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Is there a role for rare variants in DRD4 gene in the susceptibility for ADHD? Searching for an effect of allelic heterogeneity

Molecular Psychiatry volume 17, pages 520–526 (2012)Cite this article

Abstract

Although several studies have demonstrated an association between the 7-repeat (7R) allele in the 48-bp variable number of tandem repeats (VNTRs) in the exon 3 at dopamine receptor D4 (DRD4) gene and attention-deficit/hyperactivity disorder (ADHD), others failed to replicate this finding. In this study, a total of 786 individuals with ADHD were genotyped for DRD4 exon 3 VNTR. All 7R homozygous subjects were selected for VNTR re-sequencing. Subjects homozygous for the 4R allele were selected paired by age, ancestry and disorder subtypes in order to have a sample as homogeneous as possible with 7R/7R individuals. Using these criteria, 103 individuals (66 with ADHD and 37 control individuals) were further investigated. An excess of rare variants were observed in the 7R alleles of ADHD patient when compared with controls (P=0.031). This difference was not observed in 4R allele. Furthermore, nucleotide changes that predict synonymous and non-synonymous substitutions were more common in the 7R sample (P=0.008 for total substitutions and P=0.043 for non-synonymous substitutions). In silico prediction of structural/functional alterations caused by these variants have also been observed. Our findings suggest that not only repeat length but also DNA sequence should be assessed to better understand the role of DRD4 exon 3 VNTR in ADHD genetic susceptibility.

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Acknowledgements

We thank Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil), Institutos do Milênio (CNPq), PRONEX, and Fundação de Amparo a Pesquisa do Estado do Rio Grande do Sul e de São Paulo (FAPERGS e FAPESP) for financial support.

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Authors and Affiliations

  1. Departament of Genetics, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    L Tovo-Rodrigues, T Roman, F Z C Marques, V Contini, C H D Bau & M H Hutz

  2. Child and Adolescent Psychiatric Division, Hospital de Clinicas de Porto Alegre, Federal University of Rio Grande do Sul, Brazil, Instituto de Psiquiatria do Desenvolvimento para a Infância e Adolescência, Porto Alegre, RS, Brazil

    L A Rohde, M Schmitz, G Polanczyk & C Zeni

  3. Adult ADHD Outpatient Clinic, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil

    E H Grevet, P Belmonte-de-Abreu & C H D Bau

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  1. L Tovo-Rodrigues
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  2. L A Rohde
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Correspondence to M H Hutz.

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Competing interests

Dr Rohde was on the speakers’ bureau and/or acted as consultant for Eli-Lilly, Janssen-Cilag and Novartis in the last 3 years. Currently, his only industry related activity is taking part in the advisory board/speakers bureau for Eli-Lilly, Novartis and Shire (<U$ 10 000 per year and reflecting <5% of his gross income per year). The ADHD and Juvenile Bipolar Disorder Outpatient Programs chaired by him received unrestricted educational and research support from the following pharmaceutical companies in the last 3 years: Abbott, Bristol-Myers Squibb, Eli-Lilly, Janssen-Cilag and Novartis.

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Tovo-Rodrigues, L., Rohde, L., Roman, T. et al. Is there a role for rare variants in DRD4 gene in the susceptibility for ADHD? Searching for an effect of allelic heterogeneity. Mol Psychiatry 17, 520–526 (2012). https://doi.org/10.1038/mp.2011.12

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