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

Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors
Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors
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.
1061-4036
804-814
Warrington, Nicole M
b8baf55f-1bd8-45ae-ab97-cb2d582923ee
Beaumont, Robin N.
78b1b38f-c61b-4a44-ae34-914d4e3592f0
Horikoshi, Momoko
d8c9eadb-1402-442a-be0c-1cd45be763bd
Barton, Sheila
4f674382-ca0b-44ad-9670-e71a0b134ef0
Inskip, Hazel
5fb4470a-9379-49b2-a533-9da8e61058b7
Holloway, John
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
et al.
Warrington, Nicole M
b8baf55f-1bd8-45ae-ab97-cb2d582923ee
Beaumont, Robin N.
78b1b38f-c61b-4a44-ae34-914d4e3592f0
Horikoshi, Momoko
d8c9eadb-1402-442a-be0c-1cd45be763bd
Barton, Sheila
4f674382-ca0b-44ad-9670-e71a0b134ef0
Inskip, Hazel
5fb4470a-9379-49b2-a533-9da8e61058b7
Holloway, John
4bbd77e6-c095-445d-a36b-a50a72f6fe1a

Warrington, Nicole M, Beaumont, Robin N. and Horikoshi, Momoko , et al. (2019) Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors. Nature Genetics, 51 (5), 804-814. (doi:10.1038/s41588-019-0403-1).

Record type: Article

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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More information

Accepted/In Press date: 26 March 2019
e-pub ahead of print date: 1 May 2019
Published date: May 2019

Identifiers

Local EPrints ID: 430656
URI: http://eprints.soton.ac.uk/id/eprint/430656
ISSN: 1061-4036
PURE UUID: aba1ef57-e157-4800-964e-4c28d8216ab7
ORCID for Sheila Barton: ORCID iD orcid.org/0000-0003-4963-4242
ORCID for Hazel Inskip: ORCID iD orcid.org/0000-0001-8897-1749
ORCID for John Holloway: ORCID iD orcid.org/0000-0001-9998-0464

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Date deposited: 07 May 2019 16:30
Last modified: 09 Jan 2022 08:02

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Contributors

Author: Nicole M Warrington
Author: Robin N. Beaumont
Author: Momoko Horikoshi
Author: Sheila Barton ORCID iD
Author: Hazel Inskip ORCID iD
Author: John Holloway ORCID iD
Corporate Author: et al.

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