Maternal smoking during pregnancy and risks to depression and anxiety in offspring: An observational study and genome-wide gene-environment interaction analysis in UK biobank cohort

Background: Maternal smoking during pregnancy (MSDP) has been reported to be associated with increased anxiety and depression behaviors in offspring. However, there is still scant evidence to support the link between MSDP and anxiety/depression. Methods: Using the subjects from the UK Biobank cohort (n = 371,903-432,881). Logistic regression analyses were first conducted to test the correlation between MSDP and anxiety/depression in offspring. Second, genomewide gene-environment interaction study (GWGEIS) analyses were conducted by PLINK, using MSDP as environmental factor. Genetic correlation analysis of anxiety/depression and smoking was conducted by the LDSC software using the published genome-wide association study (GWAS) summary data of four smoking traits (n = 337,334-1,232,091), anxiety (n = 31,880) and depression (n = 490,359). Finally, pathway enrichment analysis was carried out to detect the pathway involved in the development of offspring anxiety caused by the interaction of MSDP x SNPs. Results: Observational analyses showed that anxiety and depression status in offspring were significantly associated with MSDP (all p < 0.0001). Further GWEGI analyses observed significant MSDP-gene interaction effects at UNC80 gene for anxiety (p = 9.09 x 10-9). LDSC did not detect significant genetic correlation between anxiety and smoking traits. Pathway analysis identified 19 significant pathways for anxiety, such as MANALO_HYPOXIA_UP (FDR = 5.50 x 10-4), REACTOME_ADHERENS_JUNCTIONS_INTERACTIONS (FDR = 0.0304) and ONDER_CDH1_TARGETS_2_UP (FDR = 0.0371). Conclusion: Our study results suggested the important impact of MDSP on the risk of anxiety in offspring, partly attributing to environment-gene interactions effects.