Gene × gene interaction in addiction has been evaluated using identified loci. However, the paucity of such loci identified so far would be insufficient for generalizations. Perhaps only by chance, the few gene × gene interaction studies performed so far in addiction are consistent with the genetic heterogeneity model and gene–gene additivity. In alcoholism, the protective effects of missense variants in ADH1B (Arg48) and ALDH2 (Lys487) are additive,16 which is perhaps not the expected result because these variants affect consecutive steps in the alcohol metabolic pathway and mediate propensity to alcohol-induced flushing. An additive effect on risk for alcoholism comorbid with other SUDs has been reported for functional loci mapping within the serotonin 3B receptor (HTR3B) and serotonin transporter (SLC6A4) genes.17,18 In nicotine addiction, two variants associated with smoking appear to act additively.19 These nicotine addiction risk variants map in the CHRNA5–CHRNA3–CHRNB4 nicotinic acetylcholine receptor subunit cluster and in the TTC12–ANKK1–DRD2 cluster, which includes DRD2, a dopamine receptor important in nicotine reward. In a community sample of 5000 Finns, the alleles most significantly associated with smoking were CHRNA5 Asp398Asn and
