TY - JOUR
T1 - Maternal plasma cortisol’s effect on offspring birth weight: a Mendelian Randomisation study
AU - Thompson, WD
AU - Reynolds, RM
AU - Beaumont, RN
AU - Warrington, NM
AU - Tyrrell, J
AU - Wood, AR
AU - Evans, DM
AU - Mcdonald, TJ
AU - Hattersley, AH
AU - Freathy, RM
AU - Lawlor, DA
AU - Borges, MC
N1 - Funding Information:
This study was supported by the US National Institute of Health (R01 DK10324), the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013) / ERC grant agreement no 669545, the British Heart Foundation (CS/16/4/32482 and AA/18/7/34219) and the NIHR Biomedical Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The Exeter Family Study of Childhood Health (EFSOCH) was supported by South West NHS Research and Development, Exeter NHS Research and Development, the Darlington Trust and the Peninsula National Institute of Health Research (NIHR) Clinical Research Facility at the University of Exeter. Genotyping of the EFSOCH study samples was funded by Wellcome Trust and Royal Society grant 104150/Z/14/Z. WDT is supported by the GW4 BIOMED DTP awarded to the Universities of Bath, Bristol, Cardiff and Exeter from the UK Medical Research Council (MRC). M-CB was supported by a UK MRC Skills Development Fellowship (MR/P014054/1). RMF and RNB were funded by a Wellcome Trust and Royal Society Sir Henry Dale Fellowship (WT104150). RMF is supported by a Wellcome Senior Research Fellowship (WT220390). M-CB, RMF and DAL work in / are affiliated with a unit that is supported by the University of Bristol and UK Medical Research Council (MC_UU_00011/6). DAL is a NIHR Senior Investigator (NF-0616-10102). ATH is supported by a NIHR Senior Investigator award and also a Wellcome Trust Senior Investigator award (098395/Z/12/Z). TJM is supported by a National Institute of Health Research Senior Clinical Lectureship (ICA-SCL-2016-02-003). RMR acknowledges the support of the British Heart Foundation (RE/18/5/34216). NMW is funded by an Australian National Health and Medical Research Council Investigator Grant (APP2008723). DME is funded by Australian National Health and Medical Research Council Senior Research Fellowships (APP1137714).The funders had no role in the design of the study, the collection, analysis, or interpretation of the data; the writing of the manuscript, or the decision to submit the manuscript for publication. The views expressed in this paper are those of the authors and not necessarily those of any funder.
Funding Information:
This research has been conducted using the UK Biobank Resource under application number 7036. We would like to thank the participants and researchers from the UK Biobank who contributed or collected data and the families that took part in EFSOCH. We are grateful to the Genetics of Complex traits team at the University of Exeter, for their assistance in learning the methods and navigating the study data. The authors would like to acknowledge the use of the University of Exeter high-performance computing (HPC) facility in carrying out this work. This research was funded in part by the Wellcome Trust [Grant number WT220390]. For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.
Funding Information:
This research has been conducted using the UK Biobank Resource under application number 7036. We would like to thank the participants and researchers from the UK Biobank who contributed or collected data and the families that took part in EFSOCH. We are grateful to the Genetics of Complex traits team at the University of Exeter, for their assistance in learning the methods and navigating the study data. The authors would like to acknowledge the use of the University of Exeter high-performance computing (HPC) facility in carrying out this work. This research was funded in part by the Wellcome Trust [Grant number WT220390]. For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.
Publisher Copyright:
© 2024, The Author(s).
PY - 2024/1/24
Y1 - 2024/1/24
N2 - BackgroundObservational studies and randomized controlled trials have found evidence that higher maternal circulating cortisol levels in pregnancy are associated with lower offspring birth weight. However, it is possible that the observational associations are due to residual confounding. Methods We performed two-sample Mendelian Randomisation (MR) using a single genetic variant (rs9989237) associated with morning plasma cortisol (GWAS; sample 1; N = 25,314). The association between this maternal genetic variant and offspring birth weight, adjusted for fetal genotype, was obtained from the published EGG Consortium and UK Biobank meta-analysis (GWAS; sample 2; N = up to 406,063) and a Wald ratio was used to estimate the causal effect. We also performed an alternative analysis using all GWAS reported cortisol variants that takes account of linkage disequilibrium. We also tested the genetic variant’s effect on pregnancy cortisol and performed PheWas to search for potential pleiotropic effects.ResultsThe estimated effect of maternal circulating cortisol on birth weight was a 50 gram (95% CI, -109 to 10) lower birth weight per 1 SD higher log-transformed maternal circulating cortisol levels, using a single variant. The alternative analysis gave similar results (-33 grams (95% CI, -77 to 11)). The effect of the cortisol variant on pregnancy cortisol was 2-fold weaker than in the original GWAS, and evidence was found of pleiotropy. ConclusionsOur findings provide some evidence that higher maternal morning plasma cortisol causes lower birth weight. Identification of more independent genetic instruments for morning plasma cortisol are necessary to explore the potential bias identified.
AB - BackgroundObservational studies and randomized controlled trials have found evidence that higher maternal circulating cortisol levels in pregnancy are associated with lower offspring birth weight. However, it is possible that the observational associations are due to residual confounding. Methods We performed two-sample Mendelian Randomisation (MR) using a single genetic variant (rs9989237) associated with morning plasma cortisol (GWAS; sample 1; N = 25,314). The association between this maternal genetic variant and offspring birth weight, adjusted for fetal genotype, was obtained from the published EGG Consortium and UK Biobank meta-analysis (GWAS; sample 2; N = up to 406,063) and a Wald ratio was used to estimate the causal effect. We also performed an alternative analysis using all GWAS reported cortisol variants that takes account of linkage disequilibrium. We also tested the genetic variant’s effect on pregnancy cortisol and performed PheWas to search for potential pleiotropic effects.ResultsThe estimated effect of maternal circulating cortisol on birth weight was a 50 gram (95% CI, -109 to 10) lower birth weight per 1 SD higher log-transformed maternal circulating cortisol levels, using a single variant. The alternative analysis gave similar results (-33 grams (95% CI, -77 to 11)). The effect of the cortisol variant on pregnancy cortisol was 2-fold weaker than in the original GWAS, and evidence was found of pleiotropy. ConclusionsOur findings provide some evidence that higher maternal morning plasma cortisol causes lower birth weight. Identification of more independent genetic instruments for morning plasma cortisol are necessary to explore the potential bias identified.
U2 - 10.1186/s12884-024-06250-3
DO - 10.1186/s12884-024-06250-3
M3 - Article
SN - 1471-2393
VL - 24
JO - BMC pregnancy and childbirth
JF - BMC pregnancy and childbirth
IS - 1
ER -