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

Raison, C L; Miller, A H

with depression and related states such as anger. 33, 34, 45 As predicted by PATHOS-D theory, the À308A allele has also been associated with reduced risk for infection with a number of pathogens, including Mycobacterium tuberculosis, parvovirus B19 and hepatitis B virus (HBV), [46] [47] [48] and with an increased likelihood of survival in critically ill hospitalized patients. 49 On a population level, Canadian First Peoples who are highly susceptible to tuberculosis have a markedly reduced prevalence of the A allele compared with Caucasians. 50 DCNP1 was initially considered to be unique to dendritic cells, 51 although it has subsequently been identified in neurons. 52 The rs12520799 T allele, which is associated with MDD, codes for a truncated version of the protein. No data are available regarding the effect of this allele on either inflammatory signaling or infection outcomes, but given strong patterns of comorbidity between asthma/atopy and MDD, it is intriguing that the allele has been associated with increased levels of immunoglobulin E for common specific antigens in individuals with asthma. 53 Candidate genes confirmed by meta-analysis Although findings on candidate genes for depression have proven remarkably difficult to replicate, 35 a recent meta-analysis provides at least some additional support for several allelic variants being risk factors for MDD, including GNB3 825T, MTHFR 677T, APOE e2, SLC6A3 40 bpVNTR 9/10 genotype and SLC6A4 44 bp ins/del short allele. 54 Although not traditionally considered as primarily immune related, each of these genes has well-documented immunological effects and hence meets the first of the three criteria for consistency with the PATHOS-D theory. In addition, each to a varying degree has some evidence consistent with either the second or third criterion.