Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors
Authors: Warrington Nicole M , Beaumont Robin N , Horikoshi Momoko , Day Felix R , Helgeland Øyvind , Laurin Charles , Bacelis Jonas , Peng Shouneng , Hao Ke , Feenstra Bjarke , Wood Andrew R , Mahajan Anubha , Tyrrell Jessica , Robertson Neil R , Rayner N William , Qiao Zhen , Øiseth Moen Gunn-Helen , Vaudel Marc , Marsit Carmen J , Chen Jia , Nodzenski Michael , Schnurr Theresia M , Zafarmand Mohammad H , Bradfield Jonathan P , Grarup Niels , Kooijman Marjolein N , Li-Gao Ruifang , Geller Frank , Ahluwalia Tarunveer S , Paternoster Lavinia , Rueedi Rico , Huikari Ville , Hottenga Jouke-Jan , Lyytikäinen Leo-Pekka , Cavadino Alana , Metrustry Sarah , Cousminer Diana L , Wu Ying , Thiering Elisabeth , Wang Carol A , Have Christian T , Vilor-Tejedor Natalia , Joshi Peter K , Painter Jodie N , Ntalla Ioanna , Myhre Ronny , Pitkänen Niina , van Leeuwen Elisabeth M , Joro Raimo , Lagou Vasiliki , Richmond Rebecca C , Espinosa Ana , Barton Sheila J , Inskip Hazel M , Holloway John W , Santa-Marina Loreto , Estivill Xavier , Ang Wei , Marsh Julie A , Reichetzeder Christoph , Marullo Letizia , Hocher Berthold , Lunetta Kathryn L , Murabito Joanne M , Relton Caroline L , Kogevinas Manolis , Chatzi Leda , Allard Catherine , Bouchard Luigi , Hivert Marie-France , Zhang Ge , Muglia Louis J , Heikkinen Jani ,   Early Growth Genetics (EGG) Consortium, Morgen Camilla S , van Kampen Antoine HC , van Schaik Barbera DC , Mentch Frank D , Langenberg Claudia , Luan Jian’an , Scott Robert A , Zhao Jing Hua , Hemani Gibran , Ring Susan M , Bennett Amanda J , Gaulton Kyle J , Fernandez-Tajes Juan , van Zuydam Natalie R , Medina-Gomez Carolina , de Haan Hugoline G , Rosendaal Frits R , Kutalik Zoltán , Marques-Vidal Pedro , Das Shikta , Willemsen Gonneke , Mbarek Hamdi , Müller-Nurasyid Martina , Standl Marie , Appel Emil V R , Fonvig Cilius E , Trier Caecilie , van Beijsterveldt Catharina EM , Murcia Mario , Bustamante Mariona , Bonas-Guarch Sílvia , Hougaard David M , Mercader Josep M , Linneberg Allan , Schraut Katharina E , Lind Penelope A , Medland Sarah E , Shields Beverley M , Knight Bridget A , Chai Jin-Fang , Panoutsopoulou Kalliope , Bartels Meike , Sánchez Friman , Stokholm Jacob , Torrents David , Vinding Rebecca K , Willems Sara M , Atalay Mustafa , Chawes Bo L , Kovacs Peter , Prokopenko Inga , Tuke Marcus A , Yaghootkar Hanieh , Ruth Katherine S , Jones Samuel E , Loh Po-Ru , Murray Anna , Weedon Michael N , Tönjes Anke , Stumvoll Michael , Michaelsen Kim F , Eloranta Aino-Maija , Lakka Timo A , van Duijn Cornelia M , Kiess Wieland , Körner Antje , Niinikoski Harri , Pahkala Katja , Raitakari Olli T , Jacobsson Bo , Zeggini Eleftheria , Dedoussis George V , Teo Yik-Ying , Saw Seang-Mei , Montgomery Grant W , Campbell Harry , Wilson James F , Vrijkotte Tanja GM , Vrijheid Martine , de Geus Eco JCN , Hayes M Geoffrey , Kadarmideen Haja N , Holm Jens-Christian , Beilin Lawrence J , Pennell Craig E , Heinrich Joachim , Adair Linda S , Borja Judith B , Mohlke Karen L , Eriksson Johan G , Widén Elisabeth E , Hattersley Andrew T , Spector Tim D , Kähönen Mika , Viikari Jorma S , Lehtimäki Terho , Boomsma Dorret I , Sebert Sylvain , Vollenweider Peter , Sørensen Thorkild IA , Bisgaard Hans , Bønnelykke Klaus , Murray Jeffrey C , Melbye Mads , Nohr Ellen A , Mook-Kanamori Dennis O , Rivadeneira Fernando , Hofman Albert , Felix Janine F , Jaddoe Vincent WV , Hansen Torben , Pisinger Charlotta , Vaag Allan A , Pedersen Oluf , Uitterlinden André G , Järvelin Marjo-Riitta , Power Christine , Hyppönen Elina , Scholtens Denise M , Lowe William L , Davey Smith George , Timpson Nicholas J , Morris Andrew P , Wareham Nicholas J , Hakonarson Hakon , Grant Struan FA , Frayling Timothy M , Lawlor Debbie A , Njølstad Pål R , Johansson Stefan , Ong Ken K , McCarthy Mark I , Perry John RB , Evans David M , Freathy Rachel M 
Published: October 2018

Birth weight (BW) variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. These associations have been proposed to reflect the lifelong consequences of an adverse intrauterine environment. In earlier work, we demonstrated that much of the negative correlation between BW and adult cardio-metabolic traits could instead be attributable to shared genetic effects. However, that work and other previous studies did not systematically distinguish the direct effects of an individual’s own genotype on BW and subsequent disease risk from indirect effects of their mother’s correlated genotype, mediated by the intrauterine environment. Here, we describe expanded genome-wide association analyses of own BW (n=321,223) and offspring BW (n=230,069 mothers), which identified 278 independent association signals influencing BW (214 novel). We used structural equation modelling to decompose the contributions of direct fetal and indirect maternal genetic influences on BW, implicating fetal- and maternal-specific mechanisms. We used Mendelian randomization to explore the causal relationships between factors influencing BW through fetal or maternal routes, for example, glycemic traits and blood pressure. Direct fetal genotype effects dominate the shared genetic contribution to the association between lower BW and higher type 2 diabetes risk, whereas the relationship between lower BW and higher later blood pressure (BP) is driven by a combination of indirect maternal and direct fetal genetic effects: indirect effects of maternal BP-raising genotypes act to reduce offspring BW, but only direct fetal genotype effects (once inherited) increase the offspring’s later BP. Instrumental variable analysis using maternal BW-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring BP. In successfully separating fetal from maternal genetic effects, this work represents an important advance in genetic studies of perinatal outcomes, and shows that the association between lower BW and higher adult BP is attributable to genetic effects, and not to intrauterine programming.