Major depressive disorder (MDD) is a VERY complex multifactorial trait in psychiatry — which is known to be “moderately” heritable. Based on identical vs fraternal twin studies, estimates of heritability are ~37%. With multifactorial traits (contributions to any phenotype by genetics and epigenetics — plus environmental factors, endogenous effects and even microbiome differences). genome-wide association studies (GWAS) with sufficiently large cohorts have detected many small-effect genes for numerous clinical disorders. However, all GWAS focused on MDD have been notoriously not reproducible or replicable, from one study population to the next. Thus, the genetic architecture (underlying genetic basis of a phenotypic trait and its variational properties; the structure of mapping from genotype-to-phenotype determines the variational properties of the trait and can be instrumental in understanding its evolutionary potential) of MDD appears to be exceedingly complicated, and identifying specific polymorphisms underlying MDD susceptibility has been very challenging — to say the least.
Back in the 1990s, early research focused on the effects of specific candidate genes postulated to underlie MDD liability; these genes were chosen on the basis of hypotheses regarding the biological underpinnings of depression. For at least 25 years, the “5-HTTLPR (5-HydroxyTryptamine (serotonin) Transporter Gene-Linked Polymorphic Region), which represents a variable number tandem repeat (VNTR) polymorphism in the promoter region of the serotonin transporter gene SLC6A4” has been the most commonly studied polymorphism in relation to MDD. Given the theorized importance of the serotonergic system in the etiology of MDD, a logical target for early association studies was a
common, relatively easy to PCR-genotype, and potentially functional VNTR polymorphism in a serotonergic gene. [Back in the 1990s, in my mind, I might add that I was never impressed by this suspicious VNTR, with regard to its “being a large-effect gene associated with MDD.”]. To many critics of candidate gene studies — replication failures (over the past 25 years) had suggested that the initial findings were artifactual.
Authors [see attached article] have tackled this controversy — by identifying 18 candidate genes for MDD “that have been studied 10 or more times” and examining evidence for their relevance to MDD phenotypes [see Figs. 1-3 and Table 2 in the article for complete list of the 18 genes chosen). Taking data from large population-based and case-control samples (numbers ranging from 62,000 to 443,000 across sub-samples), the authors conducted a series of preregistered analyses examining candidate gene polymorphism main effects, polymorphism-by-environment interactions, and gene-level effects across a number of operational definitions of MDD (e.g. lifetime diagnosis, current severity, episode recurrence) and environmental modifiers (e.g. sexual or physical abuse during childhood, socioeconomic adversity).
Authors found no unequivocal evidence for any of the 18 “most-studied” candidate gene polymorphism associations with the MDD phenotypes, nor were any polymorphism-by-environment moderator effects revealed. The MDD candidate genes were no more associated with MDD phenotypes than non-candidate genes. Authors concluded that their data do not support the hundreds of previous MDD candidate gene studies — in which “large genetic effects” are frequently reported in samples that are orders of magnitude smaller than those studied herein. Instead, the results suggest that early hypotheses about MDD candidate genes were all incorrect and that the large number of associations reported in the MDD candidate gene literature are likely to be false positives.
DwN
[I very much appreciate Professor Olavi Pelkonen bringing this fantastic fascinating NEGATIVE study to my attention.] 😊
Am J Psychiatry in Advance (doi: 10.1176/appi.ajp.2018.18070881)