Despite widespread interest in the interface between biological contributors and environmental adversity11;13;69–72, this is one of few replicated examples of genotype x environment interaction. That genotype confers resilience to the pathogenic effects of childhood physical abuse underscores the plasticity of biological and environmental underpinnings of mental health73. Importantly, this study reinforces the need to examine depression from a fine-grained phenotypic perspective, and highlights the role of anhedonia in depressive phenotypes. The role of anhedonia as a critical endophenotype is becoming increasingly apparent, particularly in genetic studies74. Hedonic capacity is heritable (46%) but the genetic correlation between anhedonia and depression is modest75. Thus, a composite measure such as MDD may attenuate genetic signals attributable to specific mechanisms underlying salient aspects of depression, such as anhedonia and this may have contributed to the general failure of genomewide association studies of depression76. Our study demonstrates that anhedonia may be the optimal target phenotype when examining the impact of childhood adversity on depression. The potential of this replicated finding will be further unveiled as future research identifies the precise mechanisms by which CNR1 confers stress adaptation in the etiology of anhedonia and depression.
