Our discovery meta-analysis of PAU yielded 29 independent variants, of which 19 were novel, with 0.059 to 0.113 of the phenotypic variance explained in different cohorts or meta-analyses. The h2 in the Phase1-Phase2 MVP meta-analysis was 0.095 (se = 0.006), which was higher than MVP phase1: 0.056 (se = 0.004, in MVP phase1 where only the actual (as opposed to effective) sample size was used) [3]. The h2 of AD in PGC was 0.098 (se = 0.018), comparable to the reported liability-scale h2 (0.090, se = 0.019) [2]. Functional and heritability analyses consistently showed enrichments in brain regions and gene expression regulatory regions, providing biological insights into the etiology of PAU. Variation associated with gene expression in the brain is central to PAU risk, a conclusion that is also consistent with our previous GWASs in MVP of both alcohol consumption and AUD diagnosis [3]. The enrichments in regulatory regions point to specific brain tissues relevant to the causative genes; the specific interactions between 16 genes and 325 drugs may provide targets for the development of medications to manage PAU. Potential
