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Distinction between the effects of parental and fetal genomes on fetal growth

Juliusdottir, Thorhildur and Steinthorsdottir, Valgerdur and Stefansdottir, Lilja and Sveinbjornsson, Gardar and Ivarsdottir, Erna V. and Thorolfsdottir, Rosa B. and Sigurdsson, Jon K. and Tragante, Vinicius and Hjorleifsson, Kristjan E. and Helgadottir, Anna and Frigge, Michael L. and Thorgeirsson, Gudmundur and Benediktsson, Rafn and Sigurdsson, Emil L. and Arnar, David O. and Steingrimsdottir, Thora and Jonsdottir, Ingileif and Holm, Hilma and Gudbjartsson, Daniel F. and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Stefansson, Kari (2021) Distinction between the effects of parental and fetal genomes on fetal growth. Nature Genetics, 53 (8). pp. 1135-1142. ISSN 1061-4036. doi:10.1038/s41588-021-00896-x. https://resolver.caltech.edu/CaltechAUTHORS:20210726-172316356

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[img] Image (JPEG) (Extended Data Fig. 1: Birth weight, offspring birth weight mothers and gestational age) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 2: Sequence variants associating with birth length and their effects on birth weight and birth length) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 3: Discovery of 243 fetal growth variants in five fetal growth analyses) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 4: Mode of action of rs10814916 in GLIS3) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 5: Heatmap displaying effects of variants associating with birth weight and cardiovascular traits arranged by mode of transmission clusters) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 6: Heatmap displaying the effects of PRSs for adult cardio-metabolic traits on fetal growth traits by different transmission modes) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 7: Heatmap displaying effects of variants associating with birth weight and anthropometric traits arranged by mode of transmission clusters) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 8: Cluster probability as a function of strength of association) - Supplemental Material
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Abstract

Birth weight is a common measure of fetal growth that is associated with a range of health outcomes. It is directly affected by the fetal genome and indirectly by the maternal genome. We performed genome-wide association studies on birth weight in the genomes of the child and parents and further analyzed birth length and ponderal index, yielding a total of 243 fetal growth variants. We clustered those variants based on the effects of transmitted and nontransmitted alleles on birth weight. Out of 141 clustered variants, 22 were consistent with parent-of-origin-specific effects. We further used haplotype-specific polygenic risk scores to directly test the relationship between adult traits and birth weight. Our results indicate that the maternal genome contributes to increased birth weight through blood-glucose-raising alleles while blood-pressure-raising alleles reduce birth weight largely through the fetal genome.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1038/s41588-021-00896-xDOIArticle
https://rdcu.be/cpVU5PublisherFree ReadCube access
https://www.decode.com/summarydata/Related ItemGWAS summary statistics
http://mccarthy.well.ox.ac.uk/publications/2019/EggBirthWeight_NatureGenetics/Fetal_BW_European_meta.NG2019.txt.gzRelated ItemDatasets
http://mccarthy.well.ox.ac.uk/publications/2019/EggBirthWeight_NatureGenetics/Maternal_BW_European_meta.NG2019.txt.gzRelated ItemDatasets
https://egg-consortium.org/downloads/EGG-GWAS-BL.txt.gzRelated ItemDatasets
https://github.com/birthw/codeRelated ItemCode
ORCID:
AuthorORCID
Steinthorsdottir, Valgerdur0000-0003-1846-6274
Sveinbjornsson, Gardar0000-0003-2429-9468
Ivarsdottir, Erna V.0000-0002-2069-0681
Thorolfsdottir, Rosa B.0000-0001-7475-0398
Tragante, Vinicius0000-0002-8223-8957
Hjorleifsson, Kristjan E.0000-0002-7851-1818
Helgadottir, Anna0000-0002-1806-2467
Frigge, Michael L.0000-0003-2984-535X
Thorgeirsson, Gudmundur/0000-0002-7146-1395
Benediktsson, Rafn0000-0002-2954-9801
Sigurdsson, Emil L.0000-0003-0796-565X
Arnar, David O.0000-0002-9719-0837
Steingrimsdottir, Thora0000-0002-8161-173X
Jonsdottir, Ingileif0000-0001-8339-150X
Holm, Hilma0000-0002-9517-6636
Gudbjartsson, Daniel F.0000-0002-5222-9857
Thorleifsson, Gudmar0000-0003-4623-9087
Stefansson, Kari0000-0003-1676-864X
Additional Information:© 2021 Nature Publishing Group. Received 16 December 2020; Accepted 11 June 2021; Published 19 July 2021. We thank the participants of this study and the investigators of the FinnGen study. Part of this work was conducted using the UKBB resource (application no. 56270). Data availability: The GWAS summary statistics from this study have been deposited at deCODE genetics (https://www.decode.com/summarydata/). Publicly available datasets used in this study were EGG Consortium datasets: http://mccarthy.well.ox.ac.uk/publications/2019/EggBirthWeight_NatureGenetics/Fetal_BW_European_meta.NG2019.txt.gz, http://mccarthy.well.ox.ac.uk/publications/2019/EggBirthWeight_NatureGenetics/Maternal_BW_European_meta.NG2019.txt.gz and https://egg-consortium.org/downloads/EGG-GWAS-BL.txt.gz. Other data generated or analyzed during this study are included in this article and Supplementary Tables 1–12. Code availability: Custom code has been uploaded to the following GitHub repository: https://github.com/birthw/code. These authors contributed equally: Thorhildur Juliusdottir, Valgerdur Steinthorsdottir. Author Contributions: T.J., V.S., H.H., D.F.G., G. Thorleifsson, U.T. and K.S. designed the study and interpreted the results. V.S., A.H., G. Thorgeirsson, R.B., E.L.S., D.O.A., T.S. and I.J. carried out participant ascertainment and recruitment. T.J., V.S., L.S., G.S., E.V.I., R.B.T., J.K.S., V.T., K.E.H., M.L.F., D.F.G. and G. Thorleifsson performed the statistical and bioinformatics analyses. T.J., V.S., U.T. and K.S. drafted the manuscript. All authors contributed to the final version of the manuscript. Competing interests: T.J., V.S., L.S., G.S., E.V.I., R.B.T., J.K.S., V.T., K.E.H., A.H., M.L.F., G. Thorgeirsson, D.O.A., I.J., H.H., D.F.G., G. Thorleifsson, U.T. and K.S. are affiliated with deCODE Genetics/Amgen and declare competing interests as employees. The other authors declare no competing interests. Peer review information: Nature Genetics thanks Rachel Freathy and David Evans for their contribution to the peer review of this work.
Subject Keywords:Genetics research; Genome-wide association studies
Issue or Number:8
DOI:10.1038/s41588-021-00896-x
Record Number:CaltechAUTHORS:20210726-172316356
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20210726-172316356
Official Citation:Juliusdottir, T., Steinthorsdottir, V., Stefansdottir, L. et al. Distinction between the effects of parental and fetal genomes on fetal growth. Nat Genet 53, 1135–1142 (2021). https://doi.org/10.1038/s41588-021-00896-x
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:110009
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:26 Jul 2021 18:59
Last Modified:13 Aug 2021 18:33

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