A previous genome-wide screen for copy number variations (CNVs) in attention deficit/hyperactivity disorder (ADHD) revealed a de novo chromosome 3q26.1 deletion in one of the patients. Candidate genes at this locus include the acetylcholine-metabolizing butyrylcholinesterase (BCHE) expressing gene (OMIM #177400), which is of particular interest. The present study investigates the hypothesis that the heterozygous deletion of the BCHE gene is associated with adult ADHD (aADHD). Ina first step, we screened 348 aADHD patients and 352 controls for stretches of loss of heterozygosity (LOH) across the entire BCHE gene to screen for the deletion. Our second aim was to clarify whether BCHE single nucleotide polymorphisms (SNPs) themselves influence the risk towards ADHD. Putative functional consequences of associated SNPs as well as their un-typed proxies were predicted by several bioinformatic tools. 96 individuals displayed entirely homozygous genotype reads in all 12 examined SNPs, making them possible candidates to harbor a heterozygous BCHE deletion. DNA from these 96 probands was further analyzed by real-time PCR using a BCHE-specific CNV assay. However, no deletion was found. Of the 12 tag SNPs that passed inclusion criteria, rs4680612 and rs829508 were significantly associated with aADHD, as their minor alleles occurred more often in cases than in controls (p = 0.018 and p = 0.039, respectively). The risk variant rs4680612 is located in the transcriptional control region of the gene and predicted to disrupt a binding site for MYT-1, which has previously been associated with mental disorders. However, when examining a second independent adult ADHD sample of 353 cases, the association did not replicate. When looking up the deletion in three genome-wide screens for CNV in ADHD and combining it with the present study, it became apparent that 3 from a total of 1030 ADHD patients, but none of 5787 controls, featured a deletion of the BCHE promoter region including rs4680612 (p = 0.00004). Taken together, there are several lines of evidence suggesting a potential involvement of BCHE in the etiopathology of ADHD, as a rare hemizygous deletion as well as a common SNP in the same region are associated with disease, although with different penetrance. Both variations result in the disruption of the binding site of the transcription factor MYT-1 suggesting epistatic effects of BCHE and MYT-1 in the pathogenesis of ADHD. As we were not able to replicate the SNP association, our findings should be considered preliminary and call for larger studies in extended phenotypes.
- Copy number variation