Gene - gene interactions (G × G) of some magnitude appear likely, a priori, to make at least some contributions to addiction vulnerability. However, if there were large amounts of epistasis, G × G interactions in which specific alleles at one gene locus are required for expression of the effects of allelic variants at a second gene locus, segregation analysis data might provide uneven patterns of familiality. With large amounts of epistasis, second degree relatives (eg cousins) of addicts would be less likely to display specific combinations of G × G alleles than first degree relatives (eg sibs). Substance dependence rates would thus drop more precipitously between first and second degree relatives of addicts than they would if most risk alleles exerted largely independent effects on addiction vulnerability.
