Investigating the causal effect of maternal vitamin B12 and folate levels on offspring birthweight
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Investigating the causal effect of maternal vitamin B12 and folate levels on offspring birthweight. / Moen, Gunn-Helen; Beaumont, Robin N.; Grarup, Niels; Sommer, Christine; Shields, Beverley M.; Lawlor, Deborah A.; Freathy, Rachel M.; Evans, David M.; Warrington, Nicole M.
In: International Journal of Epidemiology, Vol. 50, No. 1, 2021, p. 179-189.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Investigating the causal effect of maternal vitamin B12 and folate levels on offspring birthweight
AU - Moen, Gunn-Helen
AU - Beaumont, Robin N.
AU - Grarup, Niels
AU - Sommer, Christine
AU - Shields, Beverley M.
AU - Lawlor, Deborah A.
AU - Freathy, Rachel M.
AU - Evans, David M.
AU - Warrington, Nicole M.
PY - 2021
Y1 - 2021
N2 - Background: Lower maternal serum vitamin B12 (B12) and folate levels have been associated with lower offspring birthweight, in observational studies. The aim of this study was to investigate whether this relationship is causal.Methods: We performed two-sample Mendelian randomization (MR) using summary data on associations between genotype-B12 (10 genetic variants) or genotype-folate (four genetic variants) levels from: a genome-wide association study of 45 576 individuals (sample 1); and both maternal- and fetal-specific genetic effects on offspring birthweight from the latest Early Growth Genetics consortium meta-analysis with 297 356 individuals reporting their own birthweight and 210 248 women reporting their offspring's birthweight (sample 2). We used the inverse variance weighted method, and sensitivity analyses to account for pleiotropy, in addition to excluding a potentially pleiotropic variant in the FUT2 gene for B12 levels.Results: We did not find evidence for a causal effect of maternal or fetal B12 levels on offspring birthweight. The results were consistent across the different methods. We found a positive causal effect of maternal folate levels on offspring birthweight [0.146 (0.065, 0.227), which corresponds to an increase in birthweight of 71 g per 1 standard deviation higher folate]. We found some evidence for a small inverse effect of fetal folate levels on their own birthweight [-0.051 (-0.100, -0.003)].Conclusions: Our results are consistent with evidence from randomized controlled trials that higher maternal folate levels increase offspring birthweight. We did not find evidence for a causal effect of B12 levels on offspring birthweight, suggesting previous observational studies may have been confounded.
AB - Background: Lower maternal serum vitamin B12 (B12) and folate levels have been associated with lower offspring birthweight, in observational studies. The aim of this study was to investigate whether this relationship is causal.Methods: We performed two-sample Mendelian randomization (MR) using summary data on associations between genotype-B12 (10 genetic variants) or genotype-folate (four genetic variants) levels from: a genome-wide association study of 45 576 individuals (sample 1); and both maternal- and fetal-specific genetic effects on offspring birthweight from the latest Early Growth Genetics consortium meta-analysis with 297 356 individuals reporting their own birthweight and 210 248 women reporting their offspring's birthweight (sample 2). We used the inverse variance weighted method, and sensitivity analyses to account for pleiotropy, in addition to excluding a potentially pleiotropic variant in the FUT2 gene for B12 levels.Results: We did not find evidence for a causal effect of maternal or fetal B12 levels on offspring birthweight. The results were consistent across the different methods. We found a positive causal effect of maternal folate levels on offspring birthweight [0.146 (0.065, 0.227), which corresponds to an increase in birthweight of 71 g per 1 standard deviation higher folate]. We found some evidence for a small inverse effect of fetal folate levels on their own birthweight [-0.051 (-0.100, -0.003)].Conclusions: Our results are consistent with evidence from randomized controlled trials that higher maternal folate levels increase offspring birthweight. We did not find evidence for a causal effect of B12 levels on offspring birthweight, suggesting previous observational studies may have been confounded.
KW - Maternal genetic effect
KW - fetal genetic effect
KW - vitamin B12
KW - folate
KW - birthweight
KW - Mendelian randomization
U2 - 10.1093/ije/dyaa256
DO - 10.1093/ije/dyaa256
M3 - Journal article
C2 - 33347560
VL - 50
SP - 179
EP - 189
JO - International Journal of Epidemiology
JF - International Journal of Epidemiology
SN - 0300-5771
IS - 1
ER -
ID: 261215405