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

Publisher: BioMed Central Country of Publication: England NLM ID: 101190723 Publication Model: Electronic Cited Medium: Internet ISSN: 1741-7015 (Electronic) Linking ISSN: 17417015 NLM ISO Abbreviation: BMC Med Subsets: MEDLINE

Original Publication: [London] : BioMed Central, 2003-

Adiposity/*genetics ; Obesity/*genetics; Adolescent ; Alleles ; Body Mass Index ; Child ; Child, Preschool ; Cohort Studies ; Female ; Humans ; Infant ; Longitudinal Studies ; Obesity/etiology ; Pregnancy ; Risk Factors ; United Kingdom

Background: 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 (P difference = 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.
(© 2022. The Author(s).)

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MC_UU_00011/6 United Kingdom MRC_ Medical Research Council; MC_PC_21038 United Kingdom MRC_ Medical Research Council; MC_PC_19009 United Kingdom MRC_ Medical Research Council; MR/S03658X/1 United Kingdom MRC_ Medical Research Council; MR/N024397/1 United Kingdom MRC_ Medical Research Council; MR/K501281/1 United Kingdom MRC_ Medical Research Council; MC_PC_15018 United Kingdom MRC_ Medical Research Council; R01 DK10324 United States NH NIH HHS; MR/M013138/2 United Kingdom MRC_ Medical Research Council; 102215/2/13/2 United Kingdom MRC_ Medical Research Council; MR/P014054/1 United Kingdom MRC_ Medical Research Council; 001 International WHO_ World Health Organization; MC_UU_00011/1 United Kingdom MRC_ Medical Research Council; CH/F/20/90003 United Kingdom BHF_ British Heart Foundation; AA/18/7/34219 United Kingdom BHF_ British Heart Foundation; G0600705 United Kingdom MRC_ Medical Research Council; 102215/2/13/2 United Kingdom WT_ Wellcome Trust; G9815508 United Kingdom MRC_ Medical Research Council; MR/W029790/1 United Kingdom MRC_ Medical Research Council; WT101597MA United Kingdom WT_ Wellcome Trust; United Kingdom WT_ Wellcome Trust; MC_UU_12013/4 United Kingdom MRC_ Medical Research Council; MR/S019669/1 United Kingdom MRC_ Medical Research Council; WT088806 United Kingdom WT_ Wellcome Trust; MR/M013138/1 United Kingdom MRC_ Medical Research Council; CS/16/4/32482 United Kingdom BHF_ British Heart Foundation

Keywords: BMI; Child; DOHaD; Maternal; Mendelian randomisation; Obesity; Offspring; Pregnancy

Date Created: 20220201 Date Completed: 20220323 Latest Revision: 20240405

20240405

PMC8805234

10.1186/s12916-021-02216-w

35101027