The third example is a high-impact nonsense variant—a loss of stop codon in the D allele of Ahr. Ahr is an important transcription factor that modulates P450 gene expression in response to xenobiotics such as dioxin14. Although the effects of this SNP on protein length are already known22 (Fig. 5a), the pleiotropic consequences of this mutation have not been evaluated. This variant is significantly associated with mRNA (q=1.7 × 10−3; Fig. 5b) and protein abundance of Ahr in liver (q=0.0085; Fig. 5c). Classic PheWAS linked this variant to the frequency with which cleft palates is induced by 2,3,7,8-tetrachlorodibenzofuran injection (GN ID 10714; q=3.2 × 10−3) (Fig. 5c). Ahr variants have also been definitively linked to differences in locomotor activity17. Consistent with the results of the BXD PheWAS, a matched PheWAS in humans using BioVU links rs2066853 in AHR with cleft palate (P=0.012; logistic regression; Fig. 5d).
