Causal effects of maternal circulating amino acids on offspring birthweight: a Mendelian randomisation study

Jian Zhao; Isobel D Stewart; Denis Baird; Dan Mason; John Wright; Jie Zheng; Tom R Gaunt; David M Evans; Rachel M Freathy; Claudia Langenberg; Nicole M Warrington; Deborah A Lawlor; Maria Carolina Borges; MR-PREG Consortium

doi:10.1016/j.ebiom.2023.104441

Causal effects of maternal circulating amino acids on offspring birthweight: a Mendelian randomisation study

EBioMedicine. 2023 Feb:88:104441. doi: 10.1016/j.ebiom.2023.104441. Epub 2023 Jan 23.

Authors

Affiliations

¹ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Bristol NIHR Biomedical Research Centre, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; The Ministry of Education and Shanghai Key Laboratory of Children's Environmental Health, Institute of Early Life Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Maternal and Child Health, School of Public Health, Shanghai Jiao Tong University, Shanghai, China. Electronic address: jian.zhao@bristol.ac.uk.
² MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.
³ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
⁴ Bradford Institute for Health Research, Bradford Teaching Hospitals National Health Service Foundation Trust, Bradford, UK.
⁵ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁶ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Bristol NIHR Biomedical Research Centre, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
⁷ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK; University of Queensland Diamantina Institute, University of Queensland, Brisbane, QLD, Australia; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.
⁸ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter, Exeter, UK.
⁹ MRC Epidemiology Unit, University of Cambridge, Cambridge, UK; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK; Computational Medicine, Berlin Institute of Health (BIH), Charité University Medicine, Berlin, Germany.
¹⁰ University of Queensland Diamantina Institute, University of Queensland, Brisbane, QLD, Australia; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia; K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.

Abstract

Background: Amino acids are key to protein synthesis, energy metabolism, cell signaling and gene expression; however, the contribution of specific maternal amino acids to fetal growth is unclear.

Methods: We explored the effect of maternal circulating amino acids on fetal growth, proxied by birthweight, using two-sample Mendelian randomisation (MR) and summary data from a genome-wide association study (GWAS) of serum amino acids levels (sample 1, n = 86,507) and a maternal GWAS of offspring birthweight in UK Biobank and Early Growth Genetics Consortium, adjusting for fetal genotype effects (sample 2, n = 406,063 with maternal and/or fetal genotype effect estimates). A total of 106 independent single nucleotide polymorphisms robustly associated with 19 amino acids (p < 4.9 × 10^-10) were used as genetic instrumental variables (IV). Wald ratio and inverse variance weighted methods were used in MR main analysis. A series of sensitivity analyses were performed to explore IV assumption violations.

Findings: Our results provide evidence that maternal circulating glutamine (59 g offspring birthweight increase per standard deviation increase in maternal amino acid level, 95% CI: 7, 110) and serine (27 g, 95% CI: 9, 46) raise, while leucine (-59 g, 95% CI: -106, -11) and phenylalanine (-25 g, 95% CI: -47, -4) lower offspring birthweight. These findings are supported by sensitivity analyses.

Interpretation: Our findings strengthen evidence for key roles of maternal circulating amino acids during pregnancy in healthy fetal growth.

Funding: A full list of funding bodies that contributed to this study can be found under Acknowledgments.

Keywords: Amino acids; Birthweight; Causal effect; GWAS; Mendelian randomisation.

MeSH terms

Amino Acids*
Birth Weight / genetics
Female
Fetal Development
Genome-Wide Association Study*
Genotype
Humans
Mendelian Randomization Analysis / methods
Polymorphism, Single Nucleotide
Pregnancy

Substances

Amino Acids

Abstract

MeSH terms

Substances

Grants and funding