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

Raison, C L; Miller, A H

against sudden infant death syndrome, a condition often associated with unrecognized infectious morbidity. [97] [98] [99] [100] Given the PATHOS-D prediction that stress should activate inflammation as a prepotent protection against the risk of wounding (see below), it is intriguing that the 5HTTLPR short allele is associated with an increase in the ratio of circulating proinflammatory to antiinflammatory cytokines (for example, IL-6/IL-10) following a psychosocial stressor. 101 Further supporting a role for SLC6A4 in host defense is the recent finding that the gene might account for 10% of the correlation between depressive symptoms and circulating levels of IL-6 in a group of medically healthy adults. 102 Finally, the prevalence of the short allele in cultures around the world is strongly correlated with historical burden of disease-causing pathogens in these cultures, 103 consistent with the possibility that the short allele has undergone positive selection as a result of enhancing host defense. 104 Alleles identified by meta-analyses of GWAS data Far less is known about the general functionality of alleles identified in GWASs, let alone which physiological effects may be relevant to MDD. Therefore, it should not be surprising that limited data are available regarding whether these potentially depressogenic SNPs affect immunity to enhance host defense. On the other hand, it is intriguing that associations with immune/inflammatory function or other aspects of host defense against pathogens have been demonstrated for 8 of the top 10 genes (or their very close homologs) identified in the largest GWAS meta-analysis of MDD conducted to date ( Table 2) . Many other depression-relevant genes identified in earlier large GWASs (as well as meta-analyses of these studies), including PBRM1, GNL3, ATP6V1B2, SP4, AK294384, LY86, KSP37, SMG7, NFKB1, LOC654346, LAMC2, ATG7, CUGBP1, NFE2L3, LOC647167, VCAN, NLGN1, BBOX1, ATF3, RORA, EIF3F, CDH13, ITGB1 and GRM8, have also been linked to immune system and/or host defense functions (see Supplementary Table S1 for additional information/relevant references).