513 in the UCSD sample, allelic P-value = 0.236, genotypic P-value = 0.267 in the NIMH sample, allelic P-value = 0.047, genotypic P-value = 0.06 in the linked sample		Positive
DAT1_I10+117 - DAT1_I11+2078 - DAT1_I12+268 - DAT1_I13 - 481 - DAT1_I14+4217	G-C-G-A-A	LMO3	allelic P-value = 0.156, genotypic P-value = 0.209 in the UCSD sample, allelic P-value = 0.777, genotypic P-value = 0.551 in the NIMH sample, allelic P-value = 0.058, genotypic P-value = 0.06 in the linked sample; P-value = 0.025 in the linked sample		Positive
DAT1_I10+117 - DAT1_I11+2078 - DAT1_I12+268 - DAT1_I13 - 481 - DAT1_I14+4217	A-T-T-A-G	LMO3	allelic P-value = 0.156, genotypic P-value = 0.209 in the UCSD sample, allelic P-value = 0.777, genotypic P-value = 0.551 in the NIMH sample, allelic P-value = 0.058, genotypic P-value = 0.06 in the linked sample; P-value = in the linked sample		Positive
DAT1_I1+1860 - DAT1_I2+48 - DAT1_I5+448 - DAT1_I6+96 - DAT1_I7+922		LMO3	allelic P-value = 0.341, genotypic P-value = 0.438 in the UCSD sample, allelic P-value = 0.148, genotypic P-value = 0.492 in the NIMH sample, allelic P-value = 0.027, genotypic P-value = 0.001 in the linked sample	Analysis of the UCSD sample also revealed strong evidence of...... Analysis of the UCSD sample also revealed strong evidence of association for window 9, which spans the region between introns 6 and 9, with an empirical P-value < =0.003 under the genotypewise model. Analysis of the sliding windows in the Linked sample revealed empirical P-values<=0.003 for windows 5, 6, 8, 10, 12, 16, 17, and 19 under the genotypewise model. More...	Positive
DAT1_I10+117 - DAT1_I11+2078 - DAT1_I12+268 - DAT1_I13 - 481 - DAT1_I14+4217	G-C-G-G-A	LMO3	allelic P-value = 0.156, genotypic P-value = 0.209 in the UCSD sample, allelic P-value = 0.777, genotypic P-value = 0.551 in the NIMH sample, allelic P-value = 0.058, genotypic P-value = 0.06 in the linked sample; P-value = 0.005 in the linked sample		Positive
DAT1_I11+2078 - DAT1_I12+268 - DAT1_I13 - 481 - DAT1_I14+4217 - DAT1_E15+274	T-T-A-G-G	LMO3	allelic P-value = 0.362, genotypic P-value = 0.525 in the UCSD sample, allelic P-value = 0.562, genotypic P-value = 0.506 in the NIMH sample, allelic P-value = 0.034, genotypic P-value = 0.001 in the linked sample; P-value = in the linked sample	Analysis of the sliding windows in the Linked sample reveale...... Analysis of the sliding windows in the Linked sample revealed empirical P-values<=0.003 for windows 5, 6, 8, 10, 12, 16, 17, and 19 under the genotypewise model. More...	Positive
DAT1_I12+268 - DAT1_I13 - 481 - DAT1_I14+4217 - DAT1_E15+274 - DAT1_E15+352	G-G-A-G-G	LMO3	allelic P-value = 0.264, genotypic P-value = 0.029 in the UCSD sample, allelic P-value = 0.441, genotypic P-value = 0.141 in the NIMH sample, allelic P-value = 0.012, genotypic P-value = 0.0003 in the linked sample; P-value = 0.055 in the linked sample	Analysis of the sliding windows in the Linked sample reveale...... Analysis of the sliding windows in the Linked sample revealed empirical P-values<=0.003 for windows 5, 6, 8, 10, 12, 16, 17, and 19 under the genotypewise model. More...	Positive
DAT1_I11+2078 - DAT1_I12+268 - DAT1_I13 - 481 - DAT1_I14+4217 - DAT1_E15+274	C-G-G-A-G	LMO3	allelic P-value = 0.362, genotypic P-value = 0.525 in the UCSD sample, allelic P-value = 0.562, genotypic P-value = 0.506 in the NIMH sample, allelic P-value = 0.034, genotypic P-value = 0.001 in the linked sample; P-value = 0.008 in the linked sample	Analysis of the sliding windows in the Linked sample reveale...... Analysis of the sliding windows in the Linked sample revealed empirical P-values<=0.003 for windows 5, 6, 8, 10, 12, 16, 17, and 19 under the genotypewise model. More...	Positive
DAT1_I11+2078 - DAT1_I12+268 - DAT1_I13 - 481 - DAT1_I14+4217 - DAT1_E15+274	C-G-A-A-C	LMO3	allelic P-value = 0.362, genotypic P-value = 0.525 in the UCSD sample, allelic P-value = 0.562, genotypic P-value = 0.506 in the NIMH sample, allelic P-value = 0.034, genotypic P-value = 0.001 in the linked sample; P-value = 0.008 in the linked sample	Analysis of the sliding windows in the Linked sample reveale...... Analysis of the sliding windows in the Linked sample revealed empirical P-values<=0.003 for windows 5, 6, 8, 10, 12, 16, 17, and 19 under the genotypewise model. More...	Positive
DAT1_I13 - 481 - DAT1_I14+4217 - DAT1_E15+274 - DAT1_E15+352 - DAT1_E15VNTR		LMO3	allelic P-value = 0.182, genotypic P-value = 0.016 in the UCSD sample, allelic P-value = 0.134, genotypic P-value = 0.165 in the NIMH sample, allelic P-value = 0.011, genotypic P-value = 0.004 in the linked sample		Positive
DAT1_I14+4217 - DAT1_E15+274 - DAT1_E15+352 - DAT1_E15VNTR - DAT1_E15+1812	A-C-G-9-C	LMO3	allelic P-value = 0.109, genotypic P-value = 0.019 in the UCSD sample, allelic P-value = 0.372, genotypic P-value = 0.401 in the NIMH sample, allelic P-value = 0.0001, genotypic P-value = 0.0004 in the linked sample; P-value = 0.002 in the linked sample	Analysis of the sliding windows in the Linked sample reveale...... Analysis of the sliding windows in the Linked sample revealed empirical P-values<=0.003 for windows 5, 6, 8, 10, 12, 16, 17, and 19 under the genotypewise model. Similar results were obtained using the allelewise model with empirical P-values of<=0.003 observed for windows 8, 9, 10, 12, and 19. More...	Positive
DAT1_I12+268 - DAT1_I13 - 481 - DAT1_I14+4217 - DAT1_E15+274 - DAT1_E15+352	G-A-A-C-G	LMO3	allelic P-value = 0.264, genotypic P-value = 0.029 in the UCSD sample, allelic P-value = 0.441, genotypic P-value = 0.141 in the NIMH sample, allelic P-value = 0.012, genotypic P-value = 0.0003 in the linked sample; P-value = 0.025 in the linked sample	Analysis of the sliding windows in the Linked sample reveale...... Analysis of the sliding windows in the Linked sample revealed empirical P-values<=0.003 for windows 5, 6, 8, 10, 12, 16, 17, and 19 under the genotypewise model. More...	Positive
DAT1_I12+268 - DAT1_I13 - 481 - DAT1_I14+4217 - DAT1_E15+274 - DAT1_E15+352	T-A-G-G-G	LMO3	allelic P-value = 0.264, genotypic P-value = 0.029 in the UCSD sample, allelic P-value = 0.441, genotypic P-value = 0.141 in the NIMH sample, allelic P-value = 0.012, genotypic P-value = 0.0003 in the linked sample; P-value = in the linked sample	Analysis of the sliding windows in the Linked sample reveale...... Analysis of the sliding windows in the Linked sample revealed empirical P-values<=0.003 for windows 5, 6, 8, 10, 12, 16, 17, and 19 under the genotypewise model. More...	Positive
DAT1_I6+96 - DAT1_I7+922 - DAT1_I8+2086 - DAT1_E9+59 - DAT1_I9+102	G-C-A-G-T	LMO3	allelic P-value = 0.411, genotypic P-value = 0.002 in the UCSD sample, allelic P-value = 0.08, genotypic P-value = 0.001 in the NIMH sample, allelic P-value = 0.003, genotypic P-value = <0.00001 in the linked sample; P-value = 0.033 in the linked sample	TDT analysis of the sliding window haplotypes in the NIMH sa...... TDT analysis of the sliding window haplotypes in the NIMH sample revealed empirical P-values<=0.003 for windows 5, 8, 9, and 10 under the genotypewise model. Analysis of the UCSD sample also revealed strong evidence of association for window 9, which spans the region between introns 6 and 9, with an empirical P-value < =0.003 under the genotypewise model. The strongest evidence of association was observed for window 9 (P<0.00001), the window implicated in the analyses of the UCSD and NIMH samples independently. Similar results were obtained using the allelewise model with empirical P-values of<=0.003 observed for windows 8, 9, 10, 12, and 19. More...	Positive
DAT1_I7+922 - DAT1_I8+2086 - DAT1_E9+59 - DAT1_I9+102 - DAT1_I9 - 21	C-A-G-T-G	LMO3	allelic P-value = 0.277, genotypic P-value = 0.04 in the UCSD sample, allelic P-value = 0.057, genotypic P-value = 0.003 in the NIMH sample, allelic P-value = 0.0001, genotypic P-value = 0.0003 in the linked sample; P-value = 0.033 in the linked sample	TDT analysis of the sliding window haplotypes in the NIMH sa...... TDT analysis of the sliding window haplotypes in the NIMH sample revealed empirical P-values<=0.003 for windows 5, 8, 9, and 10 under the genotypewise model. Analysis of the sliding windows in the Linked sample revealed empirical P-values<=0.003 for windows 5, 6, 8, 10, 12, 16, 17, and 19 under the genotypewise model. Similar results were obtained using the allelewise model with empirical P-values of<=0.003 observed for windows 8, 9, 10, 12, and 19. More...	Positive
DAT1_I2+48 - DAT1_I5+448 - DAT1_I6+96 - DAT1_I7+922 - DAT1_I8+2086	A-G-G-C-A	LMO3	allelic P-value = 0.867, genotypic P-value = 0.766 in the UCSD sample, allelic P-value = 0.308, genotypic P-value = 0.04 in the NIMH sample, allelic P-value = 0.008, genotypic P-value = 0.029 in the linked sample; P-value = 0.052 in the linked sample		Positive
DAT1_I5+448 - DAT1_I6+96 - DAT1_I7+922 - DAT1_I8+2086 - DAT1_E9+59	G-G-C-A-G	LMO3	allelic P-value = 0.732, genotypic P-value = 0.286 in the UCSD sample, allelic P-value = 0.149, genotypic P-value = 0.0001 in the NIMH sample, allelic P-value = 0.003, genotypic P-value = 0.002 in the linked sample; P-value = 0.033 in the linked sample	TDT analysis of the sliding window haplotypes in the NIMH sa...... TDT analysis of the sliding window haplotypes in the NIMH sample revealed empirical P-values<=0.003 for windows 5, 8, 9, and 10 under the genotypewise model. Analysis of the sliding windows in the Linked sample revealed empirical P-values<=0.003 for windows 5, 6, 8, 10, 12, 16, 17, and 19 under the genotypewise model. Similar results were obtained using the allelewise model with empirical P-values of<=0.003 observed for windows 8, 9, 10, 12, and 19. More...	Positive
DAT1_I1+1735 - DAT1_I1+1859 - DAT1_I1+1860 - DAT1_I2+48 - DAT1_I5+448		LMO3	allelic P-value = 0.074, genotypic P-value = 0.102 in the UCSD sample, allelic P-value = 0.258, genotypic P-value = 0.005 in the NIMH sample, allelic P-value = 0.305, genotypic P-value = 0.025 in the linked sample		Positive
DAT1_I1+1859 - DAT1_I1+1860 - DAT1_I2+48 - DAT1_I5+448 - DAT1_I6+96		LMO3	allelic P-value = 0.109, genotypic P-value = 0.244 in the UCSD sample, allelic P-value = 0.048, genotypic P-value = 0.001 in the NIMH sample, allelic P-value = 0.12, genotypic P-value = 0.001 in the linked sample	TDT analysis of the sliding window haplotypes in the NIMH sa...... TDT analysis of the sliding window haplotypes in the NIMH sample revealed empirical P-values<=0.003 for windows 5, 8, 9, and 10 under the genotypewise model. Analysis of the sliding windows in the Linked sample revealed empirical P-values<=0.003 for windows 5, 6, 8, 10, 12, 16, 17, and 19 under the genotypewise model. More...	Positive
DAT1_E9+59 - DAT1_I9+102 - DAT1_I9 - 21 - DAT1_I10+117 - DAT1_I11+2078	G-G-A-G-C	LMO3	allelic P-value = 0.046, genotypic P-value = 0.02 in the UCSD sample, allelic P-value = 0.631, genotypic P-value = 0.574 in the NIMH sample, allelic P-value = 0.003, genotypic P-value = 0.003 in the linked sample; P-value = 0.037 in the linked sample	Analysis of the sliding windows in the Linked sample reveale...... Analysis of the sliding windows in the Linked sample revealed empirical P-values<=0.003 for windows 5, 6, 8, 10, 12, 16, 17, and 19 under the genotypewise model. Similar results were obtained using the allelewise model with empirical P-values of<=0.003 observed for windows 8, 9, 10, 12, and 19. More...	Positive
DAT1_I1+1036 - DAT1_I1+1735 - DAT1_I1+1859 - DAT1_I1+1860 - DAT1_I2+48		LMO3	allelic P-value = 0.154, genotypic P-value = 0.097 in the UCSD sample, allelic P-value = 0.096, genotypic P-value = 0.013 in the NIMH sample, allelic P-value = 0.115, genotypic P-value = 0.258 in the linked sample		Positive
DAT1_E9+59 - DAT1_I9+102 - DAT1_I9 - 21 - DAT1_I10+117 - DAT1_I11+2078	G-T-G-G-C	LMO3	allelic P-value = 0.046, genotypic P-value = 0.02 in the UCSD sample, allelic P-value = 0.631, genotypic P-value = 0.574 in the NIMH sample, allelic P-value = 0.003, genotypic P-value = 0.003 in the linked sample; P-value = 0.013 in the linked sample	Analysis of the sliding windows in the Linked sample reveale...... Analysis of the sliding windows in the Linked sample revealed empirical P-values<=0.003 for windows 5, 6, 8, 10, 12, 16, 17, and 19 under the genotypewise model. Similar results were obtained using the allelewise model with empirical P-values of<=0.003 observed for windows 8, 9, 10, 12, and 19. More...	Positive

Other variants reported by this study for BD (count: 8)

Variant Name	Related Gene	Type	Allele Change	Statistical Values	Author Comments	Result Category
SLC6A3 P+2459	SLC6A3	point mutation	A/T	TDT P-value = 0.49 in UCSD sample, TDT P-value = 1 in NIMH sample		Negative
SLC6A3 I14+4217	SLC6A3	point mutation	A/G	TDT P-value = 0.243 in UCSD sample, TDT P-value = 0.646 in NIMH sample		Negative
SLC6A3 I12+268	SLC6A3	point mutation	G/T	TDT P-value = 0.298 in UCSD sample, TDT P-value = 0.817 in NIMH sample		Negative
SLC6A3 I7+922	SLC6A3	point mutation	C/A	TDT P-value = 0.793 in UCSD sample, TDT P-value = 0.294 in NIMH sample		Negative
SLC6A3 I5+448	SLC6A3	point mutation	G/C	TDT P-value = 1 in UCSD sample, TDT P-value = 0.247 in NIMH sample		Negative
SLC6A3 I13+1457	SLC6A3	point mutation	G/A	TDT P-value = 0.024 in UCSD sample, TDT P-value = 0.645 in NIMH sample	The I13+1457 SNP was found to be moderately associated with ...... The I13+1457 SNP was found to be moderately associated with bipolar disorder in the UCSD sample (empirical P=0.024), the G allele was found to be significantly transmitted. More...	Positive
SLC6A3 I11+2478	SLC6A3	point mutation	C/T	TDT P-value = 0.298 in UCSD sample, TDT P-value = 0.646 in NIMH sample		Negative
SLC6A3 I8+2086	SLC6A3	point mutation	G/A	TDT P-value = 0.789 in UCSD sample, TDT P-value = 0.036 in NIMH sample	The I8+2086 SNP was found to be moderately associated with b...... The I8+2086 SNP was found to be moderately associated with bipolar disorder in the NIMH sample (empirical P=0.036), the G allele was found to be significantly transmitted. More...	Positive

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