The three SNPs (rs877138, rs4938013, and rs7130431) for which we observed significant association are located in a region spanning ANKK1 and TTC12. High LD between SNPs in these genes prevents determination, without additional sequencing, of the gene primarily contributing to liability. For example, rs877138 is located in the 5′ flanking region 2005 base pairs upstream from the first exon of ANKK1 but is in complete LD with several intronic TTC12 SNPs. Both rs4938013, an exonic ANKK1 SNP resulting in a synonymous substitution, and rs7130431, an intronic TTC12 SNP, are in high LD with rs877138 (respective r2 values of .898 and .912), consistent with a single association signal. Although nominally significant association extends to the Taq1A polymorphism (rs1800497) and DRD2 SNPs, analyses that controlled for allelic dose of rs877138 found no evidence of an independent signal involving this functional polymorphism or any other ANKK1, TTC12, or DRD2 SNP. Since prior studies6,11,49–53 that reported an association of rs1800497 with opioid dependence genotyped few or no additional ANKK1 SNPs, the signal they observed may have resulted from similar LD. The only association not
