One third of the QSNP discoveries from the correlated factors model appeared to operate through pathways unique to ALCH. This motivated an examination of the causal effects of ALCH on the disorders and factors using a form of multi-trait Mendelian randomization (MR) within the Genomic SEM framework. We ran two types of MR models: one using the QSNP variant in the ADH1B gene as a single instrumental variable for ALCH, and a second multi-variant MR approach using eight loci identified from an independent ALCH discovery GWAS as instrumental variables39. The multi-variant approach allowed for additional effects of the loci on other disorders or factors where appropriate (Supplementary Note). Results from the ADH1B and multi-variant Genomic SEM-MR approaches tentatively supported a causal effect of ALCH on MDD and BIP (Supplementary Note and Supplementary Figs. 39 and 40). In these models, ALCH loadings on factors 2-4 were no longer significant, but the remaining disorders continued to load significantly on their respective factors. Multiple causation by ALCH is thus insufficient to fully account for widespread genetic overlap observed across disorders.
