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

Background: A lack of genetic data across generations makes transgenerational Mendelian randomization (MR) difficult. We used UK Biobank and a novel proxy gene-by-environment MR to investigate effects of maternal smoking heaviness in pregnancy on offspring health, using participants’ (generation one [G1]) genotype (rs16969968 in CHRNA5) as a proxy for their mothers’ (G0) genotype.

Methods: We validated this approach by replicating an established effect of maternal smoking heaviness on offspring birthweight. Then we applied this approach to explore effects of maternal (G0) smoking heaviness on offspring (G1) later life outcomes and birthweight of G1 women’s child (G2).

Results: Each additional smoking-increasing allele in offspring (G1) was associated with a 0.018 [95% confidence interval (CI): -0.026, -0.009] kg lower G1 birthweight in maternal (G0) smoking stratum, but no meaningful effect (-0.002kg; 95% CI: -0.008, 0.003) in maternal non-smoking stratum (interaction P value=0.004). The differences in associations of rs16969968 with grandchild’s (G2) birthweight between grandmothers (G0) who did versus did not smoke were heterogeneous (interaction P-value=0.042) among mothers (G1) who did (-0.020kg/allele; 95% CI: -0.044, 0.003) versus did not (0.007kg/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 gene-by-environment MR. We confirmed the causal effect of maternal (G0) smoking on offspring (G1) birthweight but found little evidence of an effect on G1 longer-term health outcomes. For grandchild’s (G2) birthweight, the effect of grandmother’s (G0) smoking heaviness in pregnancy may be modulated by maternal (G1) smoking status in pregnancy.