Examining sex differences in pleiotropic effects for depression and smoking using polygenic and gene‐region aggregation techniques

Abstract

Sex differences in rates of depression are thought to contribute to sex differences in smoking initiation (SI) and number of cigarettes smoked per day (CPD). One hypothesis is that women smoke as a strategy to cope with anxiety and depression, and have difficulty quitting because of concomitant changes in hypothalamic-pituitary-adrenocortical (HPA) axis function during nicotine withdrawal states. Despite evidence of biological ties, research has not examined whether genetic factors that contribute to depression-smoking comorbidity differ by sex. We utilized two statistical aggregation techniques-polygenic scores (PGSs) and sequence kernel association testing-to assess the degree of pleiotropy between these behaviors and moderation by sex in the Health and Retirement Study (N = 8,086). At the genome-wide level, we observed associations between PGSs for depressive symptoms and SI, and measured SI and depressive symptoms (all p < .01). At the gene level, we found evidence of pleiotropy in FKBP5 for SI (p = .028), and sex-specific pleiotropy in females in NR3C2 (p = .030) and CHRNA5 (p = .025) for SI and CPD, respectively. Results suggest bidirectional associations between depression and smoking may be partially accounted for by shared genetic factors, and genetic variation in genes related to HPA-axis functioning and nicotine dependence may contribute to sex differences in SI and CPD.

Genetic susceptibility to nicotine addiction: Advances and shortcomings in our understanding of the CHRNA5/A3/B4 gene cluster contribution

“…In line with these findings, CHRNA5 rs16969968 has been shown to interact with childhood adversity in risk to develop NA in males only, even if both genders had increased NA prevalence in the case of childhood adversity (Xie et al, 2012). Finally, using recent polygenic risk scoring and genetic correlation methods, a significant interaction between CHRNA5 and NR3C2, a gene encoding glucocorticoid receptors (which play a key role in the stress response mediated by the hypothalamopituitary axis) has become evident (Schmitz et al, 2019). Overall, it seems that the gender variable, in genetic studies on NA, has been more considered as a cofactor rather than a significant parameter for refining genetic associations in specific subpopulations, despite the clinical and biological relevance to do so.…”

AVPR1A main effect and OXTR-by-environment interplay in individual differences in depression level

“…These observations can be partially explained by differential methylation in genes involved in HPA-axis and immune functions, which may cause later mental health problems in children ( Kantake et al., 2014 ; Nemoda and Szyf, 2017 ). In addition, a significant effect of addictive behavior (smoking, alcohol abuse/dependence) during adulthood on developing depression in a predictive framework based on interactions of multiple functional genetic variants has been reported ( Schmitz et al., 2019 ; Tylee et al., 2018 ; Wong et al., 2012 ). In turn, increased exposure to smoking may significantly affect epigenetic changes in HPA-axis ( Dogan et al., 2016 ) and serotonergic genes ( Smolka et al., 2019 ).…”

Implementing Core Genes and an Omnigenic Model for Behaviour Traits Prediction in Genomics

“…Gender differences in hormone levels can also affect the expression and functioning of core genes, thus affecting behaviour. For instance, the stress response, which is influenced by variations in the FKBP5 , CRHR1 , and NR3C1 genes, can vary between males and females due to the differences in the regulation of cortisol, a hormone that plays a key role in the stress response [ 68 , 69 ]. Variants of the COMT gene, involved in the metabolism of catecholamine neurotransmitters, have been implicated in impulsivity.…”