Across multiple disciplines, there is a long-standing belief that there are developmental windows when experience can have lasting effects in shaping behavior, health, and ultimately risk for disease. During these... [ view full abstract ]
Across multiple disciplines, there is a long-standing belief that there are developmental windows when experience can have lasting effects in shaping behavior, health, and ultimately risk for disease. During these “sensitive periods,” experience may become biologically embedded due to occurring at a stage in development when the foundation of organs, tissues, and physiological systems is established. For example, an exposure coinciding with peak periods of brain plasticity may shape brain circuitry and function more than the same exposure occurring earlier or later in development. Although sensitive periods shaping risk for depression are not yet identified, they likely arise through a complex orchestration of genes and experience. With respect to genes, preclinical studies in animals have identified specific genes involved in regulating the timing and duration of sensitive periods. For instance, studies using mouse knock-in genetic models in the visual system have shown that increased Bdnf expression can initiate a sensitive period, whereas disruptions to Gad2 delay sensitive period onset. With respect to experience, epidemiological studies are beginning to implicate specific age stages when the effect of adversity, including exposure to child maltreatment, is more potent in conferring risk for depression. Building from these two lines of evidence, the goal of the current study was to examine the role of sensitive period-regulating genes, alone and in interaction with exposure to adversity, on risk for depression. To accomplish this goal, we: (1) performed gene-level and gene-set-level analyses using data from the Psychiatric Genomics Consortium (PGC) to evaluate the effect on risk for major depressive disorder (MDD) of 53 genes shown in animal studies to regulate sensitive periods; (2) evaluated the developmental expression patterns of these sensitive period-regulating genes by analyzing data from BrainSpan, a transcriptional atlas of 57 healthy, post-mortem donors (ages 5.7 weeks post-conception to 82 years); and (3) tested for gene-by-development interplay by analyzing the combined effect of common variants in these sensitive period genes and timing of exposure to adversity within a population-based study of children (n=6255). Results indicated that as a set, genes regulating the opening of sensitive periods were most associated with MDD risk; this included genes regulating neurogenesis (BDNF, NTRK2) and gaba-ergic neurotransmission (GABBR1, GABRA1, GABRA2). Genes implicated in MDD risk were also developmentally regulated. That is, age was significantly associated with expression levels in about half of the 15 MDD-implicated genes, explaining up to 56% of the variation in gene-level expression. Among genes associated with MDD, 75% (6 of 8) had a nadir of expression between ages 1 and 5. Gene-by-development interplay analyses revealed a significant main environmental effect of adversity exposure between ages 1 and 5 years (β = 0.85, 95% C.I. = 0.57 – 1.12, p-value = .007), but no genetic main effect or gene-by-development interaction effect. These results indicate that genes involved in regulating sensitive periods may be implicated in depression vulnerability and be differentially expressed across the lifecourse, but that larger studies will be needed to identify developmental GxE effects.
