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

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

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J Psychiatry Neurosci 2009; 34(5): 361-366

Diego A. Forero, MD; Gonzalo H. Arboleda, MD, PhD; Rafael Vasquez, MD; Humberto Arboleda, MD, MSc

Forero (at the time of writing), G.H. Arboleda, Vasquez, H. Arboleda — Neurosciences Research Group and MSc Program in Neurosciences, School of Medicine and Institute of Genetics; G.H. Arboleda — Department of Pathology; Vasquez — Department of Psychiatry; H. Arboleda — Department of Pediatrics, School of Medicine, Universidad Nacional de Colombia, Bogotá, Colombia; Forero (current) — Applied Molecular Genomics Group, VIB Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium

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, I2 = 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

Conclusions: To our knowledge, the present study is the largest metaanalysis 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


Submitted Oct. 7, 2008; Revised Mar. 27, May 26, 2009; Accepted May 27, 2009.

Acknowledgements: This work was supported by grants from the Fundación Banco de la Republica and DIB-UNAL. We thank the researchers who answered the requests about allele frequencies not available in the original articles.

Competing interests: None declared.

Contributors: Drs. Forero, Vasquez and H. Arboleda designed the study. Drs. Forero and Vasquez acquired the data, which Drs. Forero, G. Arboleda and H. Arboleda analyzed. Drs. Forero, G. Arboleda and H. Arboleda wrote the article, which Dr. Vasquez reviewed. All authors approved the final version for publication.

Correspondence to: Drs. H. Arboleda and D.A. Forero, Instituto de Gentética, Universidad Nacional de Colombia, Ciudad Universitaria, Bogotá, Colombia; fax 57 1 3685532; harboledag@unal.edu.co, daforerog@unal.edu.co