There are several alternative explanations for the GCTA results. First, for rare variants it may not always be true that global ancestry measures (such as PCs) can account for genomically-local population stratification. That is, two individuals may have similar overall ancestry but possess some haplotypes from diverse ancestries(47, 48), which may artificially inflate GCTA estimates from local ancestry around some exons. If that confound existed in this data we might expect population stratification to inflate all GCTA estimates from rare variants, which was not observed. Second, the illicit drug phenotype has the strongest mother-father correlation (.56; Table S2 in Supplement 1), raising the possibility of confounding due to assortative mating. Note, however, that substantial mother-father correlations exist for other phenotypes (notably .40 for alcohol consumption) but these showed no GCTA effect for rare nonsynonymous variants. Third, we speculate that rare nonsynonymous variation may contribute strongly to more severe phenotypes. It appears, for example, that the strongest nonsynonymous GCTA results were for illicit drugs, behavioral disinhibition, and alcohol dependence, and lesser effects observed for nicotine dependence and alcohol consumption, the latter two considered to be relatively more normative behaviors. Future work may consider this possibility.
