Determination of shared genetic etiology and possible causal relations between tobacco smoking and depression

Abstract

Backgrounds Cigarette smoking is strongly associated with major depressive disorder (MDD). However, any genetic etiology of such comorbidity and causal relations is poorly understood, especially at the genome-wide level. Methods In the present in silico research, we analyzed summary data from the genome-wide association study of the Psychiatric Genetic Consortium for MDD (n = 191 005) and UK Biobank for smoking (n = 337 030) by using various biostatistical methods including Bayesian colocalization analysis, LD score regression, variant effect size correlation analysis, and Mendelian randomization (MR). Results By adopting a gene prioritization approach, we identified 43 genes shared by MDD and smoking, which were significantly enriched in membrane potential, gamma-aminobutyric acid receptor activity, and retrograde endocannabinoid signaling pathways, indicating that the comorbid mechanisms are involved in the neurotransmitter system. According to linkage disequilibrium score regression, we found a strong positive correlation between MDD and current smoking (rg = 0.365; p = 7.23 × 10−25) and a negative correlation between MDD and former smoking (rg = −0.298; p = 1.59 × 10−24). MR analysis suggested that genetic liability for depression increased smoking. Conclusions These findings inform the concomitant conditions of MDD and smoking and support the use of self-medication with smoking to counteract depression.

Genetic correlation, pleiotropy, and causal associations between substance use and psychiatric disorder

“…MR Egger, a classic two-sample method more robust to confounding by horizontal pleiotropy, also detected no pairs in vertical pleiotropy. In contrast, the other two-sample MR analyses more susceptible to such confounding (Verbanck et al, 2018) reported multiple pairs of causal associations, similar to past findings: genetic liability to ADHD associated with increased risk of smoking initiation (Fluharty, Sallis, & Munafò, 2018) and vice versa (Treur et al, 2019), and genetic liability to smoking associated with increased risk of schizophrenia and depression and vice versa (Wootton et al, in press; Yao et al, in press); but see also some null MR findings (Gage et al, 2017; Hodgson et al, 2020; Taylor et al, 2014). Heterogeneity statistics from classic MR were significant for five out of eight associations ( p < 0.05), indicating further the potential presence of horizontal pleiotropy for these five pairs (Bowden, Hemani, & Davey Smith, 2018).…”

Alexithymia, aggressive behavior and depression among Lebanese adolescents: A cross-sectional study

“…In addition, smokers were found to have more difficulties expressing their emotions as well as identifying their feelings in comparison with the nonsmoker group [27]. Depressive symptoms as well as aggressive behaviors where more prominent in smokers [28]. Consequently, cigarette and waterpipe smoking could be associated with alexithymic behavior and this might be attributed to higher rates of depression and aggressive behaviors among smokers [27].…”

Therapeutic Drug Monitoring of Second- and Third-Generation Antipsychotic Drugs—Influence of Smoking Behavior and Inflammation on Pharmacokinetics

“…Patients with depressive disorders also smoke more frequently than the general population. Several genetic studies have found that there is a correlation between smoking status and major depressive disorder (MDD) [51][52][53][54][55]. A recent genome-wide association study on tobacco use revealed a negative genetic correlation for MDD with age at smoking initiation and a positive genetic correlation between MDD and smoking initiation in general as well as cigarettes per day [53].…”

“…Several genetic studies have found that there is a correlation between smoking status and major depressive disorder (MDD) [51][52][53][54][55]. A recent genome-wide association study on tobacco use revealed a negative genetic correlation for MDD with age at smoking initiation and a positive genetic correlation between MDD and smoking initiation in general as well as cigarettes per day [53]. Additionally, smoking contributes to modifications of the oral, lung, and gut microbiome, potentially causing various diseases [56][57][58][59].…”