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Exploring the causal effect of maternal pregnancy adiposity on offspring adiposity: Mendelian randomisation using polygenic risk scores.

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cam.issuedOnline2022-02-01
dc.contributor.authorBond, Tom A
dc.contributor.authorRichmond, Rebecca C
dc.contributor.authorKarhunen, Ville
dc.contributor.authorCuellar-Partida, Gabriel
dc.contributor.authorBorges, Maria Carolina
dc.contributor.authorZuber, Verena
dc.contributor.authorCouto Alves, Alexessander
dc.contributor.authorMason, Dan
dc.contributor.authorYang, Tiffany C
dc.contributor.authorGunter, Marc J
dc.contributor.authorDehghan, Abbas
dc.contributor.authorTzoulaki, Ioanna
dc.contributor.authorSebert, Sylvain
dc.contributor.authorEvans, David M
dc.contributor.authorLewin, Alex M
dc.contributor.authorO'Reilly, Paul F
dc.contributor.authorLawlor, Deborah A
dc.contributor.authorJärvelin, Marjo-Riitta
dc.contributor.orcidBond, Tom A [0000-0002-9298-6860]
dc.date.accessioned2022-02-01T16:44:29Z
dc.date.available2022-02-01T16:44:29Z
dc.date.issued2022-02-01
dc.date.submitted2021-08-02
dc.date.updated2022-02-01T16:44:29Z
dc.description.abstractBACKGROUND: Greater maternal adiposity before or during pregnancy is associated with greater offspring adiposity throughout childhood, but the extent to which this is due to causal intrauterine or periconceptional mechanisms remains unclear. Here, we use Mendelian randomisation (MR) with polygenic risk scores (PRS) to investigate whether associations between maternal pre-/early pregnancy body mass index (BMI) and offspring adiposity from birth to adolescence are causal. METHODS: We undertook confounder adjusted multivariable (MV) regression and MR using mother-offspring pairs from two UK cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC) and Born in Bradford (BiB). In ALSPAC and BiB, the outcomes were birthweight (BW; N = 9339) and BMI at age 1 and 4 years (N = 8659 to 7575). In ALSPAC only we investigated BMI at 10 and 15 years (N = 4476 to 4112) and dual-energy X-ray absorptiometry (DXA) determined fat mass index (FMI) from age 10-18 years (N = 2659 to 3855). We compared MR results from several PRS, calculated from maternal non-transmitted alleles at between 29 and 80,939 single nucleotide polymorphisms (SNPs). RESULTS: MV and MR consistently showed a positive association between maternal BMI and BW, supporting a moderate causal effect. For adiposity at most older ages, although MV estimates indicated a strong positive association, MR estimates did not support a causal effect. For the PRS with few SNPs, MR estimates were statistically consistent with the null, but had wide confidence intervals so were often also statistically consistent with the MV estimates. In contrast, the largest PRS yielded MR estimates with narrower confidence intervals, providing strong evidence that the true causal effect on adolescent adiposity is smaller than the MV estimates (Pdifference = 0.001 for 15-year BMI). This suggests that the MV estimates are affected by residual confounding, therefore do not provide an accurate indication of the causal effect size. CONCLUSIONS: Our results suggest that higher maternal pre-/early-pregnancy BMI is not a key driver of higher adiposity in the next generation. Thus, they support interventions that target the whole population for reducing overweight and obesity, rather than a specific focus on women of reproductive age.
dc.identifier.doi10.17863/CAM.80934
dc.identifier.eissn1741-7015
dc.identifier.issn1741-7015
dc.identifier.others12916-021-02216-w
dc.identifier.other2216
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/333514
dc.languageen
dc.publisherSpringer Science and Business Media LLC
dc.subjectResearch Article
dc.subjectObesity
dc.subjectBMI
dc.subjectPregnancy
dc.subjectChild
dc.subjectMaternal
dc.subjectOffspring
dc.subjectDOHaD
dc.subjectMendelian randomisation
dc.titleExploring the causal effect of maternal pregnancy adiposity on offspring adiposity: Mendelian randomisation using polygenic risk scores.
dc.typeArticle
dcterms.dateAccepted2021-12-13
prism.issueIdentifier1
prism.publicationNameBMC Med
prism.volume20
pubs.funder-project-idmedical research council (102215/2/13/2, MR/N024397/1, G0600705, MR/K501281/1, MC_UU_00011/1, MC_UU_00011/6, MR/S03658X/1, MR/M013138/1, MR/P014054/1)
pubs.funder-project-idwellcome trust (102215/2/13/2, WT088806, WT101597MA)
pubs.funder-project-ideconomic and social research council (MR/N024397/1)
pubs.funder-project-idbritish heart foundation (CS/16/4/32482, AA/18/7/34219, CH/F/20/90003)
pubs.funder-project-idnational institute for health research (NF-SI-0611-10196, NF-0616-10102)
pubs.funder-project-idnational institutes of health (R01 DK10324)
pubs.funder-project-ideuropean research council (FP7/2007-2013)
pubs.funder-project-idnational health and medical research council (GNT1183074, GNT1157714)
pubs.funder-project-idhorizon 2020 (721567, 733206, 825762, 824989, 721567, 633595)
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1186/s12916-021-02216-w

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