The evolutionary significance of depression in Pathogen Host Defense (PATHOS-D)

Raison, C L; Miller, A H

In this article we have focused our analyses on allelic variants associated with phenotypic variability. Many genetic features contributing to MDD may have swept to fixation over evolutionary history and by becoming nonpolymorphic remain invisible to genetic association studies. It is possible that such sequences are preferentially associated with species-typical social, rather than immunological, factors. Were this to be the case, our analyses may have overestimated immune risk factors for depression at the cost of universal depressogenic risk alleles maintained as a 'price of being human'. It should also be noted that inflammatory biomarkers are not elevated in all individuals with MDD. Whether patients with increased inflammation represent a biologically and evolutionary distinct subset of MDD is an area of active research. 388 If this turns out to be the case, it may be that selection for enhanced host pathogen defense is relevant primarily to these individuals (and their allelic variants) and is thus only one adaptive factor driving the persistence of depressogenic alleles. Prior theorists have posited a variety of potentially fitness-enhancing psychosocial effects of low mood and/or depression not obviously related to host defense functions (that is, abandoning unattainable goals, yielding in dominance struggles and so on), [389] [390] [391] and it may be that these types of psychosocial benefits are promoted by allelic variants retained in the human genome independently of variants maintained as a result of conferring pathogen host defense benefits. If both immune and nonimmune etiological pathways contribute to MDD, the next question is how they combine. One hypothesis consistent with the general absence of documented epistatic interactions among MDD risk alleles is that inflammation/immune alleles provide one hit and social/stress factors provide a second (biologically distinct) hit, which together sum to exceed an MDD symptom threshold. If distinct social and immune-related genetic risk factors were identified, statistical analysis of epistasis could help distinguish intrinsic interactions between pathways from a simple additive model.