Genetic correlation and causality between smoking and 42 neuropsychiatric and gastrointestinal diseases

Abstract

BackgroundPrevious investigations have elucidated epidemiological associations linking smoking to neuropsychiatric and gastrointestinal diseases, yet the underlying causal relationships remain enigmatic. To shed light on this matter, we undertook a Mendelian randomisation(MR) study with the aim of gauging the potential causal association between smoking and the susceptibility to neuropsychiatric and gastrointestinal tract diseases. MethodsWe meticulously collected and preprocessed genome-wide association study (GWAS) data encompassing smoking (280,508 cases and 180,558 controls) as well as neuropsychiatric and gastrointestinal phenotypes (n = 6,681 to 87,3341). To investigate the genetic correlation between smoking and diseases, we employed linkage disequilibrium score regression. We further applied multi-trait analysis of GWAS to identify the shared risk single-nucleotide polymorphisms (SNPs) implicated in both smoking and diseases. Pleiotropic genes were annotated by enrichment analysis. Subsequently, bidirectional MR analysis was performed to infer causality. ResultsOur findings, supported by robust evidence derived from an expansive sample size, demonstrate that smoking exerts a causal influence on merely six of these diseases, while no disease was found to causally impact smoking. Intriguingly, we discovered 513 pleiotropic genes enriched in pathways such as the regulation of growth and synapses, suggesting a potential shared genetic basis between smoking and these diseases, leading to aberrant neural development. Remarkably, among the 42 diseases scrutinized, a significant genetic correlation was exclusively observed with gastroesophageal reflux disease (GRED). Furthermore, we identified risk SNPs shared by smoking and GRED. ConclusionsThis study revealed the shared genetic basis and causal effects connecting smoking to neuropsychiatric and gastrointestinal diseases, thereby providing novel etiological insights into the role of smoking in these diseases.