The complexity of these processes is ignored by GWAS, which agnostically detects any genetic variant associated with outcome regardless of how that variant exerts an effect. Some associated variants directly influence our biology to alter risk. For example, variants in the ADH and ALDH genes impact an individual’s ability to metabolize alcohol, which protects against developing an alcohol use disorder (Edenberg, 2007). Other genes create cascades of influence via social pathways (Raffington et al., 2020). A high sensation-seeking adolescent may seek out bars and risk-taking peers, elevating risk for substance use disorder. Compounding risk via environmental pathways is likely one of the reasons why heritability estimates from twin studies are higher than the variance accounted for by genetic effects identified in GWAS. Our current genetic liability scores are also limited by the methods used to calculate them, which do not take into account gene-gene interactions or fully capture the range of variation that exists across our genomes.
