Rare variant associations with birth weight identify genes involved in adipose tissue regulation, placental function and insulin-like growth factor signalling
Abstract Investigating the genetic factors influencing human birth weight may lead to biological insights into fetal growth and long-term health. We report analyses of rare variants that impact birth weight when carried by either fetus or mother, using whole exome sequencing data in up to 234,675 pa...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55761-2 |
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| author | Katherine A. Kentistou Brandon E. M. Lim Lena R. Kaisinger Valgerdur Steinthorsdottir Luke N. Sharp Kashyap A. Patel Vinicius Tragante Gareth Hawkes Eugene J. Gardner Thorhildur Olafsdottir Andrew R. Wood Yajie Zhao Gudmar Thorleifsson Felix R. Day Susan E. Ozanne Andrew T. Hattersley Stephen O’Rahilly Kari Stefansson Ken K. Ong Robin N. Beaumont John R. B. Perry Rachel M. Freathy |
| author_facet | Katherine A. Kentistou Brandon E. M. Lim Lena R. Kaisinger Valgerdur Steinthorsdottir Luke N. Sharp Kashyap A. Patel Vinicius Tragante Gareth Hawkes Eugene J. Gardner Thorhildur Olafsdottir Andrew R. Wood Yajie Zhao Gudmar Thorleifsson Felix R. Day Susan E. Ozanne Andrew T. Hattersley Stephen O’Rahilly Kari Stefansson Ken K. Ong Robin N. Beaumont John R. B. Perry Rachel M. Freathy |
| author_sort | Katherine A. Kentistou |
| collection | DOAJ |
| description | Abstract Investigating the genetic factors influencing human birth weight may lead to biological insights into fetal growth and long-term health. We report analyses of rare variants that impact birth weight when carried by either fetus or mother, using whole exome sequencing data in up to 234,675 participants. Rare protein-truncating and deleterious missense variants are collapsed to perform gene burden tests. We identify 9 genes; 5 with fetal-only effects on birth weight, 1 with maternal-only effects, 3 with both, and observe directionally concordant associations in an independent sample. Four of the genes were previously implicated by GWAS of birth weight. IGF1R and PAPPA2 (fetal and maternal-acting) have known roles in insulin-like growth factor bioavailability and signalling. PPARG, INHBE and ACVR1C (fetal-acting) are involved in adipose tissue regulation, and the latter two also show associations with favourable adiposity patterns in adults. We highlight the dual role of PPARG (fetal-acting) in adipocyte differentiation and placental angiogenesis. NOS3 (fetal and maternal-acting), NRK (fetal), and ADAMTS8 (maternal-acting) have been implicated in placental function and hypertension. To conclude, our analysis of rare coding variants identifies regulators of fetal adipose tissue and fetoplacental angiogenesis as determinants of birth weight, and further evidence for the role of insulin-like growth factors. |
| format | Article |
| id | doaj-art-aa5f7810aacc43149062ed220795d911 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-aa5f7810aacc43149062ed220795d9112025-01-19T12:31:22ZengNature PortfolioNature Communications2041-17232025-01-0116111210.1038/s41467-024-55761-2Rare variant associations with birth weight identify genes involved in adipose tissue regulation, placental function and insulin-like growth factor signallingKatherine A. Kentistou0Brandon E. M. Lim1Lena R. Kaisinger2Valgerdur Steinthorsdottir3Luke N. Sharp4Kashyap A. Patel5Vinicius Tragante6Gareth Hawkes7Eugene J. Gardner8Thorhildur Olafsdottir9Andrew R. Wood10Yajie Zhao11Gudmar Thorleifsson12Felix R. Day13Susan E. Ozanne14Andrew T. Hattersley15Stephen O’Rahilly16Kari Stefansson17Ken K. Ong18Robin N. Beaumont19John R. B. Perry20Rachel M. Freathy21MRC Epidemiology Unit, Box 285 Institute of Metabolic Science, University of Cambridge School of Clinical MedicineDepartment of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of ExeterMRC Epidemiology Unit, Box 285 Institute of Metabolic Science, University of Cambridge School of Clinical MedicinedeCODE genetics/Amgen, Inc., 102 ReykjavikDepartment of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of ExeterDepartment of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of ExeterdeCODE genetics/Amgen, Inc., 102 ReykjavikDepartment of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of ExeterMRC Epidemiology Unit, Box 285 Institute of Metabolic Science, University of Cambridge School of Clinical MedicinedeCODE genetics/Amgen, Inc., 102 ReykjavikDepartment of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of ExeterMRC Epidemiology Unit, Box 285 Institute of Metabolic Science, University of Cambridge School of Clinical MedicinedeCODE genetics/Amgen, Inc., 102 ReykjavikMRC Epidemiology Unit, Box 285 Institute of Metabolic Science, University of Cambridge School of Clinical MedicineMRC Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, University of CambridgeDepartment of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of ExeterMRC Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, University of CambridgedeCODE genetics/Amgen, Inc., 102 ReykjavikMRC Epidemiology Unit, Box 285 Institute of Metabolic Science, University of Cambridge School of Clinical MedicineDepartment of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of ExeterMRC Epidemiology Unit, Box 285 Institute of Metabolic Science, University of Cambridge School of Clinical MedicineDepartment of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of ExeterAbstract Investigating the genetic factors influencing human birth weight may lead to biological insights into fetal growth and long-term health. We report analyses of rare variants that impact birth weight when carried by either fetus or mother, using whole exome sequencing data in up to 234,675 participants. Rare protein-truncating and deleterious missense variants are collapsed to perform gene burden tests. We identify 9 genes; 5 with fetal-only effects on birth weight, 1 with maternal-only effects, 3 with both, and observe directionally concordant associations in an independent sample. Four of the genes were previously implicated by GWAS of birth weight. IGF1R and PAPPA2 (fetal and maternal-acting) have known roles in insulin-like growth factor bioavailability and signalling. PPARG, INHBE and ACVR1C (fetal-acting) are involved in adipose tissue regulation, and the latter two also show associations with favourable adiposity patterns in adults. We highlight the dual role of PPARG (fetal-acting) in adipocyte differentiation and placental angiogenesis. NOS3 (fetal and maternal-acting), NRK (fetal), and ADAMTS8 (maternal-acting) have been implicated in placental function and hypertension. To conclude, our analysis of rare coding variants identifies regulators of fetal adipose tissue and fetoplacental angiogenesis as determinants of birth weight, and further evidence for the role of insulin-like growth factors.https://doi.org/10.1038/s41467-024-55761-2 |
| spellingShingle | Katherine A. Kentistou Brandon E. M. Lim Lena R. Kaisinger Valgerdur Steinthorsdottir Luke N. Sharp Kashyap A. Patel Vinicius Tragante Gareth Hawkes Eugene J. Gardner Thorhildur Olafsdottir Andrew R. Wood Yajie Zhao Gudmar Thorleifsson Felix R. Day Susan E. Ozanne Andrew T. Hattersley Stephen O’Rahilly Kari Stefansson Ken K. Ong Robin N. Beaumont John R. B. Perry Rachel M. Freathy Rare variant associations with birth weight identify genes involved in adipose tissue regulation, placental function and insulin-like growth factor signalling Nature Communications |
| title | Rare variant associations with birth weight identify genes involved in adipose tissue regulation, placental function and insulin-like growth factor signalling |
| title_full | Rare variant associations with birth weight identify genes involved in adipose tissue regulation, placental function and insulin-like growth factor signalling |
| title_fullStr | Rare variant associations with birth weight identify genes involved in adipose tissue regulation, placental function and insulin-like growth factor signalling |
| title_full_unstemmed | Rare variant associations with birth weight identify genes involved in adipose tissue regulation, placental function and insulin-like growth factor signalling |
| title_short | Rare variant associations with birth weight identify genes involved in adipose tissue regulation, placental function and insulin-like growth factor signalling |
| title_sort | rare variant associations with birth weight identify genes involved in adipose tissue regulation placental function and insulin like growth factor signalling |
| url | https://doi.org/10.1038/s41467-024-55761-2 |
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