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
Authors: Yang Qian , Millard Louise A C , Smith George Davey 
Published: April 2019

AbstractObjectiveTo 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 GxE MR to investigate the effect of smoking heaviness in pregnancy on offspring health outcomes in later life and grandchild’s birthweight.DesignA proxy G×E MR using participants’ genotype (i.e. rs16969968 in CHRNA5) as a proxy for their mother’s genotype.SettingUK Biobank.Participants289,684 white British men and women aged 40-69 in UK Biobank.Main outcome measuresParticipants’ 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.ResultsIn 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.ConclusionsOur 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.WHAT IS ALREADY KNOWN TO THIS TOPICHeavier maternal smoking in pregnancy causes lower offspring birthweight Maternal smoking in pregnancy is also associated with offspring outcomes in later life and grandchild’s birthweight, but it is not known whether these associations are causal Understanding the transgenerational causal effects of maternal smoking heaviness in pregnancy is important to inform public health policiesWHAT THIS STUDY ADDSThe proxy gene-by-environment Mendelian randomization approach can be used to explore maternal effects on offspring phenotypes when maternal genetic information is unavailable The approach confirmed the causal effect of smoking on offspring birthweight.Maternal smoking status in pregnancy modulates the effect of grandmother’s smoking heaviness in pregnancy on grandchild’s birthweight, highlighting the importance of smoking cessation before pregnancy in each generation