Gender-specific molecular heterosis and association studies: dopamine D2 receptor gene and smoking.

If the concept of the gender-specific molecular heterosis is not considered and tested, incorrect conclusions would easily be drawn in association studies. Therein, heterosis and its gender effect in the genetic effect of DRD2 gene for smoking were examined with 187 healthy Korean individuals. The male smokers showed a higher A1 allele frequency (P = 0.016) and prevalence (P = 0.049) than those of the male non-smokers, and the female smokers showed a lower frequency of heterozygotes (P = 0.018) than the female non-smokers. However, the association of DRD2 gene with smoking found in each gender disappeared when both males and females were considered as one group because of the opposite genetic effect of DRD2 gene for smoking: (1) while 75% of heterozygotes males were smokers, only 22% of female heterozygotes were; (2) males showed an excess of heterozygotes and the deviation from Hardy-Weinberg expectations in smokers, while these were true in the female non-smokers; and (3) in non-smokers, females were different from the males exhibiting a significantly higher prevalence (P = 0.005) and frequency (P = 0.015) of A1 allele, and significantly different genotype (P = 0.017) distribution, and higher frequency of heterozygotes (P = 0.055). Meanwhile, in smokers, males showed higher frequency of heterozygotes (P = 0.019) compared to females. The results indicate that gender-specific molecular heterosis at DRD2 gene for smoking is also applicable in healthy individuals as well as schizophrenics. Moreover, this concept has general applicability to other candidate genes and biological phenotypes. Copyright 2003 Wiley-Liss, Inc.