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

Accepted version
Peer-reviewed

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Authors

Warrington, Nicole M  ORCID logo  https://orcid.org/0000-0003-4195-775X
Horikoshi, Momoko 

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.

Description

Keywords

Adult, Birth Weight, Blood Pressure, Body Height, Diabetes Mellitus, Type 2, Female, Fetal Development, Genetic Predisposition to Disease, Genome-Wide Association Study, Heart Diseases, Humans, Infant, Newborn, Male, Maternal Inheritance, Maternal-Fetal Exchange, Metabolic Diseases, Models, Genetic, Polymorphism, Single Nucleotide, Pregnancy, Risk Factors

Journal Title

Nat Genet

Conference Name

Journal ISSN

1061-4036
1546-1718

Volume Title

51

Publisher

Springer Science and Business Media LLC

Rights

All rights reserved
Sponsorship
Medical Research Council (MC_UU_12015/1)
MRC (MC_PC_13048)
MRC (MC_PC_13046)
Medical Research Council (MC_UU_12015/2)
Department of Health (via National Institute for Health Research (NIHR)) (NF-SI-0617-10149)
TCC (None)
Medical Research Council (MC_PC_13048)
Medical Research Council (MC_PC_13046)
The Fenland Study is funded by the Medical Research Council (MC_U106179471) and Wellcome Trust.
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