Candidate genes involved in neural plasticity and the risk for attention-deficit hyperactivity disorder: a meta-analysis of 8 common variants

Abstract

Background: Attention-deficit hyperactivity disorder (ADHD) is an important psychiatric condition in terms of its prevalence and impact on quality of life. It has one of the highest heritabilities found in psychiatric disorders. A number of association studies exploring several candidate genes in different populations around the world have been carried out. The objective of the present study was to carry out a meta-analysis for 8 common variants located in 5 top candidate genes for ADHD (BDNF, HTR1B, SLC6A2, SLC6A4 and SNAP25); these genes are known to be involved in synaptic transmission and plasticity.

Methods: We performed a search for published genetic association studies that analyzed the candidate polymorphisms in different populations, and we applied state-of-the-art meta-analytical procedures to obtain pooled odds ratios (ORs) and to evaluate potential basis of heterogeneity. We included 75 genetic association studies in these meta-analyses.

Results: A major part of the previously postulated associations were nonconsistent in the pooled odds ratios. We observed a weak significant association with a single nucleotide polymorphism (SNP) located in the 3' UTR region of the SNAP25 gene (rs3746544, T allele, OR 1.15, 95% confidence interval 1.01-1.31, p = 0.028, I(2) = 0%). In addition to the low coverage of genetic variability given by these variants, phenotypic heterogeneity between samples (ADHD subtypes, comorbidities) and genetic background may explain these differences.

Limitations: Limitations of our study include the retrospective nature of our meta-analysis with the incorporation of study-level data from published articles.

Conclusion: To our knowledge, the present study is the largest meta-analysis carried out for ADHD genetics; previously proposed cumulative associations with common polymorphisms in SLC6A4 and HTR1B genes were not supported. We identified a weak consistent association with a common SNP in the SNAP25 gene, a molecule that is known to be central for synaptic transmission and plasticity mechanisms.

Fig. 1

Pooled odds ratios for different genotype/phenotype correlations that were nonsignificant in our meta-analysis.

Fig. 2

Odds ratios for the A allele of the rs3746544 polymorphism in the SNAP25 gene of individuals with attention-deficit hyperactivity disorder.

Fig. 3

Haplotype block structure of the SNAP25 gene region (around 130 kb) in the Caucasian population (Northern European descent, living in Utah) from HapMap release 23a. The solid line indicates the position of the SNAP25 gene, the vertical line shows the position of the 2 studied single nucleotide polymorphisms in the 3′ UTR region and the broken line indicates the location of haplotype blocks.