TOMM40 rs2075650 May Represent a New Candidate Gene for Vulnerability to Major Depressive Disorder

Abstract

Evidence suggests that depression is a risk factor for dementia; however, the relationship between the two conditions is not fully understood. A novel gene (TOMM40) has been consistently associated with Alzheimer's disease (AD), but has received no attention in depression. We conducted a three-level cross-sectional study to investigate the association of the TOMM40 rs2075650 SNP with depression. We recruited a community sample of 1220 participants (571 controls, 649 lifetime depression) to complete a psychiatric background questionnaire, the Brief Symptom Inventory, and Big Five Inventory at Level-1, 243 (102 controls, 97 remitted, 44 currently depressed) to complete a face-toface clinical interview and neuropsychological testing at Level-2 and 58 (33 controls, 25 remitted) to complete an emotional face-processing task during fMRI at Level-3. Our results indicated that the TOMM40 rs2075650 G allele was a significant risk factor for lifetime depression (p ¼ 0.00006) and, in depressed subjects, was a significant predictor of low extraversion (p ¼ 0.009). Currently depressed risk allele carriers showed subtle executive dysfunction (p ¼ 0.004) and decreased positive memory bias (p ¼ 0.021) together with reduced activity in the posterior (p (FWE) ¼ 0.045) and anterior (p (FWE) ¼ 0.041) cingulate during sad face emotion processing. Our results suggest that TOMM40 rs2075650 may be a risk factor for the development of depression characterized by reduced extraversion, impaired executive function, and decreased positive emotional recall, and reduced top-down cortical control during sad emotion processing.

The genetics of anxiety‐related negative valence system traits

“…Genetic epidemiological studies are lacking, but candidate gene studies have identified a role of the 5‐HTTLPR S allele in greater emotion identification accuracy, increased fixation and attentiveness toward facial emotion cues, and a lower likelihood of perceiving neutral faces as happy [Boll and Gamer, ; Gohier et al, ]. Other studies have identified genetic effects on gaze duration, recognition biases, and neural activation during facial emotion processing from the HTR1A / HTR1B [Mekli et al, ], CB1 [Chakrabarti and Baron‐Cohen, ], COMT [Gohier et al, ], OXTR [Puglia et al, ], and TOMM40 [McFarquhar et al, ] genes, as well as a set of genes associated with NMDA receptor activation [Mattingsdal et al, ].…”

Aging and the genetic road towards the positivity effect in memory

“…Along with TOMM40 "523", another single-nucleotide polymorphisms (SNPs), namely, TOMM40 rs2075650 (intron 2, chromosome 19q13.32, "650") has been significantly associated with cognitive and affective dysfunctions (e.g., McFarquhar et al, 2014). In particular, McFarquhar et al (2014) conducted a study that included emotionally-charged study material.…”

“…In particular, McFarquhar et al (2014) conducted a study that included emotionally-charged study material. In particular, the authors used an emotional word recall task (with an immediate and delayed test) and compared performance between carriers with the minor (G) allele of TOMM40 and AA carriers.…”

APOE-TOMM40 in the Pharmacogenomics of Dementia

“…Recent studies also suggest that the TOMM40 gene rs10524523 ("523") variable length poly T repeat polymorphism is associated to a certain extent with similar AD phenotypes as those reported for APOE, such as brain white matter changes [56,57] or different biomarkers [58][59][60][61]. In addition, the TOMM40 rs2075650 G allele may be a risk factor for the development of depression [62] and sporadic inclusion body myositis [63]. Different markers at the 19q13-q13.2 chromosomal region, including the rs2075650 and rs157590 (TOMM40), rs1064725 (APOC1), and rs429358 and rs7412 (APOE) SNPs also show association with primary progressive aphasia and the behavioural variant frontotemporal dementia [64].…”