Although rs509208 is approximately 450 kb upstream (5′) of BCHE and not within conventional gene boundaries, the next closest genes (ZBBX, SERPINI2) are nearly 1 Mb in the opposite direction (Supplementary Figure 3). Of note, SNPs as far as 800 kb upstream of BCHE have previously demonstrated genome-wide significant association with serum butyrylcholinesterase activity in a population sample of nearly 9000 individuals from several Australian twin and family studies.41 These SNPs included a peak signal 250 kb from the gene (rs2034445) and other non-independent signals from SNPs in high linkage disequilibrium with rs509208 (e.g., rs6443374 and rs13314077), suggesting that variants upstream of the gene may exert regulatory effects on BCHE expression with consequences to the activity of its encoded enzyme. Converging evidence in genomics indicates that this kind of regulation is quite common and may involve mechanisms influencing chromatin structure, transcription factor binding, and splicing component recognition sequences, among others.42 Molecular characterization in brain tissue and cell cultures will be important to determine the complex functional architecture of the BCHE locus and the genes and other DNA elements surrounding it.
