Our results also suggest that newly discovered alternative exons, rather than constitutive exons, may represent targets for genetic variability which modifies OPRM1 receptor function. Since modifications of the function of the main receptor form may have dramatic consequences on fitness and may not reach significant frequency in the general population, genetic variations in alternative exons that are expressed at low levels or only under specific conditions may lead to more subtle phenotypic differences that underlie the observed variation in OPRM1-dependent phenotypes. Furthermore, our data and methodological approaches are of relevance to genome-wide association studies when SNPs associated with clinical phenotypes are located in genomic areas that are devoid of known structural genetic elements (65).
