Herein, we apply new multivariate methods [15, 16] to tease apart specific versus shared pathways by which genetic loci are associated with problematic alcohol use and demonstrate how moving beyond GWAS that focus on a single outcome may help us better understand the manner in which risk for psychiatric problems unfolds. Specifically, we expand upon a recent multivariate GWAS of externalizing [17] to differentiate the genetic variants that impact problematic alcohol use through this broad externalizing liability (EXT), from variants that are specific to problematic alcohol use (ALCP-specific). We compare our multivariate results to those from a previously published meta-analysis of GWAS of problematic alcohol use [18, 19], which, by definition, combined all genetic pathways that impact risk for alcohol problems (ALCP-total). Across these three GWAS results, we compare: (1) the genetic correlations with other relevant phenotypes; (2) the biological annotations of each genetic signal, and (3) the associations of polygenic scores (PGS) for each component with a variety of substance use phenotypes. Our analyses aim to better characterize the genetic pathways associated with problematic alcohol use and illustrate the use of multivariate genomic analyses to differentiate patterns of risk.
