It is important to recognize some of the limitations of these strategies at the outset. Although most common putatively functional SNPs are known, rarer SNPs may have large phenotypic effects, and there are many such variants yet to be discovered. Not all functional SNPs are easily recognized as such. SNPs vary by population, and populations differ in the extent to which common genetic variation has been identified. The same population variation is reflected in differences in haplotype structure. Finally, haplotype reconstruction is almost always accomplished via computer algorithms,

and the results are estimated. Inhibitors,research,lifescience,medical With these limitations in mind, we discuss several examples of genetic associations with DD phenotypes, focusing on interesting physiological candidates and on replicated findings. Association of variants that map

at or near the D2 dopamine receptor (DRD2 locus) with drug or alcohol dependence was proposed many years ago Inhibitors,research,lifescience,medical and has been widely debated. We identified a “suggestive” linkage peak for ND at the region of chromosome 11 that includes the NCAM1-TTC12-ANKK1-DRD2 gene cluster.23 The inconsistent results with Inhibitors,research,lifescience,medical DRD2 may be attributable to an indirect effect – observed association could actually be mediated through variation at a nearby locus in linkage disequilibrium with DRD2. To test this hypothesis, we genotyped 43 SNP markers in a region including DRD2 and the three adjacent genes, in an SD linkage sample of >1600 subjects. We found Inhibitors,research,lifescience,medical very strong evidence of association of multiple SNPs at TTC12 and ANKK1 in two different populations, EAs and AAs (minimal P=0.0007 in AAs and minimal P=0.00009 in EAs), and highly significant association of a single haplotype (set of markers) spanning TTC12 and ANKK1 to ND in the pooled sample (P=0. 0000001). Thus, a risk locus for ND maps to a region that spans TTC12

and ANKK1 . The exact localization of the risk haplotype depends on the disease definition, and whether and which co-occurring diagnoses are present in the study Inhibitors,research,lifescience,medical sample.24 These results support the hypothesis that the DRD2 findings could be attributable to variants in nearby loci. Such variants could reflect either functional variation that affect and those loci (and not DRD2), or relatively distant regulatory regions important for DRD2 function. The ANKK1 finding in ND has been replicated.25 Another set of risk loci that are of interest in learn more relation to the risk of drug dependence are those encoding proteins that regulate or mediate opioidergic function. All of the opioid receptor genes have been reported to be associated with substance dependence liability. A functional polymorphism in OPRM1 (Asn40 Asp), which encodes the mu-opioid receptor, has been the most extensively studied in this regard, though the association is controversial.

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