the same datasets examined presently, and also report positive genetic correlations between SZ and the inflammatory bowel disorders (Shi et al. 2017). The results of the HESS analysis of putative causal directionality indicate that the local genetic correlations are higher in loci occupied by SZ GW hits, as compared to the loci harboring hits for the paired autoimmune disorders (Shi et al. 2017). This pattern is consistent with the hypothesis that genetic liability toward SZ tends to impart a greater genetic risk for the corresponding paired disorder, rather than the opposite directional hypothesis. A related interpretation may be there is an unobserved intermediate phenotype (e.g., a shared biological pathways/mechanism) that is pleiotropic for both measured phenotypes, but more strongly influences the SZ phenotype. This pattern of findings could also be caused by the presence of a confounding factor (e.g., smoking, socioeconomic status) that portends risk for both phenotypes (Shi et al. 2017). Thus, we caution against over-interpretation of these findings. Extensions of Mendelian randomization methods to incorporate two GWAS samples using multi-allelic risk stratifying instruments will be better suited to address these hypotheses (Hartwig et al. 2016), especially as future GWASs provide well-powered genetic estimates of potentially relevant intermediate phenotypes
