ESPEYB25 2. Antenatal and Neonatal Endocrinology Genomic Screening, New Gene Associations (3 abstracts)
2.8. 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 & Rachel M. Freathy
Nat Commun 2025 Jan 14;16(1):648. doi: 10.1038/s41467-024-55761-2
Brief Summary: This study used whole exome sequencing of the UK Biobank cohort to identify maternal or fetal genes with rare variants impacting on birth weight. Fetal gene contributions were examined in up to 234,675 samples with a reported birth weight, and maternal gene contributions were studied in up to 181,883 females who had reported the birth weight of their first child. Independent confirmatory data was obtained from up to 45,622 Icelandic exomes, as well as GWAS common variant associations lying within 300 kb of their identified genes.
Eight genes with rare, deleterious loss of function mutations in the fetus (minor allele frequency < 0.1% ) were identified to impact on birth weight (ACVR1C, IGF1R, INHBE, NOS3, NRK, NYNRIN, PAPPA2, PPARG). For the maternal genes, 3 showed significance (IGF1R, NOS3 - also in fetus and ADAMTS8). Teasing out whether maternal effects also correlated with their effects in the fetus sharing the same genotype, they noted ACVR1C, INHBE, NRK, NYNRIN, PPARG showed evidence of only fetal genotype effects, IGF1R, PAPPA2, and NOS3 were classified as both fetal- and maternal-acting, and ADAMTS8 the only maternal-acting gene. Sex-specificity was seen for stronger PPARG effects on female fetuses. Biologic plausibility is notable for all their genes. The most obvious are the known regulators of fetal-placental growth through IGF bioactivity; IGF1R, PAPPA2 have been associated with several anthropometric measures and IGF-1 levels, with animal data and with human rare variants also strengthening the direct link. Their other key genes have been found associated with adult height, blood pressure, adipose tissue differentiation and regulation as well as likely involved in placental development/function.
This work gives insights that will no doubt be useful for better understanding fetal growth and long-term health.
Volume 22
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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