Abstract
Background/Objectives
Observational studies link elevated homocysteine concentrations (Hcy) with female fertility, pregnancy loss, and low offspring birthweight. Maternal rs1801133, a functional variant in MTHFR strongly associated with lifelong elevated Hcy, is associated with recurrent pregnancy loss and offspring birthweight in Asian women. We investigated if genetically elevated Hcy is associated with fertility, pregnancy loss, and offspring birthweight in European women.
Subjects/Methods
We performed a two-sample Mendelian randomization (MR) study using publicly available data. We obtained 18 genetic variants (five involved in Hcy metabolism) explaining up to 5.9% of the variance in Hcy from a genome-wide association meta-analysis of 44,147 European individuals (82% women). We investigated fertility (including age at menopause), pregnancy loss, and offspring birthweight in the UK Biobank (N = 194,174), EGG (N = 190,406), and ReproGen (N = 69,360–252,514) consortia using summary statistics. We calculated inverse-variance weighted, and several sensitivity MR regression statistics.
Results
rs1801133 was associated with a 7.45 months (95% CI: 4.09, 10.80) increase in age at menopause and 29.69 (12.87, 46.51) g decrease in offspring birthweight per SD increase in Hcy in the UK biobank, and confirmed in EGG and ReproGen. MR for Hcy metabolism alone (five variants in MTHFR, MTR, CBS) showed similar results for offspring birthweight across consortia. However, using all 18 variants resulted in no association for any of the outcomes across consortia.
Conclusion
Hcy and suggestively vitamin B variants are most likely the drug targets for folate supplementation in pregnant women on the offspring birthweight, while Hcy variants related to renal function or diabetes are not involved.
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Code availability
Strength of the genetic variants was calculated as F = β2exposure/SE2exposure. Two-sample MR analyses were performed by the freely available mrrobust Stata package [42].
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Acknowledgements
This study was based solely on publicly available summary statistics data from published literature (GWASs), the UK Biobank (provided by the Neale lab at: http://www.nealelab.is/uk-biobank/), EGG (Early Growth Genetics) Consortium using the UK Biobank Resource (downloaded at: www.egg-consortium.org) and ReproGen consortium (provided by ReproGen consortium at: https://www.reprogen.org/data_download.html). For this, the authors are deeply grateful to this open collaboration community.
Funding
ADK received financial support from Carl and Ellen Hertz’ foundation and Ellen Pedersen’s scholarship for traveling expenses during her stay as a visiting researcher at the Department of Laboratory Medicine, Boston Children’s Hospital, Boston, USA. YW received financial support from Hesheng Zhujiang foundation for traveling and living expenses during her stay as a visiting researcher at the Department of Laboratory Medicine, Boston Children’s Hospital, Boston, USA. ZW received funding from the National Natural Science Foundation of China (81771606). CE, MNK, and WM report no funding sources.
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Designed research: ADK, YW, CE. Conducted research: ADK, YW, MNK, CE. Provided essential materials: ADK, YW, MNK. Analyzed data and performed statistical analyses: ADK, CE. Wrote paper: ADK. Primary responsibility for final paper: ADK, CE. Supervision of YW for statistical coding and Mendelian randomization analyses: ADK, CE. Interpretation, critical revision, and final approval of the manuscript: all authors.
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Kjaergaard, A.D., Wu, Y., Ming, WK. et al. Homocysteine and female fertility, pregnancy loss and offspring birthweight: a two-sample Mendelian randomization study. Eur J Clin Nutr 76, 40–47 (2022). https://doi.org/10.1038/s41430-021-00898-2
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DOI: https://doi.org/10.1038/s41430-021-00898-2