Commentary on Holst et al: Genetically informative research can clarify mechanisms linking non-intact family structure and alcohol use disorder

Abstract

Genetically informative designs can illuminate the possible ‘outside-the-skin’ environmental exposures through which genetic risk for alcohol use disorder is transmitted in families.

In a large matched cohort study, Holst et al. [1] found that those who grew up in a non-intact family were more likely to develop an alcohol use disorder (AUD) than those who grew up in an intact family. Moreover, those with parental AUD were more likely to grow up in a non-intact family compared to those without parental AUD. These findings parallel previous reports that parental divorce or non-marital separation are associated with elevations in offspring risk for AUD [2] and related behaviors such as earlier age at first drink [3] and other forms of substance misuse [4]. These findings are also consistent with a robust literature linking AUD and marital and non-marital relationship instability [5].

Large-scale epidemiological findings like those reported in Holst et al. [1] are an important starting point for understanding the mechanisms through which family-of-origin experiences influence AUD risk. Accordingly, a critical next step is to delineate the degree to which associations between family structure and offspring risk for AUD is attributable to the direct ‘causal’ effects of non-intact family structure (i.e., a rearing environmental effect) and confounding background factors that contribute to both non-intact family structure and offspring AUD. Genetic factors represent one possible confounding background factor. Relationship instability, such as divorce, is genetically correlated with alcohol use disorder [6] and disinhibited personality traits more broadly [7]. This suggests that offspring exposed to a non-intact family structure also inherit genetic predispositions towards alcohol problems, an example of passive gene-environment correlation [8].

Historically, efforts to understand the pathways through which genes influence alcohol outcomes have focused on ‘within-the-skin’ mechanisms, such as how quickly alcohol is metabolized; perceptions and the taste of alcohol; and personality traits and characteristics such as constraint and impulsivity. Yet, the findings reported in Holst et al. [1] underscore the importance of delineating the possible ‘outside-the-skin’ environmental exposures through which genetic risk for alcohol problems is transmitted in families. The perspectives and tools of behavior genetics are useful for this purpose. For example, Figure 1 shows a twin-family model of AUD that specifies non-intact family structure as an observed familial environment. Such a model provides a direct comparison of two pathways of interest [9]. The first, shown in blue, captures the direct environmental (i.e., causal) effect of non-intact family structure on offspring AUD. The second, shown in yellow, captures an indirect pathway, whereby non-intact family structure reflects genetic risk for AUD. The results from this type of design can help clarify how genes and environmental exposures come together to confer risk for AUD.

Figure 1.

Twin-family model of alcohol use disorder (AUD) with non-intact family structure as a specified shared environment. Familial resemblance for AUD is attributable to four discernable sources: additive genetic (a) factors, shared environmental (c) factors, vertical cultural transmission [i.e., the environmental effect of growing up with an AUD-affected parent or parents (w), which is allowed to differ for mothers (w_m) and fathers (w_f)]; and assortative mating (u). The s_f and s_m paths denote direct phenotypic influences of paternal and maternal AUD on non-intact family structure. In turn, exposure to non-intact family structure (which is shared by both twins) contributes to the latent shared environmental factor C_T via the d path. Finally, the p path captures genotype-environment covariance (i.e., that exposure to high-risk environments covaries with inheriting a high-risk genotype). The ½ paths denote the degree of genetic sharing (i.e., 50% of segregating genes) between parents and offspring. The pathway highlighted in blue denotes the direct effect of non-intact family structure on offspring AUD. The pathway highlighted in yellow denotes an indirect genetic pathway, whereby non-intact family structure reflects, in part, genetic risk for AUD.

Molecular genetic designs that include genome-wide data from parents and children can also be used to explore the environmental pathways through which parental genotypes influence offspring alcohol outcomes. For example, parental genotypes for fathers and mothers can be partitioned into the variants that are shared with offspring (i.e., transmitted alleles) and those that are not shared with offspring (i.e., non-transmitted alleles) [10]. This information about allele sharing across generations can be used to disentangle the portion of each parent’s genetic loading for AUD that is directly transmitted to the offspring, and that which is indirectly transmitted to the offspring via a measured environmental indicator (e.g., non-intact family structure) in what others have coined as a ‘genetic nurturance’ pathway [10, 11]. Evidence for such genetic nurturance effects would be consistent with the interpretation that genetic influences on AUD operate, in part, through the environment.

In summary, Holst et al.’s [1] epidemiological findings provide strong evidence linking parental AUD, non-intact family structure, and offspring AUD. Genetically-informative thinking can further advance our understanding of the mechanisms driving these associations. Ultimately, a deeper understanding of these mechanisms may have downstream implications for the development of preventive interventions to disrupt the transmission of AUD in families.