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. 2022 Jun 10;12(6):537.
doi: 10.3390/metabo12060537.

Using Mendelian Randomisation to Prioritise Candidate Maternal Metabolic Traits Influencing Offspring Birthweight

Ciarrah-Jane Shannon Barry  1   2 , Deborah A Lawlor  1   2   3 , Chin Yang Shapland  1   2 , Eleanor Sanderson  1   2 , Maria Carolina Borges  1   2
Affiliations

Using Mendelian Randomisation to Prioritise Candidate Maternal Metabolic Traits Influencing Offspring Birthweight

Ciarrah-Jane Shannon Barry et al. Metabolites. .

Abstract

Marked physiological changes in pregnancy are essential to support foetal growth; however, evidence on the role of specific maternal metabolic traits from human studies is limited. We integrated Mendelian randomisation (MR) and metabolomics data to probe the effect of 46 maternal metabolic traits on offspring birthweight (N = 210,267). We implemented univariable two-sample MR (UVMR) to identify candidate metabolic traits affecting offspring birthweight. We then applied two-sample multivariable MR (MVMR) to jointly estimate the potential direct causal effect for each candidate maternal metabolic trait. In the main analyses, UVMR indicated that higher maternal glucose was related to higher offspring birthweight (0.328 SD difference in mean birthweight per 1 SD difference in glucose (95% CI: 0.104, 0.414)), as were maternal glutamine (0.089 (95% CI: 0.033, 0.144)) and alanine (0.137 (95% CI: 0.036, 0.239)). In additional analyses, UVMR estimates were broadly consistent when selecting instruments from an independent data source, albeit imprecise for glutamine and alanine, and were attenuated for alanine when using other UVMR methods. MVMR results supported independent effects of these metabolites, with effect estimates consistent with those seen with the UVMR results. Among the remaining 43 metabolic traits, UVMR estimates indicated a null effect for most lipid-related traits and a high degree of uncertainty for other amino acids and ketone bodies. Our findings suggest that maternal gestational glucose and glutamine are causally related to offspring birthweight.

Keywords: Mendelian randomisation; amino acids; birthweight; genetics; glucose; lipids; maternal; metabolites; nuclear magnetic resonance; offspring.

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Conflict of interest statement

D.A.L. receives support from several national and international government and charitable research funders, as well as from Medtronic Ltd. and Roche Diagnostics for research unrelated to that presented here. All other authors declare no conflict of interest.

Figures

Figure 1
Figure 1
UVMR effect estimates, with 95% confidence interval (CI), for the relation of maternal metabolic traits with offspring birthweight using SNPs selected from UKBB and Kettunen GWAS. Effect estimates (with 95% CI) are expressed as standard deviation (SD) units of offspring birthweight per SD unit change in metabolic trait using the Wald ratio (no. SNPs = 1) or IVW (no. SNPs > 1). The number of SNPs selected from UKBB and Kettunen GWAS for each metabolic trait is available in Table S2. Solid circles identify the metabolic traits that were taken forward to MVMR on the basis of having some evidence for statistical association with birthweight in UVMR (p < 0.05). CI: confidence interval, GWAS: genome-wide association study, MVMR: multivariable Mendelian randomisation, SNP: single-nucleotide polymorphism, UKBB: UK Biobank, UVMR: univariable Mendelian randomisation.
Figure 2
Figure 2
UVMR and MVMR effect estimates, with 95% confidence interval (CI), for six maternal metabolic traits (alanine, glucose, glutamine, isoleucine, pyruvate, and 3-hydroxybutyrate) on birthweight in SNPs selected from UKBB (a) and Kettunen (b) GWAS. UVMR estimates were calculated using the Wald estimate (no. SNPs = 1) or IVW (no. SNPs > 1). All MVMR estimates were calculated using IVW. CI: confidence interval, GWAS: genome-wide association study, IVW: inverse variance weighting, MVMR: multivariable Mendelian randomisation, SNP: single-nucleotide polymorphism, UKBB: UK Biobank, UVMR: univariable Mendelian randomisation.
Figure 2
Figure 2
UVMR and MVMR effect estimates, with 95% confidence interval (CI), for six maternal metabolic traits (alanine, glucose, glutamine, isoleucine, pyruvate, and 3-hydroxybutyrate) on birthweight in SNPs selected from UKBB (a) and Kettunen (b) GWAS. UVMR estimates were calculated using the Wald estimate (no. SNPs = 1) or IVW (no. SNPs > 1). All MVMR estimates were calculated using IVW. CI: confidence interval, GWAS: genome-wide association study, IVW: inverse variance weighting, MVMR: multivariable Mendelian randomisation, SNP: single-nucleotide polymorphism, UKBB: UK Biobank, UVMR: univariable Mendelian randomisation.
Figure 3
Figure 3
A summary of methods used to select and estimate effects of metabolic traits on offspring birthweight in the Mendelian randomisation analysis. GWAS: genome-wide association study, MVMR: multivariable Mendelian randomisation, NMR: nuclear magnetic resonance, SNP: single-nucleotide polymorphism, UKBB: UK Biobank, UVMR: univariable Mendelian randomisation, r2: genetic correlation between SNPs.
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