Rs3778150 has varying linkage disequilibrium patterns with six other SNPs located in OPRM1 intron 1, which were previously reported for their associations with heroin/opioid addiction phenotypes (12, 19) (Figures S8 and S9). The intron 1 location of these SNPs is designated according to the longest principal isoform for OPRM1 (58). Levran et al. reported rs510769 and rs3778151 as having nominally significant associations (12), whereas Zhang et al. reported rs524731 as having a nominally significant association and rs511435, rs3823010, and rs495491 as having statistically significant associations that surpassed multiple testing correction (19). Nelson et al. (10), using a subset of the Australian replication cohort reported here, tested three of these SNPs (rs510769, rs3778151, and rs495491) and found a nominal association for rs3778151. To our knowledge, the six prior SNPs have not been tested elsewhere for independent replication. In a meta-analysis across all of our heroin addiction case-control cohorts, all six of the previously reported SNPs or their proxies were significantly replicated at P<0.01 (overall α=0.05 corrected for 5 independent tests). Their meta-analysis P values ranged from 7.0×10−4 for rs510769 to 2.7×10−8 for rs3823010 (Table 3). Similarly to rs3778150, the minor alleles were all associated with increased heroin addiction risk.
