Based on LPS-stimulated blood gene expression using whole-genome microarrays (primary cohort; 21 MDD patients, 21 healthy control subjects), we identified a set of genes (CAPRIN1, CLEC4A, KRT23, MLC1, PLSCR1, PROK2, ZBTB16) that serves as a molecular signature of MDD.
We analyzed 38 MDD patients and 38 healthy control individuals and observed that the MDD group had a significantly higher VEGFA mRNA level and protein serum concentration (P=0.001; P<0.001, respectively).
Then, we genotyped two single nucleotide polymorphic markers of VEGF gene, which were reported to be associated with amyotrophic lateral sclerosis and Alzheimer's disease, in patients with MDD and control subjects (n=154, each).
We hypothesized that common genetic variants in the VEGF gene (official gene name: VEGFA) may be associated with the therapeutic response to antidepressants in major depressive disorders (MDD).
These genes included the VAMP-2 gene, which has previously been associated with Axis-I disorders including MDD, bipolar depression, schizophrenia and with antidepressant treatment response.
To determine whether the brain-derived neurotrophic factor (BDNF) gene or its high-affinity receptor gene, receptor tyrosine kinase 2 (NTRK2), confer risk for suicide attempt (SA) and MDD by investigating common genetic variants in these loci.
We found a significant allelic and genotypic association of the TSNAX-DISC1 gene region with BD, whereas a haplotypic association was found for both BD and MDD.
Genetic association studies have implicated the TSNAX/DISC1 (disrupted in schizophrenia 1) in schizophrenia (SCZ), bipolar affective disorder (BPAD) and major depression.
A rare mutation in tryptophan hydroxylase 2 (Tph2), the rate limiting enzyme for 5-HT synthesis, was identified in several patients with major depression, and knock-in mice expressing the analogous mutation (R439H Tph2 KI) show 80% reduction in 5-HT synthesis and tissue levels.
Polymorphisms in the gene encoding the serotonin synthesis enzyme Tph2 have been identified in mental illnesses, including bipolar disorder, major depression, autism, schizophrenia, and ADHD.
Single locus analysis in pooled and ethnically stratified subjects revealed no association between each of the three variants of the TPH2 gene with susceptibility to MDD.
Although the majority of first-line antidepressants increase brain serotonin and rare polymorphisms in tryptophan hydroxlase-2 (Tph2), the rate-limiting enzyme in the brain serotonin synthesis pathway, have been identified in cohorts of subjects with major depressive disorder, the circuit level alterations that results from serotonergic hypofunction remain poorly understood.
At the gene level, TNF (rs76917; OR T=1.35, 95% CI 1.13-1.63; P=0.0034) was identified as the only gene for which the association with MDD remained significant after correction for multiple testing.
Together, our data suggest that MDD per se rather than suicide is associated with the elevated plasma TNF-α, which can be inhibited with venlfaxine monotherapy.