Rare variant associations with birth weight identify genes involved in adipose tissue regulation, placental function and insulin-like growth factor signalling

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 and Rachel M. Freathy ()
Additional contact information
Katherine A. Kentistou: University of Cambridge School of Clinical Medicine
Brandon E. M. Lim: University of Exeter
Lena R. Kaisinger: University of Cambridge School of Clinical Medicine
Valgerdur Steinthorsdottir: 102 Reykjavik
Luke N. Sharp: University of Exeter
Kashyap A. Patel: University of Exeter
Vinicius Tragante: 102 Reykjavik
Gareth Hawkes: University of Exeter
Eugene J. Gardner: University of Cambridge School of Clinical Medicine
Thorhildur Olafsdottir: 102 Reykjavik
Andrew R. Wood: University of Exeter
Yajie Zhao: University of Cambridge School of Clinical Medicine
Gudmar Thorleifsson: 102 Reykjavik
Felix R. Day: University of Cambridge School of Clinical Medicine
Susan E. Ozanne: University of Cambridge
Andrew T. Hattersley: University of Exeter
Stephen O’Rahilly: University of Cambridge
Kari Stefansson: 102 Reykjavik
Ken K. Ong: University of Cambridge School of Clinical Medicine
Robin N. Beaumont: University of Exeter
John R. B. Perry: University of Cambridge School of Clinical Medicine
Rachel M. Freathy: University of Exeter

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-024-55761-2

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