Mendelian randomization analysis does not support causal associations of birth weight with hypertension risk and blood pressure in adulthood
Yan Zheng, Tao Huang, Tiange Wang, Zhendong Mei, Zhonghan Sun, Tao Zhang, Christina Ellervik, Jin-Fang Chai, Xueling Sim, Rob van Dam, E-Shyong Tai, Woon-Puay Koh, Rajkumar Dorajoo, Seang-Mei Saw, Charumathi Sabanayagam, Tien Wong, Preeti Gupta, Peter Rossing, Tarunveer Ahluwalia, Rebecca Vinding, Hans Bisgaard, Klaus Bønnelykke, Yujie Wang, Mariaelisa Graff, Trudy Voortman, van Rooij, Frank J A, Albert Hofman, Diana van Heemst, Raymond Noordam, Angela Estampador, Tibor Varga, Cornelia Enzenbach, Markus Scholz, Joachim Thiery, Ralph Burkhardt, Marju Orho-Melander, Christina-Alexandra Schulz, Ulrika Ericson, Emily Sonestedt, Michiaki Kubo, Masato Akiyama, Ang Zhou, Tuomas Kilpeläinen, Torben Hansen, Marcus Kleber, Graciela Delgado, Mark McCarthy, Rozenn Lemaitre, Janine Felix, Vincent Jaddoe, Ying Wu, Karen Mohlke, Terho Lehtimäki, Carol Wang, Craig Pennell, Heribert Schunkert, Thorsten Kessler, Lingyao Zeng, Christina Willenborg, Annette Peters, Wolfgang Lieb, Veit Grote, Peter Rzehak, Berthold Koletzko, Jeanette Erdmann, Matthias Munz, Tangchun Wu, Meian He, Caizheng Yu, Cécile Lecoeur, Philippe Froguel, Dolores Corella, Luis Moreno, Chao-Qiang Lai, Niina Pitkänen, Colin Boreham, Paul Ridker, Frits Rosendaal, Renée Mutsert, Chris Power, Lavinia Paternoster, Thorkild Sørensen, Anne Tjønneland, Kim Overvad, Luc Djousse, Fernando Rivadeneira, Nanette Lee, Olli Raitakari, Mika Kähönen, Jorma Viikari, Jean-Paul Langhendries, Joaquin Escribano, Elvira Verduci, George Dedoussis, Inke König, Beverley Balkau, Oscar Coltell, Jean Dallongeville, Aline Meirhaeghe, Philippe Amouyel, Frédéric Gottrand, Katja Pahkala, Harri Niinikoski, Elina Hyppönen, Winfried März, David Mackey, Dariusz Gruszfeld, Katherine Tucker, Frédéric Fumeron, Ramon Estruch, Jose Ordovas, Donna Arnett, Dennis Mook-Kanamori, Dariush Mozaffarian, Bruce Psaty, Kari North, Daniel Chasman, Lu Qi
Epidemiology studies suggested that low birthweight was associated with a higher risk of hypertension in later life. However, little is known about the causality of such associations. In our study, we evaluated the causal association of low birthweight with adulthood hypertension following a standard analytic protocol using the study-level data of 183,433 participants from 60 studies (CHARGE-BIG consortium), as well as that with blood pressure using publicly available summary-level genome-wide association data from EGG consortium of 153,781 participants, ICBP consortium and UK Biobank cohort together of 757,601 participants. We used seven SNPs as the instrumental variable in the study-level analysis and 47 SNPs in the summary-level analysis. In the study-level analyses, decreased birthweight was associated with a higher risk of hypertension in adults (the odds ratio per 1 standard deviation (SD) lower birthweight, 1.22; 95% CI 1.16 to 1.28), while no association was found between genetically instrumented birthweight and hypertension risk (instrumental odds ratio for causal effect per 1 SD lower birthweight, 0.97; 95% CI 0.68 to 1.41). Such results were consistent with that from the summary-level analyses, where the genetically determined low birthweight was not associated with blood pressure measurements either. One SD lower genetically determined birthweight was not associated with systolic blood pressure (β = – 0.76, 95% CI – 2.45 to 1.08 mmHg), 0.06 mmHg lower diastolic blood pressure (β = – 0.06, 95% CI – 0.93 to 0.87 mmHg), or pulse pressure (β = – 0.65, 95% CI – 1.38 to 0.69 mmHg, all p > 0.05). Our findings suggest that the inverse association of birthweight with hypertension risk from observational studies was not supported by large Mendelian randomization analyses.