TY - JOUR
T1 - Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors
AU - EGG Consortium
AU - Warrington, Nicole M.
AU - Beaumont, Robin N.
AU - Horikoshi, Momoko
AU - Day, Felix R.
AU - Helgeland, Øyvind
AU - Laurin, Charles
AU - Bacelis, Jonas
AU - Peng, Shouneng
AU - Hao, Ke
AU - Feenstra, Bjarke
AU - Wood, Andrew R.
AU - Mahajan, Anubha
AU - Tyrrell, Jessica
AU - Robertson, Neil R.
AU - Rayner, N. William
AU - Qiao, Zhen
AU - Moen, Gunn Helen
AU - Vaudel, Marc
AU - Marsit, Carmen J.
AU - Chen, Jia
AU - Nodzenski, Michael
AU - Schnurr, Theresia M.
AU - Zafarmand, Mohammad H.
AU - Bradfield, Jonathan P.
AU - Grarup, Niels
AU - Kooijman, Marjolein N.
AU - Li-Gao, Ruifang
AU - Geller, Frank
AU - Ahluwalia, Tarunveer S.
AU - Paternoster, Lavinia
AU - Rueedi, Rico
AU - Huikari, Ville
AU - Hottenga, Jouke Jan
AU - Lyytikäinen, Leo Pekka
AU - Cavadino, Alana
AU - Metrustry, Sarah
AU - Cousminer, Diana L.
AU - Wu, Ying
AU - Thiering, Elisabeth
AU - Wang, Carol A.
AU - Have, Christian T.
AU - Vilor-Tejedor, Natalia
AU - Joshi, Peter K.
AU - Painter, Jodie N.
AU - Ntalla, Ioanna
AU - Myhre, Ronny
AU - Pitkänen, Niina
AU - van Leeuwen, Elisabeth M.
AU - Joro, Raimo
AU - Zeggini, Eleftheria
N1 - Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2019/5/1
Y1 - 2019/5/1
N2 - Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight–blood pressure association is attributable to genetic effects, and not to intrauterine programming.
AB - Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight–blood pressure association is attributable to genetic effects, and not to intrauterine programming.
UR - https://www.scopus.com/pages/publications/85065213720
U2 - 10.1038/s41588-019-0403-1
DO - 10.1038/s41588-019-0403-1
M3 - Article
C2 - 31043758
AN - SCOPUS:85065213720
SN - 1061-4036
VL - 51
SP - 804
EP - 814
JO - Nature Genetics
JF - Nature Genetics
IS - 5
ER -