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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Zhao, Jian 
Stewart, Isobel D 
Baird, Denis 
Mason, Dan 
Wright, John 

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.

Description

Keywords

Amino acids, Birthweight, Causal effect, GWAS, Mendelian randomisation, Humans, Pregnancy, Female, Birth Weight, Amino Acids, Genome-Wide Association Study, Genotype, Fetal Development, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide

Journal Title

EBioMedicine

Conference Name

Journal ISSN

2352-3964
2352-3964

Volume Title

88

Publisher

Elsevier BV
Sponsorship
Medical Research Council (MC_UU_12015/1)
MRC (MC_UU_00006/1)