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 (e.g., brain structure morphometry, circulating immune cell phenotypes, and serum cytokine levels (Ahola-Olli et al. 2017; Hibar et al. 2015; Astle et al. 2016). Other limitations of the HESS method, including assumptions related to sample overlap and ancestry stratification, are discussed extensively by the method’s developers (Shi et al. 2017).
