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Large-scale studies

Data Summary

Published Variant
- SNP: 1391
- CNV: 398
- Others: 173
Published Gene: 359
Published Region: 128
Pathway by PBA: 8
Study: 361

Meta-analysis Report

Basic Info

Reference	Yang B, 2007 17440978
Citation	Yang B., Chan R. C., Jing J., Li T., Sham P. and Chen R. Y. (2007) "A meta-analysis of association studies between the 10-repeat allele of a VNTR polymorphism in the 3'-UTR of dopamine transporter gene and attention deficit hyperactivity disorder." Am J Med Genet B Neuropsychiatr Genet, 144B(4): 541-50.
Study Type	Candidate association study
Summary	This study aimed to conduct a meta-analysis of the association between the 10-repeat allele of a variable number tandem repeat (VNTR) polymorphism in the 3'-untranslated region (UTR) of the DAT1 gene and ADHD. They pooled up 18 published transmission disequilibrium test (TDT) studies between the 40-base pair VNTR polymorphism in the 3'-UTR of the DAT1 gene and ADHD. It included a total of 1,373 informative meioses, 7 haplotype-based haplotype relative risk (HHRR) studies, and 6 case-control-based association studies. There were statistically significant evidences for heterogeneity of the odds ratio in TDT and HHRR studies (P-value<0.10), but not in case-control studies. The results of random effects model showed small but significant association between ADHD and the DAT1 gene in TDT studies, but not in HHRR and case-control studies. The 10-repeat allele of a VNTR polymorphismin the 3'-UTR the DAT1 gene has a small but significant role in the genetic susceptibility of ADHD. These meta-analysis findings support the involvement of the dopamine system genes in ADHD liability variation. However, more work is required to further identify the functional allelic variants/mutations that are responsible for this association.

Detail Info

Samples	A computerized search was conducted (Medline, Embase, PsycINFO, BiosisPreview) using the following key words: 'DAT gene OR SLC6A3' and 'ADHD' from 1995 up to February 2006. Reference lists from identified articles and reviews were also used to find additional articles not indexed by Medline. In-press articles in psychiatric journals were also examined. Only those studies examining the 40-bp VNTR polymorphism in 3'-UTR of DAT1 gene were included in the current meta-analysis. Furthermore, studies had to meet all the following criteria: (1) used a family-based (transmission disequilibrium test (TDT) or haplotype-based haplotype relative risk (HHRR)) or case-control design; (2) were written in English or Chinese; (3) presented original data, and provided enough data to calculate an effect size; (4) were independent from other studies.
Statistic Method	Three meta-analyses were performede, two for the family-based studies (TDT and HHRR) and one for the case-control studies. Each study provided the two-by-two tables. The strength of association in these two-by-two tables were summarized by using the odds ratio (OR). For each meta-analysis, a Cochran Q test for heterogeneity was first performed. In addition, the I² test was used to attempt at quantifying any apparent inconsistency and was interpreted as approximately the proportion of total variation in study estimates that is due to heterogeneity rather than sampling error. An I² value greater than 50% may be considered substantial heterogeneity and not appropriate to perform a meta-analysis. A fixed effect model was chosen given the lack of heterogeneity, otherwise a random effect model was chosen under the condition that the value of I²<50%. Pooled calculations of odds ratios were obtained and compared using test statistic Z and 95% confidence intervals (CI). Publication bias was assessed by funnel plot, Begg and Mazumdar's rank correlation test and linear regression analysis [Egger et al., 1997; Vilar et al., 1997]. The meta-analysis was conducted by Comprehensive Meta-analysis Version 2 [Borenstein et al., 2005].
Basic Result	The application of foregoing criteria yielded 30 studies, and 25 studies were included in current meta-analysis (18 for TDT, 7 for HHRR, and 6 for case-control studies). For TDT studies, there was statistically significant evidence for heterogeneity of the OR among these studies and the random effect model was chosen. The studies distribution of the funnel plot was substantially symmetrical about the combined effect size. The Egger's regression intercept and Begg's rank correlation were not significant, suggesting no publication bias for TDT studies. TDT studies were further grouped according to the ethnic origin, and the results showed no significantly preferential transmission of the 10-repeat allele of the DAT gene either in Asian children with ADHD or in western children. For seven HHRR studies, there was statistically significant evidence for heterogeneity of the OR and the random effect model was chosen. The combined estimate was not statistically significant. For six case-control studies, there was no statistically significant evidence for heterogeneity of the OR and the fixed effect model was chosen. The combined estimatewas not statistically significant.

Genes reported by this study: 1