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

Research output: Contribution to journalArticle

  • EGG Consortium
Original languageEnglish
Pages (from-to)804-814
Number of pages11
JournalNature Genetics
Volume51
Issue number5
Early online date1 May 2019
DOIs
DateAccepted/In press - 26 Mar 2019
DateE-pub ahead of print - 1 May 2019
DatePublished (current) - May 2019

Abstract

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.

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