Proxy gene-by-environment Mendelian randomization study confirms a causal effect of maternal smoking on offspring birthweight, but little evidence of long-term influences on offspring health
Objective: To validate a novel proxy gene-by-environment (G×E) Mendelian randomization (MR) approach by replicating the previously established effect of maternal smoking heaviness in pregnancy on offspring birthweight, and then use G×E MR to investigate the effect of smoking heaviness in pregnancy on offspring health outcomes in later life and grandchild's birthweight. Design: A proxy G×E MR using participants' genotype (i.e. rs16969968 in CHRNA5) as a proxy for their mother's genotype. Setting: UK Biobank. Participants: 289,684 white British men and women aged 40-69 in UK Biobank. Main outcome measures: Participants' birthweight and later life outcomes (height, body mass index, lung function, asthma, blood pressure, age at menarche, years of education, fluid intelligence score, depression/anxiety, happiness), and birthweight of female participants' first child. Results: In our proof of principle analysis, each additional smoking-increasing allele was associated with a 0.018 (95% confidence interval (CI): -0.026, -0.009) kg lower birthweight in the "maternal smoking during pregnancy" stratum, but no meaningful effect (-0.002kg; 95% CI: -0.008, 0.003) in the "maternal non-smoking during pregnancy" stratum (interaction P-value=0.004). We found little evidence of an effect of maternal smoking heaviness on participants' later life outcomes. We found the differences in associations of rs16969968 with grandchild's birthweight between grandmothers who did versus did not smoke were heterogeneous (interaction P-value=0.042) among female participants who did (-0.020kg per allele; 95% CI: -0.044, 0.003) versus did not (0.007kg per allele; 95% CI: -0.005, 0.020) smoke in pregnancy. Conclusions: Our study demonstrated how offspring genotype can be used to proxy for mothers' genotype in G×E MR. We confirmed the previously established causal effect of maternal smoking on offspring birthweight but found little evidence of an effect on long-term health outcomes in the offspring. For grandchild's birthweight, the effect of grandmother's smoking heaviness in pregnancy may be modulated by maternal smoking status in pregnancy.
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