Gunn-Helen Moen1,2,3,4, Robin N Beaumont5, Niels Grarup6, Christine Sommer7, Beverley M Shields5, Deborah A Lawlor4,8,9, Rachel M Freathy5,8, David M Evans2,8, Nicole M Warrington2,3. 1. Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. 2. University of Queensland Diamantina Institute, University of Queensland, Woolloongabba, QLD, Australia. 3. K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, Norway. 4. Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK. 5. Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter, Royal Devon and Exeter Hospital, Exeter, UK. 6. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 7. Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway. 8. Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK. 9. Bristol National Institute of Health Research Biomedical Research Centre, Bristol, UK.
Abstract
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.
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.
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