Predicting Depression.

Abstract

Innate predisposition to depression is both moderately heritable and influenced by early life experience. In this issue of the Journal, Halldorsdottir and colleagues (1) use a composite genotype “score” together with measures of child abuse to ask whether genetic (G) and environmental (E) risk factors interact. The authors explore the power of predictive testing at this early point in our understanding of the genetics of depression. To do this, they studied three cohorts of patients: two that were epidemiologic and a smaller but more deeply characterized clinical sample. Together, genes and environment acted additively, and rather than either superadditively or subadditively, in accordance with true G3E interaction. These results are not the last word on genes, environment, and G3E models in depression because the assessment of genetic risk, based on a depression polygenic risk score (PRS) from a genome-wide association study (GWAS), captured less than 5% of the heritability of depression (2). Secondly, the depression phenotype, while clinically relevant, is nonspecific. Depression also occurs in specific contexts; for example, during changes in season, after traumatic events, during the premenstrual period, and during the postpartum period, as well as in chronic pain and addiction. As is inherent to the definitions of these conditions as diseases or their diagnostic exclusions in DSM-5, each of these varieties of depression could be marked by greater specificity of genes and G3E interaction. Clinically, contexts of depression can also point to more specific interventions and to, for example, the treatment of addiction or posttraumatic stress disorder (PTSD), the correction of an endocrine abnormality, or the relief of pain. Any of these more specific interventions can augment cognitive, behavioral, pharmacologic, and psychophysical therapies that are partly effective across the spectrum of depressive illnesses. Potentially, genetic loci that are not well interrogated in GWASs or that in any case are not represented in a depression PRS derived from a GWAS could display true G3E interactions. An example of a G3E interaction relevant to depression, and involving a functional locus, is FKBP5, which puts the brakes on cellular response to cortisol. As discovered by Elisabeth Binder, the senior author of the Halldorsdottir et al. article, FKBP5 alters vulnerability to PTSD and major depression in the context of prior stress exposure (3). SLC6A4, the gene encoding the serotonin transporter, has been strongly connected to anxiety, depression, response to antidepressant drugs, and modulation of emotional circuits, including in animal models. The ability of a molecularly well-validated functional polymorphism at SLC6A4 (4) to increase depression and anxiety was thought to be conditional on stress exposure. However, a recent meta-analysis revealed that this polymorphism and stress are individually significant but act additively (5). Replication studies and meta-analyses have at times replicated (5) and at other times have failed to replicate (6) the main effects of SLC6A4. The failure of depression GWASs to detect a gene such as SLC6A4 may say a great deal about the power of a GWAS to detect genes’ effects, but it also drives questions of the nature and actions of genes implicated by depressionGWASs. It isworthwhile to ask how the loci so far detected by GWASs modulate risk, even if we do not understand their nature, and it is imperative to know if depression PRSs, or a future,more informative depression PRS, might be delivered direct to consumer or disclosed physician to patient (Figure 1). When is a genetic test or combined genetic-environmental predictor ready? At least three elements are needed: predictive power (measured as sensitivity and specificity), actionability, and a sound plan for delivering the information (Figure 1). In their clinical sample, Halldorsdottir et al. found that a depression PRS alone explained about 5% of the variance in case-control status in major depression, and with the additive effect of child abuse, somewhat less than one-fifth of the variance was explained. Moreover, it is also clear that PRS scores derived from psychiatric diseases predict risk of several diseases, each of which may require different treatment or prevention, if an intervention is available. The environmental risk factor studied by Halldorsdottir et al., child abuse, is also nonspecific, increasing odds of a variety of psychiatric diseases, including affective illness, anxiety disorders, addictions, and PTSD (7). Actionable genetic predictors are available for many rare, Mendelian diseases. For these diseases, molecular diagnosis points to effective early interventions and can also spare patients from ineffective and dangerous treatments. As of July 2018, the U.S. Department of Health and Human Services recommends neonatal testing for 35 “core conditions,” including metabolic disorders such as phenylketonuria, endocrine disorders such as primary congenital hyperplasia, When is a genetic test or combined geneticenvironmental predictor ready?