Association study of the nicotinic acetylcholine receptor alpha4 subunit gene, CHRNA4, in attention-deficit hyperactivity disorder

Abstract

Attention-deficit hyperactivity disorder (ADHD) is a common childhood-onset psychiatric condition with a strong genetic component. Evidence from pharmacological, clinical and animal studies has suggested that the nicotinic system could be involved in the disorder. Previous studies have implicated the nicotinic acetylcholine receptor alpha4 subunit gene, CHRNA4, in ADHD. Particularly, a polymorphism in the exon 2-intron 2 junction of CHRNA4 has been associated with severe inattention defined by latent class analysis. In the current study, we used the transmission disequilibrium test (TDT) to investigate four polymorphisms encompassing this region of CHRNA4 for association with ADHD in a sample of 264 nuclear families from Toronto. No significant evidence of biased transmission was observed for any of the marker alleles for ADHD defined as a categorical trait (all subtypes included), although one haplotype showed marginal evidence of under-transmission. No association was found with the ADHD predominantly inattentive subtype or with symptom dimension scores of inattention. On the contrary, nominally significant evidence of association of individual markers was obtained for the ADHD combined subtype and with teacher-rated hyperactivity-impulsivity scores, with the same haplotype being under-transmitted. Based on our results and others, CHRNA4 may be involved in ADHD; however, its role in ADHD symptomatology remains to be clarified.

Figure 1. Schematic representation of the CHRNA4 gene and association results reported for ADHD

Lower panel shows the structure of the CHRNA4 gene. The six exons of the gene are represented by boxes, with black boxes for coding sequences and empty boxes for untranslated regions. Association findings are shown in the top panel with positive (+) and negative (−) results for the different studies. Of note, the Todd et al. findings presented here are not corrected for multiple tests and only rs6090384 remains significant after correction in that study. Markers involved in haplotypes showing evidence of association are shaded. Haplotypes from this study and Todd et al. were under-transmitted. The haplotype reported by Brookes et al. has a very low frequency (17 transmissions). Twelve other single nucleotide polymorphisms (SNPs), from intron 2 to 3′ untranslated region, have been tested by Brookes et al. (not shown here) and were all negative.