Exploring the causal effect of maternal pregnancy adiposity on offspring adiposity: Mendelian randomisation using polygenic risk scores
Year: 2022
Type: article
Study design: Observational Study
Abstract: 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.
Source: BMC Medicine
Authors: Tom A Bond, Rebecca C Richmond, Ville Karhunen, Gabriel Cuellar-Partida, Maria Carolina Borges, Verena Zuber, Alexessander Couto Alves, Dan Mason, Tiffany C Yang, Marc J Gunter, Abbas Dehghan, Ioanna Tzoulaki, Sylvain Sebert, David M Evans, Alex M Lewin, Paul F O’Reilly, Deborah A Lawlor, Marjo-Riitta Järvelin
Institutions: The University of Queensland, University of Bristol, MRC Integrative Epidemiology Unit, MRC Centre for Environment and Health, Imperial College London, University of Oulu, 23andMe (United States), University of Cambridge, MRC Biostatistics Unit, University of Surrey, Bradford Teaching Hospitals NHS Foundation Trust, Bradford Institute for Health Research, Centre international de recherche sur le cancer, University of Ioannina, Institute for Molecular Bioscience, London School of Hygiene & Tropical Medicine, Icahn School of Medicine at Mount Sinai, Oulu University Hospital, Brunel University of London
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,690
Funders: World Health Organization, Centre International de Recherche sur le Cancer, Wellcome Trust, Joint Programming Initiative A healthy diet for a healthy life, National Institute for Health and Care Research, British Heart Foundation, European Commission, University of Bristol, Agence Nationale de la Recherche, National Institutes of Health, Horizon 2020 Framework Programme, Medical Research Council, Biotechnology and Biological Sciences Research Council, Economic and Social Research Council, European Research Council, National Health and Medical Research Council, Horizon 2020, H2020 European Research Council
Awards: Understanding the role of fatty acids in the aetiology of cardiovascular disease using novel causal inference methods, G108234597, G1093531541, G1112915806, G1192034430, G119964413, G120984652, G1280324459, Reproductive and cardio-metabolic health, G1340122008, HDHL: A precision nutri-epigenetic approach to tackle the mother-to-child transmission of impaired glucose metabolism, Born in Bradford 2nd Wave, G1430203965, G1502031688, G1605161196, G1653514516, G1693598558, G177484282, G1795554050, NIHR Senior Investigator Award, G1859760469, G1938092250, G2001806450, G205230472, G2216029211, G2233672494, G2326297700, Understanding the dynamic determinants of glucose homeostasis and social capability to promote Healthy and active aging, G2473961061, G2538597952, G2745558375, G2786058305, G2819467015, G2947762186, A precision nutri-epigenetic approach to tackle the mother-to-child transmission of impaired glucose metabolism, Methods and tools for structural models integrating multiple high-throughput omics data sets in genetic epidemiology, Developing and Applying Statistical Genetics Methods to Elucidate the Developmental Origins of Health and Disease, G3102536349, G3105035837, G3198076048, G3207356259, G3345895242, Metabolic effects of Endocrine Disrupting Chemicals: novel testing METhods and adverse outcome pathways, Early-life stressors and LifeCycle health, G3526825588, G3601192221, The Avon Longitudinal Study of Parents and Children (ALSPAC): A multi- generation, longitudinal resource focusing on life course health and well- being., G3683387937, G3831911591, G393177772, G4062506641, G4089438869, G4104038149, G4209017682, G4257455355, G4311186569, G434337789, G4418645022, The Avon Longitudinal Study for Parents and Children: An international resource for population genomic and lifecourse epidemiology. Core programme support 2014-2019., G4471019337, G4586264007, G4596488776, G4633028345, G4735382418, G4758008823, G4815361747, G490277885, G4937468798, G495187929, G4967040218, G5030582063, G5260012927, G5321324157, G5335488906, DTG 2013 & 2014, G5562631338, G5607908600, NIHR Senior Investigator Award, G5640424767, G5702163051, G5834588201, G5959597055, G6073614834, A federated FAIR platform enabling large-scale analysis of high-value cohort data connecting Europe and Canada in personalized health, G6167112780, G621551485, G6230231060, G6251221280, G6421092503, G6562605244, G6620715435, G6689231961, G6726075898, Mendelian randomization to hypothesis-free causal inference, Effects of maternal gestational adiposity on fetal development and perinatal, postnatal and next generation health., G7095874527, G7115303499, Childhood and Adolescence Psychopathology: unravelling the complex etiology by a large Interdisciplinary Collaboration in Europe, G7194418384, G7264751730, G7407801207, G7689853932, G7984235579, G7990456425, G801210579, G819257276, G8201869620, G824700880, G8299541977, G8340598841, G8502142660, G8512683158, Identifying maternal and fetal genetic determinants of infant birthweight and their relationship to offspring cardiometabolic risk, G8789231540, G8793412166
OpenAlex ID: W4210575818