There are 44 markers in MANEA with appreciable frequency in 1 or more populations (http://www.ncbi.nlm.nih.gov/SNP), but none are known to effect structural changes in the translated protein. Remarkably, 34 of these SNPs have minor allele frequencies of 0.24 or greater in both EAs and AAs. This excess of high-frequency polymorphisms suggests that balancing selection is occurring in this region.46 The most robust evidence for association in the collective data sets in this study was obtained with rs9387522, which is located in the 3′ UTR. The 3′ UTR is the major site of gene regulation by microRNA binding.47 Polymorphic target sites for microRNA binding in the 3′ UTRs of SLITRK1, FGF20, and HTR1B have been identified as leading to increased risk of Tourette syndrome,48 Parkinson disease,49 and aggressive human behaviors,50 respectively. The possibility that MANEA 3′ UTR SNPs, including rs987522, may influence risk of CD or CIP could be investigated by microRNA studies in brains of rodents exposed to cocaine or constructs transfected into cell lines to demonstrate effects on gene expression.
