Genome-wide association study of placental weight in 179,025 children and parents reveals distinct and shared genetic influences between placental and fetal growth

Abstract A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight after term delivery as a proxy for placental growth, we report genome-wide association analyses in the fetal ( n = 65,405), maternal ( n = 61,228), and paternal ( n = 52,392) genomes, yielding 40 independent association signals. Twenty-six signals are confidently classified as fetal only, four maternal only, and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1 . Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but twelve loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with risk of preeclampsia or shorter gestational duration. Moreover, these analyses support a role for insulin produced by the fetus in regulating the growth of the placenta, providing a key link between fetal and placental growth.