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

Author

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 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 VR, Fonvig, Cilius E, and Trier, Caecilie

Subjects
Biological Sciences, Genetics, Cardiovascular, Perinatal Period - Conditions Originating in Perinatal Period, Nutrition, Prevention, Preterm, Low Birth Weight and Health of the Newborn, Pediatric, Obesity, Conditions Affecting the Embryonic and Fetal Periods, Infant Mortality, 2.1 Biological and endogenous factors, Aetiology, Reproductive health and childbirth, Good Health and Well Being, Adult, Birth Weight, Blood Pressure, Body Height, Diabetes Mellitus, Type 2, Female, Fetal Development, Genetic Predisposition to Disease, Genome-Wide Association Study, Heart Diseases, Humans, Infant, Newborn, Male, Maternal Inheritance, Maternal-Fetal Exchange, Metabolic Diseases, Models, Genetic, Polymorphism, Single Nucleotide, Pregnancy, Risk Factors, EGG Consortium, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
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.

Published
2019

2. Genome-wide survey of parent-of-origin effects on DNA methylation identifies candidate imprinted loci in humans

Author

Cuellar Partida, Gabriel, Laurin, Charles, Ring, Susan M, Gaunt, Tom R, McRae, Allan F, Visscher, Peter M, Montgomery, Grant W, Martin, Nicholas G, Hemani, Gibran, Suderman, Matthew, Relton, Caroline L, Davey Smith, George, and Evans, David M

Subjects
Male, Adolescent, Genome, Human, Quantitative Trait Loci, Infant, Newborn, DNA Methylation, Epigenesis, Genetic, Genomic Imprinting, Surveys and Questionnaires, Humans, CpG Islands, Female, Longitudinal Studies, Association Studies Article, Child, Alleles, Genome-Wide Association Study
Abstract

Genomic imprinting is an epigenetic mechanism leading to parent-of-origin silencing of alleles. So far, the precise number of imprinted regions in humans is uncertain. In this study, we leveraged genome-wide DNA methylation in whole blood measured longitudinally at three time points (birth, childhood and adolescence) and genome-wide association studies (GWAS) data in 740 mother–child duos from the Avon Longitudinal Study of parents and children to identify candidate imprinted loci. We reasoned that cis-meQTLs at genomic regions that were imprinted would show strong evidence of parent-of-origin associations with DNA methylation, enabling the detection of imprinted regions. Using this approach, we identified genome-wide significant cis-meQTLs that exhibited parent-of-origin effects (POEs) at 82 loci, 34 novel and 48 regions previously implicated in imprinting (3.7−10

Published
2018

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

Author

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, 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 VR, 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, 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 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, and Freathy, Rachel M

Subjects
Adult, Male, Heart Diseases, Models, Genetic, Infant, Newborn, Blood Pressure, Polymorphism, Single Nucleotide, Body Height, 3. Good health, Fetal Development, Diabetes Mellitus, Type 2, Metabolic Diseases, Pregnancy, Risk Factors, Birth Weight, Humans, Female, Genetic Predisposition to Disease, Maternal Inheritance, Maternal-Fetal Exchange, Genome-Wide Association Study
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.

4. Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases

Author

Zheng, Jie, Haberland, Valeriia, Baird, Denis, Walker, Venexia, Haycock, Philip C, Hurle, Mark R, Gutteridge, Alex, Erola, Pau, Liu, Yi, Luo, Shan, Robinson, Jamie, Richardson, Tom G, Staley, James R, Elsworth, Benjamin, Burgess, Stephen, Sun, Benjamin B, Danesh, John, Runz, Heiko, Maranville, Joseph C, Martin, Hannah M, Yarmolinsky, James, Laurin, Charles, Holmes, Michael V, Liu, Jimmy Z, Estrada, Karol, Santos, Rita, McCarthy, Linda, Waterworth, Dawn, Nelson, Matthew R, Smith, George Davey, Butterworth, Adam S, Hemani, Gibran, Scott, Robert A, and Gaunt, Tom R

Subjects
Phenotype, Proteome, Humans, Genetic Predisposition to Disease, Blood Proteins, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, 3. Good health, Genome-Wide Association Study
Abstract

The human proteome is a major source of therapeutic targets. Recent genetic association analyses of the plasma proteome enable systematic evaluation of the causal consequences of variation in plasma protein levels. Here we estimated the effects of 1,002 proteins on 225 phenotypes using two-sample Mendelian randomization (MR) and colocalization. Of 413 associations supported by evidence from MR, 130 (31.5%) were not supported by results of colocalization analyses, suggesting that genetic confounding due to linkage disequilibrium is widespread in naïve phenome-wide association studies of proteins. Combining MR and colocalization evidence in cis-only analyses, we identified 111 putatively causal effects between 65 proteins and 52 disease-related phenotypes ( https://www.epigraphdb.org/pqtl/ ). Evaluation of data from historic drug development programs showed that target-indication pairs with MR and colocalization support were more likely to be approved, evidencing the value of this approach in identifying and prioritizing potential therapeutic targets.

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

Author

David Torrents, Thorkild I. A. Sørensen, André G. Uitterlinden, Dorret I. Boomsma, Harry Campbell, Vasiliki Lagou, Joachim Heinrich, Anna Murray, Nicholas J. Timpson, George Dedoussis, Beverley M. Shields, Timo A. Lakka, Lawrence J. Beilin, Carmen J. Marsit, Katharina E. Schraut, Marie Standl, Torben Hansen, James F. Wilson, Jonas Bacelis, Allan Vaag, Louis J. Muglia, Wei Ang, Josep M. Mercader, Ruifang Li-Gao, Ying Wu, Jessica Tyrrell, Pål R. Njølstad, Mohammad Hadi Zafarmand, Marie-France Hivert, Ioanna Ntalla, Debbie A Lawlor, Martina Müller-Nurasyid, Alana Cavadino, Natalia Vilor-Tejedor, Andrew R. Wood, Zoltán Kutalik, Jodie N. Painter, Tanja G. M. Vrijkotte, Kyle J. Gaulton, Xavier Estivill, George Davey Smith, Christine Power, Andrew T. Hattersley, Berthold Hocher, Gibran Hemani, Sheila J. Barton, Aino-Maija Eloranta, Kathryn L. Lunetta, Kim F. Michaelsen, Frank Geller, Bjarke Feenstra, Carol A. Wang, Peter Vollenweider, Wieland Kiess, Anubha Mahajan, Elina Hyppönen, Elisabeth M. van Leeuwen, Felix R. Day, Natalie R. van Zuydam, Leda Chatzi, Bo L. Chawes, Antje Körner, Dennis O. Mook-Kanamori, Ken K. Ong, Joanne M. Murabito, David M. Hougaard, Jian'an Luan, Letizia Marullo, Catharina E. M. van Beijsterveldt, Yik Ying Teo, Andrew P. Morris, Sarah E. Medland, Juan Fernández-Tajes, Jouke-Jan Hottenga, Frits R. Rosendaal, Inga Prokopenko, Katja Pahkala, Struan F.A. Grant, Sylvain Sebert, Judith B. Borja, Camilla Schmidt Morgen, Charlotta Pisinger, Jia Chen, Øyvind Helgeland, Christian Theil Have, Vincent W. V. Jaddoe, Marjolein N. Kooijman, Mika Kähönen, Timothy M. Frayling, Diana L. Cousminer, Bo Jacobsson, Antoine H. C. van Kampen, Eco J. C. de Geus, Manolis Kogevinas, Rico Rueedi, Grant W. Montgomery, Raimo Joro, Craig E. Pennell, Jonathan P. Bradfield, Janine F. Felix, Ge Zhang, Loreto Santa-Marina, Kalliope Panoutsopoulou, John R. B. Perry, Jeff Murray, Albert Hofman, Terho Lehtimäki, John W. Holloway, Barbera D. C. van Schaik, Pedro Marques-Vidal, Ronny Myhre, Haja N. Kadarmideen, Robert A. Scott, Frank D. Mentch, Katherine S. Ruth, Hans Bisgaard, Marjo-Riitta Järvelin, Catherine Allard, Rachel M. Freathy, Julie A. Marsh, Mariona Bustamante, Elisabeth Thiering, Cæcilie Trier, Marcus A. Tuke, William L. Lowe, Elisabeth Widen, Caroline L Relton, Christoph Reichetzeder, Penelope A. Lind, M. Geoffrey Hayes, Charles Laurin, Tarunveer S. Ahluwalia, Meike Bartels, Mads Melbye, Claudia Langenberg, Ke Hao, Shouneng Peng, Nicholas J. Wareham, Susan M. Ring, Hamdi Mbarek, Mario Murcia, Jing Hua Zhao, Michael Nodzenski, Cornelia M. van Duijn, Hakon Hakonarson, Hanieh Yaghootkar, Po-Ru Loh, Linda S. Adair, Sílvia Bonàs-Guarch, Eleftheria Zeggini, Sarah Metrustry, Shikta Das, Gonneke Willemsen, Ana Espinosa, Lavinia Paternoster, Marc Vaudel, Theresia M. Schnurr, Michael Stumvoll, David M. Evans, Bridget A. Knight, Luigi Bouchard, Robin N Beaumont, Mustafa Atalay, Zhen Qiao, Denise M. Scholtens, Klaus Bønnelykke, Samuel E. Jones, Peter K. Joshi, Oluf Pedersen, Jin-Fang Chai, Fernando Rivadeneira, Leo-Pekka Lyytikäinen, Rebecca K. Vinding, Hazel Inskip, Sara M. Willems, Cilius Esmann Fonvig, Momoko Horikoshi, Ellen A. Nohr, Jani Heikkinen, Emil V. R. Appel, Niels Grarup, Michael N. Weedon, Rebecca C Richmond, Peter Kovacs, Jorma Viikari, Amanda J. Bennett, Jens-Christian Holm, Carolina Medina-Gomez, Nicole M. Warrington, Anke Tönjes, Jakob Stokholm, Hugoline G. de Haan, Seang-Mei Saw, Ville Huikari, N. William Rayner, Johan G. Eriksson, Niina Pitkänen, Allan Linneberg, Gunn-Helen Moen, Olli T. Raitakari, Martine Vrijheid, Neil Robertson, Stefan Johansson, Tim D. Spector, Friman Sánchez, Mark I. McCarthy, Harri Niinikoski, Karen L. Mohlke, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Methodology, Warrington, Nicole M, Beaumont, Robin N, Horikoshi, Momoko, Day, Felix R, Hypponen, E, Freathy, RM, EGG consortium, Medical and Clinical Psychology, University of Helsinki, Johan Eriksson / Principal Investigator, University of Helsinki, Institute for Molecular Medicine Finland, Warrington, Nicole M [0000-0003-4195-775X], Beaumont, Robin N [0000-0003-0750-8248], Day, Felix R [0000-0003-3789-7651], Helgeland, Øyvind [0000-0002-5612-2985], Laurin, Charles [0000-0003-2439-9004], Bacelis, Jonas [0000-0002-2450-732X], Feenstra, Bjarke [0000-0003-1478-649X], Mahajan, Anubha [0000-0001-5585-3420], Moen, Gunn-Helen [0000-0002-8768-0904], Schnurr, Theresia M [0000-0002-6573-4959], Grarup, Niels [0000-0001-5526-1070], Paternoster, Lavinia [0000-0003-2514-0889], Rueedi, Rico [0000-0002-6713-2214], Lyytikäinen, Leo-Pekka [0000-0002-7200-5455], Metrustry, Sarah [0000-0003-2028-7486], Wang, Carol A [0000-0002-4301-3974], Joshi, Peter K [0000-0002-6361-5059], Pitkänen, Niina [0000-0001-7383-4987], Richmond, Rebecca C [0000-0003-0574-5071], Inskip, Hazel M [0000-0001-8897-1749], Holloway, John W [0000-0001-9998-0464], Estivill, Xavier [0000-0002-0723-2256], Hocher, Berthold [0000-0001-8143-0579], Lunetta, Kathryn L [0000-0002-9268-810X], Allard, Catherine [0000-0002-8829-4984], Muglia, Louis J [0000-0002-0301-8770], van Kampen, Antoine HC [0000-0003-1025-7232], van Schaik, Barbera DC [0000-0002-5568-8127], Langenberg, Claudia [0000-0002-5017-7344], Hemani, Gibran [0000-0003-0920-1055], Gaulton, Kyle J [0000-0003-1318-7161], Medina-Gomez, Carolina [0000-0001-7999-5538], Kutalik, Zoltán [0000-0001-8285-7523], Marques-Vidal, Pedro [0000-0002-4548-8500], Mbarek, Hamdi [0000-0002-1108-0371], Müller-Nurasyid, Martina [0000-0003-3793-5910], Appel, Emil VR [0000-0001-7704-6611], Fonvig, Cilius E [0000-0002-5031-0125], Hougaard, David M [0000-0001-5928-3517], Mercader, Josep M [0000-0001-8494-3660], Linneberg, Allan [0000-0002-0994-0184], Lind, Penelope A [0000-0002-3887-2598], Medland, Sarah E [0000-0003-1382-380X], Bartels, Meike [0000-0002-9667-7555], Stokholm, Jakob [0000-0003-4989-9769], Chawes, Bo L [0000-0001-6846-6243], Kovacs, Peter [0000-0002-0290-5423], Prokopenko, Inga [0000-0003-1624-7457], Tuke, Marcus A [0000-0003-0008-9263], Ruth, Katherine S [0000-0003-4966-9170], Jones, Samuel E [0000-0003-0153-922X], Zeggini, Eleftheria [0000-0003-4238-659X], Wilson, James F [0000-0001-5751-9178], Vrijkotte, Tanja GM [0000-0003-3641-4048], de Geus, Eco JCN [0000-0001-6022-2666], Kadarmideen, Haja N [0000-0001-6294-382X], Mohlke, Karen L [0000-0001-6721-153X], Sørensen, Thorkild IA [0000-0003-4821-430X], Bisgaard, Hans [0000-0003-4131-7592], Bønnelykke, Klaus [0000-0003-2003-1018], Melbye, Mads [0000-0001-8264-6785], Rivadeneira, Fernando [0000-0001-9435-9441], Felix, Janine F [0000-0002-9801-5774], Jaddoe, Vincent WV [0000-0003-2939-0041], Hansen, Torben [0000-0001-8748-3831], Hyppönen, Elina [0000-0003-3670-9399], Davey Smith, George [0000-0002-1407-8314], Morris, Andrew P [0000-0002-6805-6014], Hakonarson, Hakon [0000-0003-2814-7461], Grant, Struan FA [0000-0003-2025-5302], Lawlor, Debbie A [0000-0002-6793-2262], Njølstad, Pål R [0000-0003-0304-6728], Ong, Ken K [0000-0003-4689-7530], McCarthy, Mark I [0000-0002-4393-0510], Evans, David M [0000-0003-0663-4621], Freathy, Rachel M [0000-0003-4152-2238], Apollo - University of Cambridge Repository, Department of Medical and Clinical Genetics, Institute for Molecular Medicine Finland, Neuroscience Center, Doctoral Programme Brain & Mind, Ecology and Evolutionary Biology, University of Helsinki, Research Groups, Department of General Practice and Primary Health Care, Research Programs Unit, Diabetes and Obesity Research Program, Johan Eriksson / Principal Investigator, Doctoral Programme in Clinical Research, Doctoral Programme in Oral Sciences, Doctoral Programme in Population Health, Centre of Excellence in Complex Disease Genetics, Elisabeth Ingrid Maria Widen / Principal Investigator, Genomic Discoveries and Clinical Translation, University Management, Epidemiology, Erasmus MC other, Internal Medicine, Pediatrics, Epidemiology and Data Science, APH - Global Health, APH - Aging & Later Life, ACS - Atherosclerosis & ischemic syndromes, ARD - Amsterdam Reproduction and Development, Experimental Immunology, Public and occupational health, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism

Subjects
Male, Netherlands Twin Register (NTR), LD SCORE REGRESSION, Birth Weight/genetics, Physiology, Genome-wide association study, BLOOD-PRESSURE, Blood Pressure, Type 2 diabetes, DISEASE, Fetal Development, 0302 clinical medicine, Models, Pregnancy, Risk Factors, Genotype, Birth Weight, maternal genetic, 030212 general & internal medicine, Maternal-Fetal Exchange, 0303 health sciences, Body Height/genetics, 1184 Genetics, developmental biology, physiology, Heart Diseases/etiology, Single Nucleotide, ASSOCIATION, Metabolic Diseases/etiology, 3. Good health, Type 2/etiology, MENDELIAN RANDOMIZATION, GROWTH, Female, Maternal Inheritance, Maternal Inheritance/genetics, Adult, Blood Pressure/genetics, Heart Diseases, Offspring, Birth weight, cardio-metabolic health outcomes, Biology, Diabetes Mellitus, Type 2/etiology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Genetic, Metabolic Diseases, SDG 3 - Good Health and Well-being, Diabetes mellitus, Mendelian randomization, Genetics, medicine, Diabetes Mellitus, Humans, Genetic Predisposition to Disease, Polymorphism, 030304 developmental biology, Glycemic, Fetus, IDENTIFICATION, Models, Genetic, Infant, Newborn, Infant, birth weight, DIABETES-MELLITUS, medicine.disease, Newborn, Fetal Development/genetics, Body Height, Maternal-Fetal Exchange/genetics, LIFE, Blood pressure, Diabetes Mellitus, Type 2, ORIGINS, Institut für Ernährungswissenschaft, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

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.

Published
2019

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