Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors.

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

Nat Genet 2019 05 1;51(5):804-814. Epub 2019 May 1.

Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter, Royal Devon and Exeter Hospital, Exeter, UK.

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.

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http://dx.doi.org/10.1038/s41588-019-0403-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522365PMC
May 2019
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