POMC is conservative in its coding region, presumably because several important hormonal peptides are derived from the same POMC precursor. A single mutation in the POMC coding region may have a detrimental effect on the expression and biological functions of several of these peptides. A few diseases or conditions, such as severe early-onset obesity, adrenal insufficiency, and red hair pigmentation have been attributable to these rare loss-of-function mutations (21). Because variants in the POMC coding regions are rare and they may have a harmful impact on POMC expression or cleavage, it is unlikely that these rare coding variants contribute to the risk of common disorders such as drug or alcohol dependence. Instead, variation in non-coding regions may regulate POMC expression and contribute to the risk for these common disorders. Therefore, we chose five non-coding SNP markers for this study.
