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

Raison, C L; Miller, A H

Apolipoprotein E (APOE), a glycoprotein central to lipid transport and metabolism, has been implicated as a risk and/or protective factor in a wide range of illnesses. The APOE gene has three primary alleles, termed e2, e3 and e4, with e3 being the most common worldwide, but with significant data suggesting that e4 is the ancestral human allele. 82-85 APOE affects immune functioning in complex and apparently contradictory ways, with both immune-enhancing and immune-suppressing effects reported. The depression-protective e2 allele does not appear to be associated with reduced inflammation per se, as PATHOS-D theory would predict, but may meet the third criteria required by PATHOS-D by being a risk factor for diseases known to have exerted significant selection pressure on humans, including tuberculosis and malaria. 86 Conversely, the e4 allele, which increases the risk for MDD when compared with e2, is associated with increases in many measures of inflammation and related processes such as oxidative stress, [82] [83] [84] [85] and has been reported to protect against the development of childhood diarrhea in highpathogen environments. Dopamine and serotonin are pivotal neurotransmitters in mood regulation, and yet like other factors linked to depression, these monoamines both affect, and are affected by, the immune system. The bulk of available evidence suggests that MDD is best characterized as a condition of low dopamine availability, at least in CNS regions linked to motivation and reward. [87] [88] [89] [90] The possibility that reduced dopamine availability in MDD may serve host defense purposes is suggested by animal studies showing that hyperdopaminemia is associated with reductions in both innate and adaptive T helper 1-type cellular immunity, with resultant increased susceptibility to infection. 91, 92 That dopamine transporter activity in particular may be important for host defense in humans is suggested by findings from two recent genome-wide linkage analyses of risk factors for tuberculosis in geographic areas in which the disease is endemic. Both studies localized a genetic protective factor to a locus of chromosome 15. 93, 94 Fine mapping of this locus identified a SNP (rs250682) within the dopamine transporter gene (SLC6A3) as conferring the strongest protective effect. 93 The G allele of rs250682 was found to be associated with reduced skin reactions to the tuberculin test, which predicts reduced risk of later active disease in endemic areas. 93 However, no data were found indicating that rs250682 is in linkage disequilibrium with the SLC6A3 40 bpVNTR that has been associated with MDD. Nor do any data address whether the 9 repeat allele of the VNTR has immunological effects that would enhance host defense. Indeed, even the question of whether this putative depression risk allele is a gain-of-function or loss-of-function variant for the dopamine transporter remains to be definitively clarified. 95, 96 The SLC6A4 44 bp ins/del polymorphism (often referred to as 5HTTLPR) is by far the most extensively studied, and debated, genetic risk factor for MDD. Significant data suggest that the 'short' allele of this serotonin transporter polymorphism (which is less efficient in the reuptake of serotonin) increases the risk for developing depression in response to psychosocial adversity, both during development and in adulthood. Less well known, but consistent with PATHOS-D predictions, the short allele has also been shown to protect