Mutational analysis of the nicotinic acetylcholine receptor alpha 4 subunit gene in attention deficit|[sol]|hyperactivity disorder: evidence for association of an intronic polymorphism with attention problems

doi:doi:10.1038/sj.mp.4001257

Molecular Psychiatry (2003) 8, 103–108. doi:10.1038/sj.mp.4001257

Mutational analysis of the nicotinic acetylcholine receptor alpha 4 subunit gene in attention deficit/hyperactivity disorder: evidence for association of an intronic polymorphism with attention problems

R D Todd¹, E A Lobos¹, L-W Sun¹ and R J Neuman¹

¹Departments of Psychiatry and Genetics, School of Medicine, Washington University, 660 South Euclid Avenue, Box 8134, St Louis, MO 63110, USA

Correspondence: RD Todd, PhD, MD, Departments of Psychiatry and Genetics, School of Medicine, Washington University, 660 South Euclid Avenue, Box 8134, St Louis, MO 63110, USA. E-mail: toddr@psychiatry.wustl.edu

Received 22 March 2002; Revised 23 May 2002; Accepted 24 May 2002.

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Abstract

Recent studies suggest the presence of genetically distinct subtypes of attention deficit/hyperactivity disorder (ADHD) and that attention problems can be treated with receptor subtype selective nicotine agonists. In this study, individuals with two independent familial subtypes of ADHD defined by latent class analysis were systematically screened for sequence variations in the coding regions and intron/exon junctions of the nicotinic acetylcholine receptor alpha 4 subunit gene (CHRNA4). Common polymorphisms were used for transmission disequilibrium test (TDT) analyses. A significant association was found for a 5' intron 2 single nucleotide polymorphism and severe inattention problems (P=0.007, effect size=4, 95% CI 1.3–14.1). The location of the polymorphism is compatible with it affecting pre-mRNA stability or splicing.