Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors

Funding Information: A.A.V. is an employee of AstraZeneca. S.F.A.G. has received support from GlaxoSmithKline for research that is not related to the study presented in this paper. D.A.L. has received support from Medtronic and Roche Diagnostics for biomarker research that is not related to the study presented in this paper. M.I.M. serves on advisory panels for Pfizer, Novo Nordisk and Zoe Global, has received honoraria from Merck, Pfizer, Novo Nordisk and Eli Lilly, has stock options in Zoe Global, and has received research funding from AbbVie, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Pfizer, Roche, Sanofi–Aventis, Servier and Takeda. Publisher Copyright: © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.Peer reviewe