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

Raison, C L; Miller, A H

The failed promise of genome-wide association studies (GWASs) to unambiguously identify genetic risk variants for MDD has led increasingly to the suggestion that depression and other major psychiatric conditions arise not from common allelic variants with small effect sizes, but rather from an array of highly nonadaptive genetic variants too rare to be identified by GWASs that nonetheless have large effect sizes. 26, 27 Confirmation of this would effectively preclude the possibility that depressive risk alleles conferred any selective advantage during human evolution. 28 However, an alternative possibility is that differences in common allelic variants between depressed and nondepressed individuals might be more apparent/consistent if the unit of analysis was extended from single genes to groupings of genes that form functional units. In the context of the PATHOS-D theory, this suggests that small allelic differences between depressed and nondepressed groups should not be randomly distributed across the genome, but rather should be largely localized to genes with host defense functions, and that the effect sizes for differences in individual host defense alleles should be additive (that is, positive epistasis), so that large effect size differences should emerge when functionally related host defense-enhancing alleles are evaluated as a unit. Support for this possibility comes from a recent network analysis of candidate genes for MDD. Although this analysis only interpreted findings in terms of potential central nervous system (CNS) effects, 29 from a PATHOS-D perspective, it is striking that pathways identified as central to the best-supported MDD gene networks all have welldocumented inflammatory and/or anti-inflammatory effects.