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

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 & 188 others 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

Research output: Contribution to journalArticleScientificpeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)804-814
JournalNature Genetics
Volume51
Issue number5
DOIs
Publication statusPublished - 2019

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Mothers
Alleles
Genome-Wide Association Study
Proxy

Keywords

  • Adult
  • Birth Weight/genetics
  • Blood Pressure/genetics
  • Body Height/genetics
  • Diabetes Mellitus, Type 2/etiology
  • Female
  • Fetal Development/genetics
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Heart Diseases/etiology
  • Humans
  • Infant, Newborn
  • Male
  • Maternal Inheritance/genetics
  • Maternal-Fetal Exchange/genetics
  • Metabolic Diseases/etiology
  • Models, Genetic
  • Polymorphism, Single Nucleotide
  • Pregnancy
  • Risk Factors
  • MENDELIAN RANDOMIZATION
  • BLOOD-PRESSURE
  • DIABETES-MELLITUS
  • GROWTH
  • LD SCORE REGRESSION
  • LIFE
  • IDENTIFICATION
  • ORIGINS
  • DISEASE
  • ASSOCIATION

Cite this

Warrington, N. M., Beaumont, R. N., Horikoshi, M., Day, F. R., Helgeland, Ø., Laurin, C., ... Freathy, R. M. (2019). Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors. Nature Genetics, 51(5), 804-814. https://doi.org/10.1038/s41588-019-0403-1
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 ; 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 ; Morgen, Camilla S. ; Van Kampen, Antoine H. C. ; Van Schaik, Barbera D. C. ; 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 E. M. ; 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, Jakob ; 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 G. M. ; Vrijheid, Martine ; De Geus, Eco J. C. N. ; 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 I. A. ; 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 W. V. ; 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 F. A. ; Frayling, Timothy M. ; Lawlor, Debbie A. ; Njølstad, Pål R. ; Johansson, Stefan ; Ong, Ken K. ; Mccarthy, Mark I. ; Perry, John R. B. ; Evans, David M. ; Freathy, Rachel M. / Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors. In: Nature Genetics. 2019 ; Vol. 51, No. 5. pp. 804-814.
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title = "Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors",
abstract = "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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author = "Warrington, {Nicole M.} and Beaumont, {Robin N.} and Momoko Horikoshi and Day, {Felix R.} and {\O}yvind Helgeland and Charles Laurin and Jonas Bacelis and Shouneng Peng and Ke Hao and Bjarke Feenstra and Wood, {Andrew R.} and Anubha Mahajan and Jessica Tyrrell and Robertson, {Neil R.} and Rayner, {N. William} and Zhen Qiao and Gunn-helen Moen and Marc Vaudel and Marsit, {Carmen J.} and Jia Chen and Michael Nodzenski and Schnurr, {Theresia M.} and Zafarmand, {Mohammad H.} and Bradfield, {Jonathan P.} and Niels Grarup and Kooijman, {Marjolein N.} and Ruifang Li-gao and Frank Geller and Ahluwalia, {Tarunveer S.} and Lavinia Paternoster and Rico Rueedi and Ville Huikari and Jouke-jan Hottenga and Leo-pekka Lyytik{\"a}inen and Alana Cavadino and Sarah Metrustry and Cousminer, {Diana L.} and Ying Wu and Elisabeth Thiering and Wang, {Carol A.} and Have, {Christian T.} and Natalia Vilor-tejedor and Joshi, {Peter K.} and Painter, {Jodie N.} and Ioanna Ntalla and Ronny Myhre and Niina Pitk{\"a}nen and {Van Leeuwen}, {Elisabeth M.} and Raimo Joro and Vasiliki Lagou and Richmond, {Rebecca C.} and Ana Espinosa and Barton, {Sheila J.} and Inskip, {Hazel M.} and Holloway, {John W.} and Loreto Santa-marina and Xavier Estivill and Wei Ang and Marsh, {Julie A.} and Christoph Reichetzeder and Letizia Marullo and Berthold Hocher and Lunetta, {Kathryn L.} and Murabito, {Joanne M.} and Relton, {Caroline L.} and Manolis Kogevinas and Leda Chatzi and Catherine Allard and Luigi Bouchard and Marie-france Hivert and Ge Zhang and Muglia, {Louis J.} and Jani Heikkinen and Morgen, {Camilla S.} and {Van Kampen}, {Antoine H. C.} and {Van Schaik}, {Barbera D. C.} and Mentch, {Frank D.} and Claudia Langenberg and Jian’an Luan and Scott, {Robert A.} and Zhao, {Jing Hua} and Gibran Hemani and Ring, {Susan M.} and Bennett, {Amanda J.} and Gaulton, {Kyle J.} and Juan Fernandez-tajes and {Van Zuydam}, {Natalie R.} and Carolina Medina-gomez and {De Haan}, {Hugoline G.} and Rosendaal, {Frits R.} and Zolt{\'a}n Kutalik and Pedro Marques-vidal and Shikta Das and Gonneke Willemsen and Hamdi Mbarek and Martina M{\"u}ller-nurasyid and Marie Standl and Appel, {Emil V. R.} and Fonvig, {Cilius E.} and Caecilie Trier and {Van Beijsterveldt}, {Catharina E. M.} and Mario Murcia and Mariona Bustamante and S{\'i}lvia Bonas-guarch and Hougaard, {David M.} and Mercader, {Josep M.} and Allan Linneberg and Schraut, {Katharina E.} and Lind, {Penelope A.} and Medland, {Sarah E.} and Shields, {Beverley M.} and Knight, {Bridget A.} and Jin-fang Chai and Kalliope Panoutsopoulou and Meike Bartels and Friman S{\'a}nchez and Jakob Stokholm and David Torrents and Vinding, {Rebecca K.} and Willems, {Sara M.} and Mustafa Atalay and Chawes, {Bo L.} and Peter Kovacs and Inga Prokopenko and Tuke, {Marcus A.} and Hanieh Yaghootkar and Ruth, {Katherine S.} and Jones, {Samuel E.} and Po-ru Loh and Anna Murray and Weedon, {Michael N.} and Anke T{\"o}njes and Michael Stumvoll and Michaelsen, {Kim F.} and Aino-maija Eloranta and Lakka, {Timo A.} and {Van Duijn}, {Cornelia M.} and Wieland Kiess and Antje K{\"o}rner and Harri Niinikoski and Katja Pahkala and Raitakari, {Olli T.} and Bo Jacobsson and Eleftheria Zeggini and Dedoussis, {George V.} and Yik-ying Teo and Seang-mei Saw and Montgomery, {Grant W.} and Harry Campbell and Wilson, {James F.} and Vrijkotte, {Tanja G. M.} and Martine Vrijheid and {De Geus}, {Eco J. C. N.} and Hayes, {M. Geoffrey} and Kadarmideen, {Haja N.} and Jens-christian Holm and Beilin, {Lawrence J.} and Pennell, {Craig E.} and Joachim Heinrich and Adair, {Linda S.} and Borja, {Judith B.} and Mohlke, {Karen L.} and Eriksson, {Johan G.} and Wid{\'e}n, {Elisabeth E.} and Hattersley, {Andrew T.} and Spector, {Tim D.} and Mika K{\"a}h{\"o}nen and Viikari, {Jorma S.} and Terho Lehtim{\"a}ki and Boomsma, {Dorret I.} and Sylvain Sebert and Peter Vollenweider and S{\o}rensen, {Thorkild I. A.} and Hans Bisgaard and Klaus B{\o}nnelykke and Murray, {Jeffrey C.} and Mads Melbye and Nohr, {Ellen A.} and Mook-kanamori, {Dennis O.} and Fernando Rivadeneira and Albert Hofman and Felix, {Janine F.} and Jaddoe, {Vincent W. V.} and Torben Hansen and Charlotta Pisinger and Vaag, {Allan A.} and Oluf Pedersen and Uitterlinden, {Andr{\'e} G.} and Marjo-riitta J{\"a}rvelin and Christine Power and Elina Hypp{\"o}nen and Scholtens, {Denise M.} and Lowe, {William L.} and {Davey Smith}, George and Timpson, {Nicholas J.} and Morris, {Andrew P.} and Wareham, {Nicholas J.} and Hakon Hakonarson and Grant, {Struan F. A.} and Frayling, {Timothy M.} and Lawlor, {Debbie A.} and Nj{\o}lstad, {P{\aa}l R.} and Stefan Johansson and Ong, {Ken K.} and Mccarthy, {Mark I.} and Perry, {John R. B.} and Evans, {David M.} and Freathy, {Rachel M.}",
year = "2019",
doi = "10.1038/s41588-019-0403-1",
language = "English",
volume = "51",
pages = "804--814",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "5",

}

Warrington, NM, Beaumont, RN, Horikoshi, M, Day, FR, Helgeland, Ø, Laurin, C, Bacelis, J, Peng, S, Hao, K, Feenstra, B, Wood, AR, Mahajan, A, Tyrrell, J, Robertson, NR, Rayner, NW, Qiao, Z, Moen, G, Vaudel, M, Marsit, CJ, Chen, J, Nodzenski, M, Schnurr, TM, Zafarmand, MH, Bradfield, JP, Grarup, N, Kooijman, MN, Li-gao, R, Geller, F, Ahluwalia, TS, Paternoster, L, Rueedi, R, Huikari, V, Hottenga, J, Lyytikäinen, L, Cavadino, A, Metrustry, S, Cousminer, DL, Wu, Y, Thiering, E, Wang, CA, Have, CT, Vilor-tejedor, N, Joshi, PK, Painter, JN, Ntalla, I, Myhre, R, Pitkänen, N, Van Leeuwen, EM, Joro, R, Lagou, V, Richmond, RC, Espinosa, A, Barton, SJ, Inskip, HM, Holloway, JW, Santa-marina, L, Estivill, X, Ang, W, Marsh, JA, Reichetzeder, C, Marullo, L, Hocher, B, Lunetta, KL, Murabito, JM, Relton, CL, Kogevinas, M, Chatzi, L, Allard, C, Bouchard, L, Hivert, M, Zhang, G, Muglia, LJ, Heikkinen, J, Morgen, CS, Van Kampen, AHC, Van Schaik, BDC, Mentch, FD, Langenberg, C, Luan, J, Scott, RA, Zhao, JH, Hemani, G, Ring, SM, Bennett, AJ, Gaulton, KJ, Fernandez-tajes, J, Van Zuydam, NR, Medina-gomez, C, De Haan, HG, Rosendaal, FR, Kutalik, Z, Marques-vidal, P, Das, S, Willemsen, G, Mbarek, H, Müller-nurasyid, M, Standl, M, Appel, EVR, Fonvig, CE, Trier, C, Van Beijsterveldt, CEM, Murcia, M, Bustamante, M, Bonas-guarch, S, Hougaard, DM, Mercader, JM, Linneberg, A, Schraut, KE, Lind, PA, Medland, SE, Shields, BM, Knight, BA, Chai, J, Panoutsopoulou, K, Bartels, M, Sánchez, F, Stokholm, J, Torrents, D, Vinding, RK, Willems, SM, Atalay, M, Chawes, BL, Kovacs, P, Prokopenko, I, Tuke, MA, Yaghootkar, H, Ruth, KS, Jones, SE, Loh, P, Murray, A, Weedon, MN, Tönjes, A, Stumvoll, M, Michaelsen, KF, Eloranta, A, Lakka, TA, Van Duijn, CM, Kiess, W, Körner, A, Niinikoski, H, Pahkala, K, Raitakari, OT, Jacobsson, B, Zeggini, E, Dedoussis, GV, Teo, Y, Saw, S, Montgomery, GW, Campbell, H, Wilson, JF, Vrijkotte, TGM, Vrijheid, M, De Geus, EJCN, Hayes, MG, Kadarmideen, HN, Holm, J, Beilin, LJ, Pennell, CE, Heinrich, J, Adair, LS, Borja, JB, Mohlke, KL, Eriksson, JG, Widén, EE, Hattersley, AT, Spector, TD, Kähönen, M, Viikari, JS, Lehtimäki, T, Boomsma, DI, Sebert, S, Vollenweider, P, Sørensen, TIA, Bisgaard, H, Bønnelykke, K, Murray, JC, Melbye, M, Nohr, EA, Mook-kanamori, DO, Rivadeneira, F, Hofman, A, Felix, JF, Jaddoe, VWV, Hansen, T, Pisinger, C, Vaag, AA, Pedersen, O, Uitterlinden, AG, Järvelin, M, Power, C, Hyppönen, E, Scholtens, DM, Lowe, WL, Davey Smith, G, Timpson, NJ, Morris, AP, Wareham, NJ, Hakonarson, H, Grant, SFA, Frayling, TM, Lawlor, DA, Njølstad, PR, Johansson, S, Ong, KK, Mccarthy, MI, Perry, JRB, Evans, DM & Freathy, RM 2019, 'Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors', Nature Genetics, vol. 51, no. 5, pp. 804-814. https://doi.org/10.1038/s41588-019-0403-1

Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors. / 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; 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; Morgen, Camilla S.; Van Kampen, Antoine H. C.; Van Schaik, Barbera D. C.; 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 E. M.; 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, Jakob; 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 G. M.; Vrijheid, Martine; De Geus, Eco J. C. N.; 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 I. A.; 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 W. V.; 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 F. A.; Frayling, Timothy M.; Lawlor, Debbie A.; Njølstad, Pål R.; Johansson, Stefan; Ong, Ken K.; Mccarthy, Mark I.; Perry, John R. B.; Evans, David M.; Freathy, Rachel M.

In: Nature Genetics, Vol. 51, No. 5, 2019, p. 804-814.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors

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 - Lagou, Vasiliki

AU - Richmond, Rebecca C.

AU - Espinosa, Ana

AU - Barton, Sheila J.

AU - Inskip, Hazel M.

AU - Holloway, John W.

AU - Santa-marina, Loreto

AU - Estivill, Xavier

AU - Ang, Wei

AU - Marsh, Julie A.

AU - Reichetzeder, Christoph

AU - Marullo, Letizia

AU - Hocher, Berthold

AU - Lunetta, Kathryn L.

AU - Murabito, Joanne M.

AU - Relton, Caroline L.

AU - Kogevinas, Manolis

AU - Chatzi, Leda

AU - Allard, Catherine

AU - Bouchard, Luigi

AU - Hivert, Marie-france

AU - Zhang, Ge

AU - Muglia, Louis J.

AU - Heikkinen, Jani

AU - Morgen, Camilla S.

AU - Van Kampen, Antoine H. C.

AU - Van Schaik, Barbera D. C.

AU - Mentch, Frank D.

AU - Langenberg, Claudia

AU - Luan, Jian’an

AU - Scott, Robert A.

AU - Zhao, Jing Hua

AU - Hemani, Gibran

AU - Ring, Susan M.

AU - Bennett, Amanda J.

AU - Gaulton, Kyle J.

AU - Fernandez-tajes, Juan

AU - Van Zuydam, Natalie R.

AU - Medina-gomez, Carolina

AU - De Haan, Hugoline G.

AU - Rosendaal, Frits R.

AU - Kutalik, Zoltán

AU - Marques-vidal, Pedro

AU - Das, Shikta

AU - Willemsen, Gonneke

AU - Mbarek, Hamdi

AU - Müller-nurasyid, Martina

AU - Standl, Marie

AU - Appel, Emil V. R.

AU - Fonvig, Cilius E.

AU - Trier, Caecilie

AU - Van Beijsterveldt, Catharina E. M.

AU - Murcia, Mario

AU - Bustamante, Mariona

AU - Bonas-guarch, Sílvia

AU - Hougaard, David M.

AU - Mercader, Josep M.

AU - Linneberg, Allan

AU - Schraut, Katharina E.

AU - Lind, Penelope A.

AU - Medland, Sarah E.

AU - Shields, Beverley M.

AU - Knight, Bridget A.

AU - Chai, Jin-fang

AU - Panoutsopoulou, Kalliope

AU - Bartels, Meike

AU - Sánchez, Friman

AU - Stokholm, Jakob

AU - Torrents, David

AU - Vinding, Rebecca K.

AU - Willems, Sara M.

AU - Atalay, Mustafa

AU - Chawes, Bo L.

AU - Kovacs, Peter

AU - Prokopenko, Inga

AU - Tuke, Marcus A.

AU - Yaghootkar, Hanieh

AU - Ruth, Katherine S.

AU - Jones, Samuel E.

AU - Loh, Po-ru

AU - Murray, Anna

AU - Weedon, Michael N.

AU - Tönjes, Anke

AU - Stumvoll, Michael

AU - Michaelsen, Kim F.

AU - Eloranta, Aino-maija

AU - Lakka, Timo A.

AU - Van Duijn, Cornelia M.

AU - Kiess, Wieland

AU - Körner, Antje

AU - Niinikoski, Harri

AU - Pahkala, Katja

AU - Raitakari, Olli T.

AU - Jacobsson, Bo

AU - Zeggini, Eleftheria

AU - Dedoussis, George V.

AU - Teo, Yik-ying

AU - Saw, Seang-mei

AU - Montgomery, Grant W.

AU - Campbell, Harry

AU - Wilson, James F.

AU - Vrijkotte, Tanja G. M.

AU - Vrijheid, Martine

AU - De Geus, Eco J. C. N.

AU - Hayes, M. Geoffrey

AU - Kadarmideen, Haja N.

AU - Holm, Jens-christian

AU - Beilin, Lawrence J.

AU - Pennell, Craig E.

AU - Heinrich, Joachim

AU - Adair, Linda S.

AU - Borja, Judith B.

AU - Mohlke, Karen L.

AU - Eriksson, Johan G.

AU - Widén, Elisabeth E.

AU - Hattersley, Andrew T.

AU - Spector, Tim D.

AU - Kähönen, Mika

AU - Viikari, Jorma S.

AU - Lehtimäki, Terho

AU - Boomsma, Dorret I.

AU - Sebert, Sylvain

AU - Vollenweider, Peter

AU - Sørensen, Thorkild I. A.

AU - Bisgaard, Hans

AU - Bønnelykke, Klaus

AU - Murray, Jeffrey C.

AU - Melbye, Mads

AU - Nohr, Ellen A.

AU - Mook-kanamori, Dennis O.

AU - Rivadeneira, Fernando

AU - Hofman, Albert

AU - Felix, Janine F.

AU - Jaddoe, Vincent W. V.

AU - Hansen, Torben

AU - Pisinger, Charlotta

AU - Vaag, Allan A.

AU - Pedersen, Oluf

AU - Uitterlinden, André G.

AU - Järvelin, Marjo-riitta

AU - Power, Christine

AU - Hyppönen, Elina

AU - Scholtens, Denise M.

AU - Lowe, William L.

AU - Davey Smith, George

AU - Timpson, Nicholas J.

AU - Morris, Andrew P.

AU - Wareham, Nicholas J.

AU - Hakonarson, Hakon

AU - Grant, Struan F. A.

AU - Frayling, Timothy M.

AU - Lawlor, Debbie A.

AU - Njølstad, Pål R.

AU - Johansson, Stefan

AU - Ong, Ken K.

AU - Mccarthy, Mark I.

AU - Perry, John R. B.

AU - Evans, David M.

AU - Freathy, Rachel M.

PY - 2019

Y1 - 2019

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.

KW - Adult

KW - Birth Weight/genetics

KW - Blood Pressure/genetics

KW - Body Height/genetics

KW - Diabetes Mellitus, Type 2/etiology

KW - Female

KW - Fetal Development/genetics

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Heart Diseases/etiology

KW - Humans

KW - Infant, Newborn

KW - Male

KW - Maternal Inheritance/genetics

KW - Maternal-Fetal Exchange/genetics

KW - Metabolic Diseases/etiology

KW - Models, Genetic

KW - Polymorphism, Single Nucleotide

KW - Pregnancy

KW - Risk Factors

KW - MENDELIAN RANDOMIZATION

KW - BLOOD-PRESSURE

KW - DIABETES-MELLITUS

KW - GROWTH

KW - LD SCORE REGRESSION

KW - LIFE

KW - IDENTIFICATION

KW - ORIGINS

KW - DISEASE

KW - ASSOCIATION

U2 - 10.1038/s41588-019-0403-1

DO - 10.1038/s41588-019-0403-1

M3 - Article

VL - 51

SP - 804

EP - 814

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 5

ER -