Genetic overlap and causal associations between smoking behaviours and psychiatric traits and disorders in adolescents and adults

Abstract

Background: Epidemiological research shows that smoking is associated with psychiatric disorders and psychotic experiences, even after controlling for confounds such as cannabis use and sleep problems. We investigated degree of genetic overlap and tested for causal associations between smoking and psychiatric traits and disorders using genetic data. We tested whether genetic associations existed beyond genetic influences shared with confounding variables.Methods: Genetic correlations were estimated with LD-score regression between smoking behaviours (N=262,990-632,802) and psychiatric disorders (schizophrenia, bipolar disorder and depression; N=41,653-173,005), psychotic experiences in adolescents (N=6,297-10,098) and adults (N=116,787-117,794) and adult schizotypy (N=3,967-4,057). Genomic Structural Equation Modelling was performed to explore the associations while accounting for genetic influences of confounders (cannabis and alcohol use, risk-taking and insomnia). Causal associations were tested using Generalized Summary-based Mendelian Randomization (GSMR).Results: Significant genetic correlations were found between smoking and psychiatric disorders (rg = .10 -.38) and adult PE (rg = .33 -.40). After accounting for covarying genetic influences, genetic associations between most smoking phenotypes and schizophrenia and depression remained but not between smoking behaviours and bipolar disorder or most psychotic experiences. GSMR results supported a causal role of smoking initiation on psychiatric disorders and adolescent cognitive and negative psychotic experiences. Conclusions: Pleiotropy between smoking behaviours and schizophrenia and depressionexists beyond the common genetic basis of known confounders. Smoking also appears to be causally associated with psychiatric disorders and with cognitive PEs and negative symptoms during adolescence. Exploration of the biological links underlying smoking and psychiatric illness would be well-justified.

Using Mendelian randomization analysis to better understand the relationship between mental health and substance use: a systematic review

“…Adams ( 2019 ), using a larger data set for the outcome than Sallis et al ( 2019 ), did not find clear evidence that neuroticism affects smoking. There was no clear evidence for causal effects of depression or bipolar disorder on smoking (Barkhuizen, Dudbridge, & Ronald, 2020 ; Vermeulen et al, 2019 ). Most studies also tested effects in the other direction.…”

“…Earlier studies showed no clear evidence for causal effects (Bjorngaard et al, 2013 ; Skov-Ettrup, Nordestgaard, Petersen, & Tolstrup, 2017 ; Taylor et al, 2014a ; Wium-Andersen, Orsted, & Nordestgaard, 2015a ), with one exception: a small study ( n = 6294) of low-rated quality reporting that smoking decreased depression during pregnancy (Lewis et al, 2011 ). More recent studies, employing much larger samples, found strong evidence for causal, increasing effects of smoking initiation and lifetime smoking on depression and bipolar disorder risk (Barkhuizen et al, 2020 ; Vermeulen et al, 2019 ; Wootton et al, 2019 ). There was weak evidence that smoking initiation increases feelings of loneliness (a phenotype closely related to depression) from one study (Wootton et al, 2020 ), but no such evidence from another (Harrison et al, 2020b ).…”

“…Multiple studies reported evidence (ranging from weak to strong) that smoking causally increases schizophrenia risk (Barkhuizen et al, 2020 ; Byrne et al, 2019 ; Gage et al, 2017b ; Wium-Andersen et al, 2015a , ; Wootton et al, 2019 ). In the other direction there was no clear evidence for causal effects of liability to schizophrenia on smoking from one study (Gage et al, 2017a , 2017b ), and some evidence for such effects from two recent, better-powered studies with largely overlapping samples (Barkhuizen et al, 2020 ; Wootton et al, 2019 ).…”