Genetic risk by experience interaction for childhood internalizing problems: converging evidence across multiple methods.

Depression has been designated as the top cause of disability in the world (World Health Organization, 2001). Given that childhood internalizing problems often precede the onset of depression in adolescence and adulthood (Costello, Foley, & Angold, 2006), understanding the etiology of child internalizing problems has become a top priority (Costello et al., 2002). Heritability estimates ranging from 23–62% (Rice & Thapar, 2009) indicate that both genetic and experiential factors play important roles in child internalizing problems. Both historically (Erlenmeyer-Kimling, 1972) and more recently (Rutter, Moffitt, & Caspi, 2006), scientists have promoted the notion of genetic risk by experience interaction (GxE) as an approach to understanding the etiology of complex psychological patterns, such as childhood internalizing problems. In very basic terms, the GxE approach suggests that the influence of genes on behavior may differ depending on the types of experiences to which the individual has been exposed. Conversely, GxE also indicates that the influence of experience on behavior may differ depending on the genotype of the individual. As attractive as the idea of GxE is for non-deterministic views of etiology, the paradigm comes bundled with conceptual and statistical difficulties. On the genetic side, it is currently impossible to quantify the full genetic effect in a specific way. We know the identity of only a few genes associated with any given complex human phenotype and thus can only test for interaction of a fraction of the “genotypic risk” with experience. Results using these already-identified genes (the “low-hanging fruit”) may prove non-representative. If willing to sacrifice the specificity that measured genes provide, we can adopt the traditional practice of genetic epidemiology and infer genotypic risk from the phenotypes of genetic relatives. However, this genetic risk assessment is indirect and imprecise. On the environmental side, the chief difficulty lies in conceptualizing risk factors that are fully independent of genetic influence, since many risk factors traditionally thought to be experiential (e.g., socioeconomic status) are heritable to some degree (Plomin & Bergeman, 1991). Given this, genotype by environment correlations and interactions might be as ubiquitous in the construction of human psychological environments as they are thought to be in the development of human psychological phenotypes. From a strictly statistical perspective, at least three classes of problems plague the field. First is the possibility of selective reporting of positive findings, a problem that looms large with the recent feasibility of testing thousands of genes. In the present study, we emphasize interactions that provide converging evidence across two methods. Second is the well-known scaling problem: observed ordinal interactions can often be eliminated by scale transformations (Cohen, Cohen, West, & Aiken, 2003). The scaling problem is difficult to negotiate when interactions are ordinal, as they are in the present study and in the great majority of prior reports. However, our use of a multi-source outcome composite should at least preclude idiosyncratic scaling properties of any single instrument. Third, and more tentatively, some GxE reported in the literature could represent statistical artifacts rather than describe developmental phenomena (Eaves, 2006). However, Eaves' (2006) cautions apply to measured risk alleles and dichotomous outcomes analyzed with logistic regression, conditions that do not apply to the present study. Previewing our own approach to demonstrating GxE for internalizing problems, we take into account both children's gender and co-occurrence of externalizing symptoms, focus on detailed measurement of the environment and of symptoms, and rely on converging results across methods to provide more convincing evidence of GxE than is typically found in the literature.