A Genetic Variant in 12q13, a Possible Risk Factor for Bipolar Disorder, Is Associated with Depressive State, Accounting for Stressful Life Events

Abstract

Genome-wide association studies (GWASs) have identified a number of susceptibility genes for schizophrenia (SCZ) and bipolar disorder (BD). However, the identification of risk genes for major depressive disorder (MDD) has been unsuccessful because the etiology of MDD is more influenced by environmental factors; thus, gene–environment (G×E) interactions are important, such as interplay with stressful life events (SLEs). We assessed the G×E interactions and main effects of genes targeting depressive symptoms. Using a case–control design, 922 hospital staff members were evaluated for depressive symptoms according to Beck Depressive Inventory (BDI; “depression” and “control” groups were classified by scores of 10 in the BDI test), SLEs, and personality. A total of sixty-three genetic variants were selected on the basis of previous GWASs of MDD, SCZ, and BD as well as candidate-gene (SLC6A4, BDNF, DBH, and FKBP5) studies. Logistic regression analysis revealed a marginally significant interaction (genetic variant × SLE) at rs4523957 (Puncorrected = 0.0034) with depression and a significant association of single nucleotide polymorphism identified from evidence of BD GWAS (rs7296288, downstream of DHH at 12q13.1) with depression as the main effect (Puncorrected = 9.4×10−4, Pcorrected = 0.0424). We also found that SLEs had a larger impact on depression (odds ratio∼3), as reported previously. These results suggest that DHH plays a possible role in depression etiology; however, variants from MDD or SCZ GWAS evidence or candidate genes showed no significant associations or minimal effects of interactions with SLEs on depression.

Brain-Derived Neurotrophic Factor and Major Depressive Disorder: Evidence from Meta-Analyses

“…Because the heritability of MDD is low, but its prevalence is high, the pathophysiology of MDD is considered to be highly heterogeneous. Therefore, GWAS could not detect any genetic markers associated with the clinical risk of MDD (i.e., the effect size of markers was extremely small) because of insufficient statistical power ( 22 , 23 ). Because the meta-analysis of late-life depression was performed in only four studies ( n = 1,002), and the effect size of Val66Met for late-life depression was relatively high, we considered that this positive result might be a type I error ( 11 ).…”

“…The cause of heterogeneity might be the methodological quality of the studies, including age and gender matching and assay type (serum or plasma). Several researchers reported an absence of association between the BDNF gene and MDD, stating that the pathophysiology as well as diagnosis of MDD is extensively heterogeneous and, hence, it is very difficult to detect a susceptibility gene for MDD ( 4 , 23 ).…”

Risk factors and clinical characteristics of the depressive state induced by pegylated interferon therapy in patients with hepatitis C virus infection: A prospective study

“…Therefore, we hypothesized that the ‘core’ symptoms of PegIFN‐induced depressive state are different from those of the ‘general’ depressive state, which is usually associated with SLE. To clarify whether the core symptoms of PegIFN‐induced depressive state were unique, we compared the effect size (increase in subscale change between the baseline and worst point) for all BDI items between the current results and our previous cohort data (see Appendix S1 for details of our previous report of general depressive state) . In this explorative analysis, we found that ‘somatic symptoms’ (larger changes observed in the PegIFN therapy group, including sleep disturbance, loss of appetite, and weight loss) showed a relatively small effect size in our previous data for general depressive state (Table ).…”

“…However, interestingly, we identified a second peak for the onset of the depressive state in the later period of PegIFN therapy (after 20 weeks). Furthermore, we observed a different rate of SLE in depressive subjects between the two peaks: we speculate that the peak observed in the later onset of PegIFN therapy might not be due solely to the effect of PegIFN, but might also be influenced by SLE, which are definitive risk factors for general depressive state and depression . Presumably, PegIFN initiates the susceptibility for the development of a depressive state, and as a double hit, SLE induce depressive symptoms for subjects that develop a depressive state at later stages of therapy.…”

d-Serine as the gatekeeper of NMDA receptor activity: implications for the pharmacologic management of anxiety disorders

“…Finally, there is genetic evidence linking D-serine with PTSD. A single nucleotide polymorphism (SNP; rs4523957) within the human serine racemase (SRR) gene previously associated with other disorders [55][56][57] , is a functional eQTL at the level of regulating SR mRNA expression in post-mortem human brain and is associated with PTSD 33 in a highly traumatized civilian population 58,59 .…”