Another interesting finding in our study is the sex effect. In our analyses, sex was considered a modifier covariate. In these analyses, both main effect and sex effect were estimated simultaneously in the regression model. For both SI and ND phenotypes tested in this study, sex has a significant modifying effect. A similar effect was observed by Zuo et al.31 In the tables reported in that study, sex was used as a covariate and its effect was statistically significant for all phenotypes studied. This is consistent with our observation. This finding raises a possibility that the failure to find evidence of association in some previous studies may be due to heterogeneity in the sexes. This finding may have a molecular basis. There is an estrogen response element in the promoter region of the CNR1 gene63 (Figure 1A). There is also evidence that estrogen modulates the expression of the CNR1 gene.64
