Exploring the role of genetic confounding in the association between maternal and offspring body mass index: evidence from three birth cohorts

Tom A Bond, Ville Karhunen, Matthias Wielscher, Juha Auvinen, Minna Männikkö, Sirkka M Keinanen-Kiukaanniemi, Marc J Gunter, Janine F Felix, Inga Prokopenko, Jian Yang, Peter M Visscher, David Evans, Sylvain Sebert, Alex Lewin, Paul F O'Reilly, Debbie Lawlor, Marjo-Ritta Jarvelin

Research output: Contribution to journalArticle (Academic Journal)peer-review

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Abstract

Maternal pre-pregnancy body mass index (BMI) is positively associated with offspring birth weight (BW) and BMI in childhood and adulthood. Each of these associations could be due to causal intrauterine effects, or confounding (genetic or environmental), or some combination of these. Here we estimate the extent to which the association between maternal BMI and offspring body size is explained by offspring genotype, as a first step towards establishing the importance of genetic confounding.

Methods
We examined the associations of maternal pre-pregnancy BMI with offspring BW and BMI at 1, 5, 10 and 15 years, in three European birth cohorts (N up to 11 498). Bivariate Genomic-relatedness-based Restricted Maximum Likelihood implemented in the GCTA software (GCTA-GREML) was used to estimate the extent to which phenotypic covariance was explained by offspring genotype as captured by common imputed single nucleotide polymorphisms (SNPs). We merged individual participant data from all cohorts, enabling calculation of pooled estimates.


Results
Phenotypic covariance (equivalent here to Pearson’s correlation coefficient) between maternal BMI and offspring phenotype was 0.15 (95% CI: 0.13, 0.17) for offspring BW, increasing to 0.29 (95% CI: 0.26, 0.31) for offspring 15 year BMI. Covariance explained by offspring genotype was negligible for BW (-0.04 [95% CI: -0.09, 0.01]), but increased to 0.12 (95% CI: 0.04, 0.21) at 15 years, which is equivalent to 43% (95% CI: 15%, 72%) of the phenotypic covariance. Sensitivity analyses using weight, BMI and ponderal index as the offspring phenotype at all ages showed similar results.

Conclusions
Offspring genotype explains a substantial fraction of the covariance between maternal BMI and offspring adolescent BMI. This is consistent with a potentially important role for genetic confounding as a driver of the maternal BMI-offspring BMI association.
Original languageEnglish
Number of pages11
JournalInternational Journal of Epidemiology
DOIs
Publication statusPublished - 10 May 2019

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