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1. Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight

Author

Tyrrell, Jessica, Richmond, Rebecca C., Palmer, Tom M., Feenstra, Bjarke, Rangarajan, Janani, Metrustry, Sarah, Cavadino, Alana, Paternoster, Lavinia, Armstrong, Loren L., De Silva, N. Maneka G., Wood, Andrew R., Horikoshi, Momoko, Geller, Frank, Myhre, Ronny, Bradfield, Jonathan P., Kreiner-Møller, Eskil, Huikari, Ville, Painter, Jodie N., Hottenga, Jouke-Jan, Allard, Catherine, Berry, Diane J., Bouchard, Luigi, Das, Shikta, Evans, David M., Hakonarson, Hakon, Hayes, M. Geoffrey, Heikkinen, Jani, Hofman, Albert, Knight, Bridget, Lind, Penelope A., McCarthy, Mark I., McMahon, George, Medland, Sarah E., Melbye, Mads, Morris, Andrew P., Nodzenski, Michael, Reichetzeder, Christoph, Ring, Susan M., Sebert, Sylvain, Sengpiel, Verena, Sørensen, Thorkild I. A., Willemsen, Gonneke, de Geus, Eco J. C., Martin, Nicholas G., Spector, Tim D., Power, Christine, Järvelin, Marjo-Riitta, Bisgaard, Hans, Grant, Struan F. A., Nohr, Ellen A., Jaddoe, Vincent W., Jacobsson, Bo, Murray, Jeffrey C., Hocher, Berthold, Hattersley, Andrew T., Scholtens, Denise M., Davey Smith, George, Hivert, Marie-France, Felix, Janine F., Hyppönen, Elina, Lowe, William L., Jr, Frayling, Timothy M., Lawlor, Debbie A., and Freathy, Rachel M.

Published
2016
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2. Genome-Wide Association Study Identifies Two Novel Loci Associated with Female Stress and Urgency Urinary Incontinence

Author

Cartwright, Rufus, primary, Franklin, Larissa, additional, Tikkinen, Kari A. O., additional, Kalliala, Ilkka, additional, Miotla, Pawel, additional, Rechberger, Tomasz, additional, Offiah, Ifeoma, additional, McMahon, Steve, additional, O’Reilly, Barry, additional, Lince, Sabrina, additional, Kluivers, Kirsten, additional, Post, Wilke M., additional, Poelmans, Geert, additional, Palmer, Melody R., additional, Wessells, Hunter, additional, Wong, Andrew, additional, Kuh, Diana, additional, Kivimaki, Mika, additional, Kumari, Meena, additional, Mangino, Massimo, additional, Spector, Tim, additional, Guggenheim, Jeremy A., additional, Lehne, Benjamin, additional, De Silva, N. Maneka G., additional, Evans, David M., additional, Lawlor, Debbie, additional, Karhunen, Ville, additional, Männikkö, Minna, additional, Marczak, Malgorzata, additional, Bennett, Phillip R., additional, Khullar, Vik, additional, Järvelin, Marjo-Riitta, additional, and Walley, Andrew, additional

Published
2021
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3. Mendelian Randomization Studies Do Not Support a Role for Raised Circulating Triglyceride Levels Influencing Type 2 Diabetes, Glucose Levels, or Insulin Resistance

Author

De Silva, N. Maneka G., Freathy, Rachel M., Palmer, Tom M., Donnelly, Louise A., Luan, Jianʼan, Gaunt, Tom, Langenberg, Claudia, Weedon, Michael N., Shields, Beverley, Knight, Beatrice A., Ward, Kirsten J., Sandhu, Manjinder S., Harbord, Roger M., McCarthy, Mark I., Smith, George Davey, Ebrahim, Shah, Hattersley, Andrew T., Wareham, Nicholas, Lawlor, Debbie A., Morris, Andrew D., Palmer, Colin N.A., and Frayling, Timothy M.

Published
2011
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4. Could vitamin D reduce obesity-associated inflammation? Observational and Mendelian randomization study

Author

Palaniswamy, Saranya, primary, Gill, Dipender, additional, De Silva, N Maneka, additional, Lowry, Estelle, additional, Jokelainen, Jari, additional, Karhu, Toni, additional, Mutt, Shivaprakash J, additional, Dehghan, Abbas, additional, Sliz, Eeva, additional, Chasman, Daniel I, additional, Timonen, Markku, additional, Viinamäki, Heimo, additional, Keinänen-Kiukaanniemi, Sirkka, additional, Hyppönen, Elina, additional, Herzig, Karl-Heinz, additional, Sebert, Sylvain, additional, and Järvelin, Marjo-Riitta, additional

Published
2020
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6. GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI

Author

Da Silva Couto Alves, Alexessander, De Silva, N. Maneka G., Karhunen, Ville, Sovio, Ulla, Das, Shikta, Taal, H. Rob, Warrington, Nicole M., Lewin, Alexandra M., Kaakinen, Marika, Cousminer, Diana L., Thiering, Elisabeth, Timpson, Nicholas J., Bond, Tom A., Lowry, Estelle, Brown, Christopher D., Estivill, Xavier, Lindi, Virpi, Bradfield, Jonathan P., Geller, Frank, Speed, Doug, Coin, Lachlan J. M., Loh, Marie, Barton, Sheila J., Beilin, Lawrence J., Bisgaard, Hans, Bonnelykke, Klaus, Alili, Rohia, Hatoum, Ida J., Schramm, Katharina, Cartwright, Rufus, Charles, Marie-Aline, Salerno, Vincenzo, Clement, Karine, Claringbould, Annique A.J, Consortium, BIOS, van Duijin, Cornelia M., Moltchanova, Elena, Eriksson, Johan G., Elks, Cathy, Feenstra, Bjarke, Flexeder, Claudia, Franks, Stephen, Frayling, Timothy M., Freathy, Rachel M., Elliot, Paul, Widen, Elisabeth, Hakonarson, Hakon, Hattersley, Andrew T., Rodriguez, Alina, Banterle, Marco, Heinrich, Joachim, Heude, Barbara, Holloway, John W., Hofman, Albert, Hypponen, Elina, Inskip, Hazel, Kaplan, Lee M., Hedman, Asa K., Laara, Esa, Prokisch, Holger, Grallert, Harald, Lakka, Timo A., Lawlor, Debbie A., Melbye, Mads, Ahluwalia, Tarunveer S., Marinelli, Marcella, Millwood, Iona Y., Palmer, Lyle J., Pennell, Craig E., Perry, John R., Ring, Susan M., Savolainen, Markku J., Rivadeneira, Fernando, Standl, Marie, Sunyer, Jordi, Tiesler, Carla M.T, Uitterlinden, Andre G., Schierding, William, O'Sullivan, Justin M., Prokopenko, Inga, Herzig, Karl-Heinz, Smith, George Davey, O'Reilly, Paul, Felix, Janine F., Buxton, Jessica L., Blakemore, Alexandra L. F, Ong, Ken K., Jaddoe, Vincent W.V, Grant, Struan F.A, Sebert, Sylvain, McCarthy, Mark L., and Jarvelin, Marjo-Riitta

Abstract

Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.

Published
2019

7. GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child and adult BMI

Author

Alves, Alexessander Couto, De Silva, N. Maneka G., Inskip, Hazel, and Barton, Sheila

Abstract

Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.

Published
2019

8. GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI

Author

BIOS Consortium, Early Growth Genetics EGG Conso, Alves, Alexessander Couto, De Silva, N. Maneka G., Cousminer, Diana L., Eriksson, Johan G., Widen, Elisabeth, Institute for Molecular Medicine Finland, Research Programs Unit, Diabetes and Obesity Research Program, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, HUS Helsinki and Uusimaa Hospital District, Centre of Excellence in Complex Disease Genetics, Elisabeth Ingrid Maria Widen / Principal Investigator, University Management, and Genomic Discoveries and Clinical Translation

Subjects
BODY-MASS INDEX, EARLY-LIFE, AGE, BIRTH COHORT, OBESITY, 1184 Genetics, developmental biology, physiology, BLOOD-PRESSURE, ADIPOSITY, 3111 Biomedicine, GENOME-WIDE ASSOCIATION, METABOLIC RISK, FTO GENE
Abstract

Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.

Published
2019

9. Liver Function and Risk of Type 2 Diabetes: Bidirectional Mendelian Randomization Study

Author

De Silva, N Maneka G, Borges, Maria Carolina, Hingorani, Aroon D, Engmann, Jorgen, Shah, Tina, Zhang, Xiaoshuai, Luan, Jian'an, Langenberg, Claudia, Wong, Andrew, Kuh, Diana, Chambers, John C, Zhang, Weihua, Jarvelin, Marjo-Ritta, Sebert, Sylvain, Auvinen, Juha, UCLEB Consortium, Gaunt, Tom R, Lawlor, Deborah A, Borges, Maria Carolina [0000-0001-7785-4547], Lawlor, Deborah A [0000-0002-6793-2262], and Apollo - University of Cambridge Repository

Subjects
Blood Glucose, endocrine system diseases, nutritional and metabolic diseases, Alanine Transaminase, Fasting, gamma-Glutamyltransferase, Mendelian Randomization Analysis, digestive system, digestive system diseases, Diabetes Mellitus, Type 2, Liver, Risk Factors, Humans, Aspartate Aminotransferases, Insulin Resistance, human activities
Abstract

Liver dysfunction and type 2 diabetes (T2D) are consistently associated. However, it is currently unknown whether liver dysfunction contributes to, results from, or is merely correlated with T2D due to confounding. We used Mendelian randomization to investigate the presence and direction of any causal relation between liver function and T2D risk including up to 64,094 T2D case and 607,012 control subjects. Several biomarkers were used as proxies of liver function (i.e., alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], and γ-glutamyl transferase [GGT]). Genetic variants strongly associated with each liver function marker were used to investigate the effect of liver function on T2D risk. In addition, genetic variants strongly associated with T2D risk and with fasting insulin were used to investigate the effect of predisposition to T2D and insulin resistance, respectively, on liver function. Genetically predicted higher circulating ALT and AST were related to increased risk of T2D. There was a modest negative association of genetically predicted ALP with T2D risk and no evidence of association between GGT and T2D risk. Genetic predisposition to higher fasting insulin, but not to T2D, was related to increased circulating ALT. Since circulating ALT and AST are markers of nonalcoholic fatty liver disease (NAFLD), these findings provide some support for insulin resistance resulting in NAFLD, which in turn increases T2D risk.

Published
2019
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10. The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia

Author

Middeldorp, Christel M., Mahajan, Anubha, Horikoshi, Momoko, Robertson, Neil R., Beaumont, Robin N., Bradfield, Jonathan P., Bustamante, Mariona, Cousminer, Diana L., Day, Felix R., De Silva, N. Maneka, Guxens, Monica, Mook-Kanamori, Dennis O., St Pourcain, Beate, Warrington, Nicole M., Adair, Linda S., Ahlqvist, Emma, Ahluwalia, Tarunveer Singh, Almgren, Peter, Ang, Wei, Atalay, Mustafa, Auvinen, Juha, Bartels, Meike, Beckmann, Jacques S., Bilbao, Jose Ramon, Bond, Tom, Borja, Judith B., Cavadino, Alana, Charoen, Pimphen, Chen, Zhanghua, Coin, Lachlan, Cooper, Cyrus, Curtin, John A., Custovic, Adnan, Das, Shikta, Davies, Gareth E., Dedoussis, George V., Duijts, Liesbeth, Eastwood, Peter R., Eliasen, Anders U., Elliott, Paul, Eriksson, Johan G., Estivill, Xavier, Fadista, Joao, Fedko, Iryna O., Frayling, Timothy M., Gaillard, Romy, Gauderman, W. James, Geller, Frank, Gilliland, Frank, Gilsanz, Vincente, Granell, Raquel, Grarup, Niels, Groop, Leif, Hadley, Dexter, Hakonarson, Hakon, Hansen, Torben, Hartman, Catharina A., Hattersley, Andrew T., Hayes, M. Geoffrey, Hebebrand, Johannes, Heinrich, Joachim, Helgeland, Oyvind, Henders, Anjali K., Henderson, John, Henriksen, Tine B., Hirschhorn, Joel N., Hivert, Marie-France, Hocher, Berthold, Holloway, John W., Holt, Patrick, Hottenga, Jouke-Jan, Hypponen, Elina, Iniguez, Carmen, Johansson, Stefan, Jugessur, Astanand, Kahonen, Mika, Kalkwarf, Heidi J., Kaprio, Jaakko, Karhunen, Ville, Kemp, John P., Kerkhof, Marjan, Koppelman, Gerard H., Korner, Antje, Kotecha, Sailesh, Kreiner-Moller, Eskil, Kulohoma, Benard, Kumar, Ashish, Kutalik, Zoltan, Lahti, Jari, Lappe, Joan M., Larsson, Henrik, Lehtimaki, Terho, Lewin, Alexandra M., Li, Jin, Lichtenstein, Paul, Lindgren, Cecilia M., Lindi, Virpi, Linneberg, Allan, Liu, Xueping, Liu, Jun, Lowe, William L., Lundstrom, Sebastian, Lyytikainen, Leo-Pekka, Ma, Ronald C. W., Mace, Aurelien, Magi, Reedik, Magnus, Per, Mamun, Abdullah A., Mannikko, Minna, Martin, Nicholas G., Mbarek, Hamdi, McCarthy, Nina S., Medland, Sarah E., Melbye, Mads, Melen, Erik, Mohlke, Karen L., Monnereau, Claire, Morgen, Camilla S., Morris, Andrew P., Murray, Jeffrey C., Myhre, Ronny, Najman, Jackob M., Nivard, Michel G., Nohr, Ellen A., Nolte, Ilja M., Ntalla, Ioanna, Oberfield, Sharon E., Oken, Emily, Oldehinkel, Albertine J., Pahkala, Katja, Palviainen, Teemu, Panoutsopoulou, Kalliope, Pedersen, Oluf, Pennell, Craig E., Pershagen, Goran, Pitkanen, Niina, Plomin, Robert, Power, Christine, Prasad, Rashmi B., Prokopenko, Inga, Pulkkinen, Lea, Raikkonen, Katri, Raitakari, Olli T., Reynolds, Rebecca M., Richmond, Rebecca C., Rivadeneira, Fernando, Rodriguez, Alina, Rose, Richard J., Salem, Rany, Santa-Marina, Loreto, Saw, Seang-Mei, Schnurr, Theresia M., Scott, James G., Selzam, Saskia, Shepherd, John A., Simpson, Angela, Skotte, Line, Sleiman, Patrick M. A., Snieder, Harold, Sorensen, Thorkild I. A., Standl, Marie, Steegers, Eric A. P., Strachan, David P., Straker, Leon, Strandberg, Timo, Taylor, Michelle, Teo, Yik-Ying, Thiering, Elisabeth, Torrent, Maties, Tyrrell, Jessica, Uitterlinden, Andre G., van Beijsterveldt, Toos, van der Most, Peter J., van Duijn, Cornelia M., Viikari, Jorma, Vilor-Tejedor, Natalia, Vogelezang, Suzanne, Vonk, Judith M., Vrijkotte, Tanja G. M., Vuoksimaa, Eero, Wang, Carol A., Watkins, William J., Wichmann, H-Erich, Willemsen, Gonneke, Williams, Gail M., Wilson, James F., Wray, Naomi R., Xu, Shujing, Xu, Cheng-Jian, Yaghootkar, Hanieh, Yi, Lu, Zafarmand, Mohammad Hadi, Zeggini, Eleftheria, Zemel, Babette S., Hinney, Anke, Lakka, Timo A., Whitehouse, Andrew J. O., Sunyer, Jordi, Widen, Elisabeth E., Feenstra, Bjarke, Sebert, Sylvain, Jacobsson, Bo, Njolstad, Pal R., Stoltenberg, Camilla, Smith, George Davey, Lawlor, Debbie A., Paternoster, Lavinia, Timpson, Nicholas J., Ong, Ken K., Bisgaard, Hans, Bonnelykke, Klaus, Jaddoe, Vincent W. V., Tiemeier, Henning, Jarvelin, Marjo-Riitta, Evans, David M., Perry, John R. B., Grant, Struan F. A., Boomsma, Dorret I., Freathy, Rachel M., McCarthy, Mark I., and Felix, Janine F.

Subjects
ddc:570, Institut für Biochemie und Biologie
Abstract

The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.

Published
2019

11. GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI

Author

Couto Alves, Alexessander, De Silva, N Maneka G, Karhunen, Ville, Sovio, Ulla, Das, Shikta, Taal, H Rob, Warrington, Nicole M, Lewin, Alexandra M, Kaakinen, Marika, Cousminer, Diana L, Thiering, Elisabeth, Timpson, Nicholas J, Bond, Tom A, Lowry, Estelle, Brown, Christopher D, Estivill, Xavier, Lindi, Virpi, Bradfield, Jonathan P, Geller, Frank, Speed, Doug, Coin, Lachlan J M, Loh, Marie, Barton, Sheila J, Beilin, Lawrence J, Bisgaard, Hans, Bønnelykke, Klaus, Alili, Rohia, Hatoum, Ida J, Schramm, Katharina, Cartwright, Rufus, Charles, Marie-Aline, Salerno, Vincenzo, Clément, Karine, Claringbould, Annique A J, Van Duijn, Cornelia M, Moltchanova, Elena, Eriksson, Johan G, Elks, Cathy, Feenstra, Bjarke, Flexeder, Claudia, Franks, Stephen, Frayling, Timothy M, Freathy, Rachel M, Elliott, Paul, Widén, Elisabeth, Hakonarson, Hakon, Hattersley, Andrew T, Rodriguez, Alina, Banterle, Marco, Heinrich, Joachim, Heude, Barbara, Holloway, John W, Hofman, Albert, Hyppönen, Elina, Inskip, Hazel, Kaplan, Lee M, Hedman, Asa K, Läärä, Esa, Prokisch, Holger, Grallert, Harald, Lakka, Timo A, Lawlor, Debbie A, Melbye, Mads, Ahluwalia, Tarunveer S, Marinelli, Marcella, Millwood, Iona Y, Palmer, Lyle J, Pennell, Craig E, Perry, John R, Ring, Susan M, Savolainen, Markku J, Rivadeneira, Fernando, Standl, Marie, Sunyer, Jordi, Tiesler, Carla M T, Uitterlinden, Andre G, Schierding, William, O'Sullivan, Justin M, Prokopenko, Inga, Herzig, Karl-Heinz, Smith, George Davey, O'Reilly, Paul, Felix, Janine F, Buxton, Jessica L, Blakemore, Alexandra I F, Ong, Ken K, Jaddoe, Vincent W V, Grant, Struan F A, Sebert, Sylvain, McCarthy, Mark I, Järvelin, Marjo-Riitta, Erasmus MC other, Epidemiology, Internal Medicine, Pediatrics, Medical Research Council (MRC), Sovio, Ulla [0000-0002-0799-1105], Perry, John [0000-0001-6483-3771], Ong, Kenneth [0000-0003-4689-7530], Apollo - University of Cambridge Repository, Warrington, Nicole M [0000-0003-4195-775X], Lewin, Alexandra M [0000-0003-0081-7582], Kaakinen, Marika [0000-0002-9228-0462], Cousminer, Diana L [0000-0001-8864-7893], Timpson, Nicholas J [0000-0002-7141-9189], Lowry, Estelle [0000-0002-4655-416X], Brown, Christopher D [0000-0002-3785-5008], Estivill, Xavier [0000-0002-0723-2256], Geller, Frank [0000-0002-9238-3269], Speed, Doug [0000-0002-0096-9765], Coin, Lachlan J M [0000-0002-4300-455X], Loh, Marie [0000-0003-3626-8466], Barton, Sheila J [0000-0003-4963-4242], Alili, Rohia [0000-0002-0158-4250], Schramm, Katharina [0000-0002-8809-3170], Charles, Marie-Aline [0000-0003-4025-4390], Claringbould, Annique A J [0000-0002-9201-6557], van Duijn, Cornelia M [0000-0002-2374-9204], Feenstra, Bjarke [0000-0003-1478-649X], Frayling, Timothy M [0000-0001-8362-2603], Freathy, Rachel M [0000-0003-4152-2238], Widén, Elisabeth [0000-0001-7108-2806], Hakonarson, Hakon [0000-0003-2814-7461], Rodriguez, Alina [0000-0003-1209-8802], Heude, Barbara [0000-0002-1565-1629], Holloway, John W [0000-0001-9998-0464], Hofman, Albert [0000-0002-9865-121X], Hyppönen, Elina [0000-0003-3670-9399], Inskip, Hazel [0000-0001-8897-1749], Kaplan, Lee M [0000-0002-6301-2696], Prokisch, Holger [0000-0003-2379-6286], Lakka, Timo A [0000-0002-9199-2871], Lawlor, Debbie A [0000-0002-6793-2262], Melbye, Mads [0000-0001-8264-6785], Ahluwalia, Tarunveer S [0000-0002-7464-3354], Marinelli, Marcella [0000-0002-5450-3960], Palmer, Lyle J [0000-0002-1628-3055], Pennell, Craig E [0000-0002-0937-6165], Perry, John R [0000-0001-6483-3771], Ring, Susan M [0000-0003-3103-9330], Savolainen, Markku J [0000-0002-2557-6423], Rivadeneira, Fernando [0000-0001-9435-9441], Sunyer, Jordi [0000-0002-2602-4110], Schierding, William [0000-0001-5659-2701], O'Sullivan, Justin M [0000-0003-2927-450X], Prokopenko, Inga [0000-0003-1624-7457], Smith, George Davey [0000-0002-1407-8314], Felix, Janine F [0000-0002-9801-5774], Ong, Ken K [0000-0003-4689-7530], Jaddoe, Vincent W V [0000-0003-2939-0041], Sebert, Sylvain [0000-0001-6681-6983], McCarthy, Mark I [0000-0002-4393-0510], and Järvelin, Marjo-Riitta [0000-0002-2149-0630]

Subjects
Adult, Male, Pharmacogenomic Variants, Quantitative Trait Loci, BLOOD-PRESSURE, 030209 endocrinology & metabolism, Polymorphism, Single Nucleotide, Body Mass Index, EARLY-LIFE, 03 medical and health sciences, AGE, Quantitative Trait, Heritable, 0302 clinical medicine, Humans, Genetic Predisposition to Disease, Longitudinal Studies, 030212 general & internal medicine, GENOME-WIDE ASSOCIATION, METABOLIC RISK, Growth Charts, FTO GENE, Child, Research Articles, Genetic Association Studies, Adaptor Proteins, Signal Transducing, 2. Zero hunger, Science & Technology, BIRTH COHORT, Intracellular Signaling Peptides and Proteins, nutritional and metabolic diseases, SciAdv r-articles, Infant, Human Genetics, Genomics, 3. Good health, Multidisciplinary Sciences, BODY-MASS INDEX, OBESITY, Science & Technology - Other Topics, Receptors, Leptin, ADIPOSITY, Female, biological, Research Article, Genome-Wide Association Study
Abstract

Longitudinal data find a new variant controlling BMI in infancy and reveal genetic differences between infant and adult BMI., Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.

Published
2019

12. The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia : design, results and future prospects

Author

Middeldorp, Christel M., Mahajan, Anubha, Horikoshi, Momoko, Robertson, Neil R., Beaumont, Robin N., Bradfield, Jonathan P., Bustamante, Mariona, Cousminer, Diana L., Day, Felix R., De Silva, N. Maneka, Guxens, Monica, Mook-Kanamori, Dennis O., St Pourcain, Beate, Warrington, Nicole M., Adair, Linda S., Ahlqvist, Emma, Ahluwalia, Tarunveer S., Almgren, Peter, Ang, Wei, Atalay, Mustafa, Auvinen, Juha, Bartels, Meike, Beckmann, Jacques S., Bilbao, Jose Ramon, Bond, Tom, Borja, Judith B., Cavadino, Alana, Charoen, Pimphen, Chen, Zhanghua, Coin, Lachlan, Cooper, Cyrus, Curtin, John A., Custovic, Adnan, Das, Shikta, Davies, Gareth E., Dedoussis, George V., Duijts, Liesbeth, Eastwood, Peter R., Eliasen, Anders U., Elliott, Paul, Eriksson, Johan G., Estivill, Xavier, Fadista, Joao, Fedko, Iryna O., Frayling, Timothy M., Gaillard, Romy, Gauderman, W. James, Geller, Frank, Gilliland, Frank, Gilsanz, Vincente, Granell, Raquel, Grarup, Niels, Groop, Leif, Hadley, Dexter, Hakonarson, Hakon, Hansen, Torben, Hartman, Catharina A., Hattersley, Andrew T., Hayes, M. Geoffrey, Hebebrand, Johannes, Heinrich, Joachim, Helgeland, Oyvind, Henders, Anjali K., Henderson, John, Henriksen, Tine B., Hirschhorn, Joel N., Hivert, Marie-France, Hocher, Berthold, Holloway, John W., Holt, Patrick, Hottenga, Jouke-Jan, Hypponen, Elina, Iniguez, Carmen, Johansson, Stefan, Jugessur, Astanand, Kahonen, Mika, Kalkwarf, Heidi J., Kaprio, Jaakko, Karhunen, Ville, Kemp, John P., Kerkhof, Marjan, Koppelman, Gerard H., Korner, Antje, Kotecha, Sailesh, Kreiner-Moller, Eskil, Kulohoma, Benard, Kumar, Ashish, Kutalik, Zoltan, Lahti, Jari, Lappe, Joan M., Larsson, Henrik, Lehtimaki, Terho, Lewin, Alexandra M., Li, Jin, Lichtenstein, Paul, Lindgren, Cecilia M., Lindi, Virpi, Linneberg, Allan, Liu, Xueping, Liu, Jun, Lowe, William L., Jr., Lundstrom, Sebastian, Lyytikainen, Leo-Pekka, Ma, Ronald C. W., Mace, Aurelien, Magi, Reedik, Magnus, Per, Mamun, Abdullah A., Mannikko, Minna, Martin, Nicholas G., Mbarek, Hamdi, McCarthy, Nina S., Medland, Sarah E., Melbye, Mads, Melen, Erik, Mohlke, Karen L., Monnereau, Claire, Morgen, Camilla S., Morris, Andrew P., Murray, Jeffrey C., Myhre, Ronny, Najman, Jackob M., Nivard, Michel G., Nohr, Ellen A., Nolte, Ilja M., Ntalla, Ioanna, O'Reilly, Paul, Oberfield, Sharon E., Oken, Emily, Oldehinkel, Albertine J., Pahkala, Katja, Palviainen, Teemu, Panoutsopoulou, Kalliope, Pedersen, Oluf, Pennell, Craig E., Pershagen, Goran, Pitkanen, Niina, Plomin, Robert, Power, Christine, Prasad, Rashmi B., Prokopenko, Inga, Pulkkinen, Lea, Raikkonen, Katri, Raitakari, Olli T., Reynolds, Rebecca M., Richmond, Rebecca C., Rivadeneira, Fernando, Rodriguez, Alina, Rose, Richard J., Salem, Rany, Santa-Marina, Loreto, Saw, Seang-Mei, Schnurr, Theresia M., Scott, James G., Selzam, Saskia, Shepherd, John A., Simpson, Angela, Skotte, Line, Sleiman, Patrick M. A., Snieder, Harold, Sørensen, Thorkild I. A., Standl, Marie, Steegers, Eric A. P., Strachan, David P., Straker, Leon, Strandberg, Timo, Taylor, Michelle, Teo, Yik-Ying, Thiering, Elisabeth, Torrent, Maties, Tyrrell, Jessica, Uitterlinden, Andre G., van Beijsterveldt, Toos, van der Most, Peter J., van Duijn, Cornelia M., Viikari, Jorma, Vilor-Tejedor, Natalia, Vogelezang, Suzanne, Vonk, Judith M., Vrijkotte, Tanja G. M., Vuoksimaa, Eero, Wang, Carol A., Watkins, William J., Wichmann, H-Erich, Willemsen, Gonneke, Williams, Gail M., Wilson, James F., Wray, Naomi R., Xu, Shujing, Xu, Cheng-Jian, Yaghootkar, Hanieh, Yi, Lu, Zafarmand, Mohammad Hadi, Zeggini, Eleftheria, Zemel, Babette S., Hinney, Anke, Lakka, Timo A., Whitehouse, Andrew J. O., Sunyer, Jordi, Widen, Elisabeth E., Feenstra, Bjarke, Sebert, Sylvain, Jacobsson, Bo, Njolstad, Pal R., Stoltenberg, Camilla, Smith, George Davey, Lawlor, Debbie A., Paternoster, Lavinia, Timpson, Nicholas J., Ong, Ken K., Bisgaard, Hans, Bonnelykke, Klaus, Jaddoe, Vincent W. V., Tiemeier, Henning, Jarvelin, Marjo-Riitta, Evans, David M., Perry, John R. B., Grant, Struan F. A., Boomsma, Dorret I., Freathy, Rachel M., McCarthy, Mark I., Felix, Janine F., Sorensen, Thorkild I. A., Tiemeier, Hen-Ning, Biological Psychology, APH - Mental Health, APH - Personalized Medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Methodology, APH - Health Behaviors & Chronic Diseases, Pediatrics, Epidemiology, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Groningen Research Institute for Asthma and COPD (GRIAC), Life Course Epidemiology (LCE), Public and occupational health, APH - Aging & Later Life, ARD - Amsterdam Reproduction and Development, ACS - Atherosclerosis & ischemic syndromes, APH - Global Health, Epidemiology and Data Science, Medical Research Council (MRC), Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Centre of Excellence in Complex Disease Genetics, Institute for Molecular Medicine Finland, University of Helsinki, Department of Public Health, Clinicum, Doctoral Programme in Cognition, Learning, Instruction and Communication, Department of Psychology and Logopedics, Helsinki Collegium for Advanced Studies, Faculty of Medicine, Timo Strandberg / Principal Investigator, Department of Medicine, Elisabeth Ingrid Maria Widen / Principal Investigator, HUS Internal Medicine and Rehabilitation, HUS Abdominal Center, Developmental Psychology Research Group, Genetic Epidemiology, Genomic Discoveries and Clinical Translation, Cognitive and Brain Aging, Middeldorp, Christel M [0000-0002-6218-0428], and Apollo - University of Cambridge Repository

Subjects
Male, Netherlands Twin Register (NTR), embarazo, Epidemiology, C840 Clinical Psychology, LD SCORE REGRESSION, humanos, LOCI, Medizin, adolescente, Genome-wide association study, BLOOD-PRESSURE, Disease, 030204 cardiovascular system & hematology, Cohort Studies, 0302 clinical medicine, Pregnancy, Medicine, 030212 general & internal medicine, Early childhood, C820 Developmental Psychology, estudios de cohortes, Child, C440 Molecular Genetics, Public, Environmental & Occupational Health, Genetics, education.field_of_study, United Kingdom/epidemiology, COMMON VARIANTS, Hälsovetenskaper, adulto, A900 Others in Medicine and Dentistry, 3142 Public health care science, environmental and occupational health, 3. Good health, predicción, ddc, Childhood traits and disorders, Phenotype, Disease/genetics, Research Design, Child, Preschool, fenotipo, Female, ICEP, medicine.symptom, CHILDHOOD OBESITY, Life Sciences & Biomedicine, EArly Genetics Lifecourse Epidemiology (EAGLE) consortium, Adult, medicine.medical_specialty, Adolescent, Birth weight, Population, Consortium, Childhood Traits And Disorders, Longitudinal, enfermedad, Childhood obesity, 1117 Public Health and Health Services, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Health Sciences, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, education, LONGITUDINAL TWIN, METAANALYSIS, lactante, Science & Technology, Early Growth Genetics (EGG) consortium, business.industry, Infant, Newborn, Infant, predisposición genética a la enfermedad, medicine.disease, BODY-MASS, C800 Psychology, BIRTH-WEIGHT, C420 Human Genetics, United Kingdom, Low birth weight, business, diseño de la investigación, Forecasting
Abstract

The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites., We are grateful to all families and participants who took part in these studies. We also acknowledge and appreciate the unique efforts of the research teams and practitioners contributing to the collection of this wealth of data. C. M. M. is supported by funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement no. 721567. J. F. F. has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 633595 (DynaHEALTH) and 733206 (LifeCycle). R. M. F. and R. N. B. are supported by Sir Henry Dale Fellowship (Wellcome Trust and Royal Society grant: WT104150). D. L. C. is funded by the American Diabetes Association Grant 1-17-PDF-077. D. O. M-K. was supported by Dutch Science Organization (ZonMW-VENI Grant 916.14.023). N. M. W. is supported by an Australian National Health and Medical Research Council Early Career Fellowship (APP1104818). T. S. A. was partially funded by the Gene-Diet Interactions in Obesity (GENDINOB) project on behalf of GOYA male cohort data management and analyses and acknowledges the same. S. D. was supported by National Institute of Health Research. T. M. F. is supported by the European Research Council grant: 323195 SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (www.metabol.ku.dk).H.H.is funded by The Children's Hospital of Philadelphia Endowed Chair in Genomic Research. A. T. H. is supported by the Wellcome Trust Senior Investigator Awards (WT098395), National Institute for Health Research (NIHR) Senior Investigator Award (NF-SI-0611-10219). J. Hebebrand received grants from German Research Society, German Ministry of Education and Research. M-F. H. is currently supported by an American Diabetes Association (ADA) Pathway Program Accelerator Early Investigator Award (1-15-ACE-26). S. J. is supported by Helse Vest no. 23929, Bergen Forskningsstiftelse and KG Jebsen Foundation and University of Bergen. J. K. has been supported by the Academy of Finland Research Professor program (grants 265240 & 263278). J. P. K. is funded by a University of Queensland Development Fellowship (UQFEL1718945). H. L. has served as a speaker for Eli-Lilly and Shire and has received research grants from Shire; all outside the submitted work. C. M. L is supported by the Li Ka Shing Foundation, WT-SSI/John Fell funds and by the NIHR Biomedical Research Centre, Oxford, by Widenlife and NIH (5P50HD028138-27). S. E. M. was funded by an NHMRC Senior Reseach Fellowship (APP1103623). K. Panoutsopoulou is funded by a career development fellowship (grant 20308) and by the Wellcome Trust (WT098051). C. P. at UCL Institute of Child Health, with support from the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. I. P. was funded in part by the Wellcome Trust (WT205915), and the European Union's Horizon 2020 research, the European Union FP7-IDEAS-ERC Advanced Grant (GEPIDIAB, ERC-AG -ERC-294785), and innovation programme (DYNAhealth, H2020-PHC-2014-633595). R. C. R. is supported by CRUK (grant number C18281/A19169). J. G. S. is supported by an NHMRC Practitioner Fellowship Grant (APP1105807). J. T.; r is funded by the European Regional Development Fund (ERDF), the European Social Fund (ESF), Convergence Programme for Cornwall and the Isles of Scilly and the Diabetes Research and Wellness Foundation Non-Clinical Fellowship. N. V-T. is funded by a pre-doctoral grant from the Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR) (2015 FI_B 00636), Generalitat de Catalunya. T. G. M. V was supported by ZonMW (TOP 40-00812-98-11010. J. F. W. is supported by the MRC Human Genetics Unit quinquennial programme QTL in Health and Disease. H. Y. is funded by Diabetes UK RD Lawrence fellowship (grant: 17/0005594). M. H. Z was supported by BBMRI-NL (CP2013-50). E. Z. is supported by the Wellcome Trust (098051). B. F. is supported by Novo Nordisk Foundation (12955) and an Oak Foundation Fellowship. S. S. and M-R. J. have received funding from the European Union's Horizon 2020 research and innovation programme [under grant agreement No 633595] for the DynaHEALTH action. P. R. N. was supported by the European Research Council (ERC), University of Bergen, KG Jebsen and Helse Vest. G. D. S. works within the MRC Integrative Epidemiology Unit at the University of Bristol (MC_UU_12013/1). D. A. L was supported by the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement (Grant number 669545; DevelopObese), US National Institute of Health (grant: R01 DK10324), the UK Medical Research Council (grant: MC_UU_00011/6), Wellcome Trust GWAS grant (WT088806), an NIHR Senior Investigator Award (NF-SI-0611-10196) and the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. L. Paternoster was supported by the UK Medical Research Council Unit grants MC_UU_12013_5. N. J. T. is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 102215/2/13/2), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC) and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A19169). V.W.V.J. received an additional grant from the Netherlands Organization for Health Research and Development (NWO, ZonMw-VIDI 016.136.361), a European Research Council Consolidator Grant (ERC-2014-CoG-648916) and funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 633595 (DynaHEALTH) and 733206 (LifeCycle). D. M. E. is funded by the UK Medical Research Council Unit grant MC_UU_12013_4, Australian Research Council Future Fellowship (FT130101709) and a NHMRC Senior Research Fellowship (GNT1137714). S. F. A. G. is funded by the Daniel B. Burke Endowed Chair for Diabetes Research and R01 HD056465. D. I. B. is supported by Spinozapremie (NWO-56-464-14192) and the Royal Netherlands Academy of Science Professor Award (PAH/6635) to DIB. M. I. M. is a Wellcome Senior Investgator and NIHR Senior Investigator supported by the Wellcome (090532, 098381, 203141), NIHR (NF-SI-0617-10090) and the US National Institute of Health (grant: R01 DK10324), the UK Medical Research Council (grant: MCiabetes UK RD Lawrence fellowship (grant: 17/0005594). M. H. Z was supported by BBMRI-NLNIHR Biomedical Research Centre, Oxford. The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.

Published
2019
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13. The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia:design, results and future prospects

Author

Middeldorp, Christel M., Mahajan, Anubha, Horikoshi, Momoko, Robertson, Neil R., Beaumont, Robin N., Bradfield, Jonathan P., Bustamante, Mariona, Cousminer, Diana L., Day, Felix R., De Silva, N. Maneka, Guxens, Monica, Mook-Kanamori, Dennis O., St Pourcain, Beate, Warrington, Nicole M., Adair, Linda S., Ahlqvist, Emma, Ahluwalia, Tarunveer S., Almgren, Peter, Ang, Wei, Atalay, Mustafa, Auvinen, Juha, Bartels, Meike, Beckmann, Jacques S., Bilbao, Jose Ramon, Bond, Tom, Borja, Judith B., Cavadino, Alana, Charoen, Pimphen, Chen, Zhanghua, Coin, Lachlan, Cooper, Cyrus, Curtin, John A., Custovic, Adnan, Das, Shikta, Davies, Gareth E., Dedoussis, George V., Duijts, Liesbeth, Eastwood, Peter R., Eliasen, Anders U., Elliott, Paul, Eriksson, Johan G., Estivill, Xavier, Fadista, Joao, Fedko, Iryna O., Frayling, Timothy M., Gaillard, Romy, Gauderman, W. James, Geller, Frank, Gilliland, Frank, Gilsanz, Vincente, Granell, Raquel, Grarup, Niels, Groop, Leif, Hadley, Dexter, Hakonarson, Hakon, Hansen, Torben, Hartman, Catharina A., Hattersley, Andrew T., Hayes, M. Geoffrey, Hebebrand, Johannes, Heinrich, Joachim, Helgeland, Oyvind, Henders, Anjali K., Henderson, John, Henriksen, Tine B., Hirschhorn, Joel N., Hivert, Marie-France, Hocher, Berthold, Holloway, John W., Holt, Patrick, Hottenga, Jouke-Jan, Hypponen, Elina, Iniguez, Carmen, Johansson, Stefan, Jugessur, Astanand, Kahonen, Mika, Kalkwarf, Heidi J., Kaprio, Jaakko, Karhunen, Ville, Kemp, John P., Kerkhof, Marjan, Koppelman, Gerard H., Korner, Antje, Kotecha, Sailesh, Kreiner-Moller, Eskil, Kulohoma, Benard, Kumar, Ashish, Kutalik, Zoltan, Lahti, Jari, Lappe, Joan M., Larsson, Henrik, Lehtimaki, Terho, Lewin, Alexandra M., Li, Jin, Lichtenstein, Paul, Lindgren, Cecilia M., Lindi, Virpi, Linneberg, Allan, Liu, Xueping, Liu, Jun, Lowe, William L., Jr., Lundstrom, Sebastian, Lyytikainen, Leo-Pekka, Ma, Ronald C. W., Mace, Aurelien, Magi, Reedik, Magnus, Per, Mamun, Abdullah A., Mannikko, Minna, Martin, Nicholas G., Mbarek, Hamdi, McCarthy, Nina S., Medland, Sarah E., Melbye, Mads, Melen, Erik, Mohlke, Karen L., Monnereau, Claire, Morgen, Camilla S., Morris, Andrew P., Murray, Jeffrey C., Myhre, Ronny, Najman, Jackob M., Nivard, Michel G., Nohr, Ellen A., Nolte, Ilja M., Ntalla, Ioanna, O'Reilly, Paul, Oberfield, Sharon E., Oken, Emily, Oldehinkel, Albertine J., Pahkala, Katja, Palviainen, Teemu, Panoutsopoulou, Kalliope, Pedersen, Oluf, Pennell, Craig E., Pershagen, Goran, Pitkanen, Niina, Plomin, Robert, Power, Christine, Prasad, Rashmi B., Prokopenko, Inga, Pulkkinen, Lea, Raikkonen, Katri, Raitakari, Olli T., Reynolds, Rebecca M., Richmond, Rebecca C., Rivadeneira, Fernando, Rodriguez, Alina, Rose, Richard J., Salem, Rany, Santa-Marina, Loreto, Saw, Seang-Mei, Schnurr, Theresia M., Scott, James G., Selzam, Saskia, Shepherd, John A., Simpson, Angela, Skotte, Line, Sleiman, Patrick M. A., Snieder, Harold, Sørensen, Thorkild I. A., Standl, Marie, Steegers, Eric A. P., Strachan, David P., Straker, Leon, Strandberg, Timo, Taylor, Michelle, Teo, Yik-Ying, Thiering, Elisabeth, Torrent, Maties, Tyrrell, Jessica, Uitterlinden, Andre G., van Beijsterveldt, Toos, van der Most, Peter J., van Duijn, Cornelia M., Viikari, Jorma, Vilor-Tejedor, Natalia, Vogelezang, Suzanne, Vonk, Judith M., Vrijkotte, Tanja G. M., Vuoksimaa, Eero, Wang, Carol A., Watkins, William J., Wichmann, H-Erich, Willemsen, Gonneke, Williams, Gail M., Wilson, James F., Wray, Naomi R., Xu, Shujing, Xu, Cheng-Jian, Yaghootkar, Hanieh, Yi, Lu, Zafarmand, Mohammad Hadi, Zeggini, Eleftheria, Zemel, Babette S., Hinney, Anke, Lakka, Timo A., Whitehouse, Andrew J. O., Sunyer, Jordi, Widen, Elisabeth E., Feenstra, Bjarke, Sebert, Sylvain, Jacobsson, Bo, Njolstad, Pal R., Stoltenberg, Camilla, Smith, George Davey, Lawlor, Debbie A., Paternoster, Lavinia, Timpson, Nicholas J., Ong, Ken K., Bisgaard, Hans, Bonnelykke, Klaus, Jaddoe, Vincent W. V., Tiemeier, Henning, Jarvelin, Marjo-Riitta, Evans, David M., Perry, John R. B., Grant, Struan F. A., Boomsma, Dorret I., Freathy, Rachel M., McCarthy, Mark I., Felix, Janine F., Sorensen, Thorkild I. A., Tiemeier, Hen-Ning, Middeldorp, Christel M., Mahajan, Anubha, Horikoshi, Momoko, Robertson, Neil R., Beaumont, Robin N., Bradfield, Jonathan P., Bustamante, Mariona, Cousminer, Diana L., Day, Felix R., De Silva, N. Maneka, Guxens, Monica, Mook-Kanamori, Dennis O., St Pourcain, Beate, Warrington, Nicole M., Adair, Linda S., Ahlqvist, Emma, Ahluwalia, Tarunveer S., Almgren, Peter, Ang, Wei, Atalay, Mustafa, Auvinen, Juha, Bartels, Meike, Beckmann, Jacques S., Bilbao, Jose Ramon, Bond, Tom, Borja, Judith B., Cavadino, Alana, Charoen, Pimphen, Chen, Zhanghua, Coin, Lachlan, Cooper, Cyrus, Curtin, John A., Custovic, Adnan, Das, Shikta, Davies, Gareth E., Dedoussis, George V., Duijts, Liesbeth, Eastwood, Peter R., Eliasen, Anders U., Elliott, Paul, Eriksson, Johan G., Estivill, Xavier, Fadista, Joao, Fedko, Iryna O., Frayling, Timothy M., Gaillard, Romy, Gauderman, W. James, Geller, Frank, Gilliland, Frank, Gilsanz, Vincente, Granell, Raquel, Grarup, Niels, Groop, Leif, Hadley, Dexter, Hakonarson, Hakon, Hansen, Torben, Hartman, Catharina A., Hattersley, Andrew T., Hayes, M. Geoffrey, Hebebrand, Johannes, Heinrich, Joachim, Helgeland, Oyvind, Henders, Anjali K., Henderson, John, Henriksen, Tine B., Hirschhorn, Joel N., Hivert, Marie-France, Hocher, Berthold, Holloway, John W., Holt, Patrick, Hottenga, Jouke-Jan, Hypponen, Elina, Iniguez, Carmen, Johansson, Stefan, Jugessur, Astanand, Kahonen, Mika, Kalkwarf, Heidi J., Kaprio, Jaakko, Karhunen, Ville, Kemp, John P., Kerkhof, Marjan, Koppelman, Gerard H., Korner, Antje, Kotecha, Sailesh, Kreiner-Moller, Eskil, Kulohoma, Benard, Kumar, Ashish, Kutalik, Zoltan, Lahti, Jari, Lappe, Joan M., Larsson, Henrik, Lehtimaki, Terho, Lewin, Alexandra M., Li, Jin, Lichtenstein, Paul, Lindgren, Cecilia M., Lindi, Virpi, Linneberg, Allan, Liu, Xueping, Liu, Jun, Lowe, William L., Jr., Lundstrom, Sebastian, Lyytikainen, Leo-Pekka, Ma, Ronald C. W., Mace, Aurelien, Magi, Reedik, Magnus, Per, Mamun, Abdullah A., Mannikko, Minna, Martin, Nicholas G., Mbarek, Hamdi, McCarthy, Nina S., Medland, Sarah E., Melbye, Mads, Melen, Erik, Mohlke, Karen L., Monnereau, Claire, Morgen, Camilla S., Morris, Andrew P., Murray, Jeffrey C., Myhre, Ronny, Najman, Jackob M., Nivard, Michel G., Nohr, Ellen A., Nolte, Ilja M., Ntalla, Ioanna, O'Reilly, Paul, Oberfield, Sharon E., Oken, Emily, Oldehinkel, Albertine J., Pahkala, Katja, Palviainen, Teemu, Panoutsopoulou, Kalliope, Pedersen, Oluf, Pennell, Craig E., Pershagen, Goran, Pitkanen, Niina, Plomin, Robert, Power, Christine, Prasad, Rashmi B., Prokopenko, Inga, Pulkkinen, Lea, Raikkonen, Katri, Raitakari, Olli T., Reynolds, Rebecca M., Richmond, Rebecca C., Rivadeneira, Fernando, Rodriguez, Alina, Rose, Richard J., Salem, Rany, Santa-Marina, Loreto, Saw, Seang-Mei, Schnurr, Theresia M., Scott, James G., Selzam, Saskia, Shepherd, John A., Simpson, Angela, Skotte, Line, Sleiman, Patrick M. A., Snieder, Harold, Sørensen, Thorkild I. A., Standl, Marie, Steegers, Eric A. P., Strachan, David P., Straker, Leon, Strandberg, Timo, Taylor, Michelle, Teo, Yik-Ying, Thiering, Elisabeth, Torrent, Maties, Tyrrell, Jessica, Uitterlinden, Andre G., van Beijsterveldt, Toos, van der Most, Peter J., van Duijn, Cornelia M., Viikari, Jorma, Vilor-Tejedor, Natalia, Vogelezang, Suzanne, Vonk, Judith M., Vrijkotte, Tanja G. M., Vuoksimaa, Eero, Wang, Carol A., Watkins, William J., Wichmann, H-Erich, Willemsen, Gonneke, Williams, Gail M., Wilson, James F., Wray, Naomi R., Xu, Shujing, Xu, Cheng-Jian, Yaghootkar, Hanieh, Yi, Lu, Zafarmand, Mohammad Hadi, Zeggini, Eleftheria, Zemel, Babette S., Hinney, Anke, Lakka, Timo A., Whitehouse, Andrew J. O., Sunyer, Jordi, Widen, Elisabeth E., Feenstra, Bjarke, Sebert, Sylvain, Jacobsson, Bo, Njolstad, Pal R., Stoltenberg, Camilla, Smith, George Davey, Lawlor, Debbie A., Paternoster, Lavinia, Timpson, Nicholas J., Ong, Ken K., Bisgaard, Hans, Bonnelykke, Klaus, Jaddoe, Vincent W. V., Tiemeier, Henning, Jarvelin, Marjo-Riitta, Evans, David M., Perry, John R. B., Grant, Struan F. A., Boomsma, Dorret I., Freathy, Rachel M., McCarthy, Mark I., Felix, Janine F., Sorensen, Thorkild I. A., and Tiemeier, Hen-Ning

Published
2019

14. GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI

Author

Couto Alves, Alexessander, De Silva, N. Maneka G., Karhunen, Ville, Sovio, Ulla, Das, Shikta, Taal, H. Rob, Warrington, Nicole M., Lewin, Alexandra M., Kaakinen, Marika, Cousminer, Diana L., Thiering, Elisabeth, Timpson, Nicholas J., Bond, Tom A., Lowry, Estelle, Brown, Christopher D., Estivill, Xavier, Lindi, Virpi, Bradfield, Jonathan P., Geller, Frank, Speed, Doug, Coin, Lachlan J. M., Loh, Marie, Barton, Sheila J., Beilin, Lawrence J., Bisgaard, Hans, Bønnelykke, Klaus, Alili, Rohia, Hatoum, Ida J., Schramm, Katharina, Cartwright, Rufus, Charles, Marie-Aline, Salerno, Vincenzo, Clément, Karine, Claringbould, Annique A. J., van Duijn, Cornelia M., Moltchanova, Elena, Eriksson, Johan G., Elks, Cathy, Feenstra, Bjarke, Flexeder, Claudia, Franks, Stephen, Frayling, Timothy M., Freathy, Rachel M., Elliott, Paul, Widén, Elisabeth, Hakonarson, Hakon, Hattersley, Andrew T., Rodriguez, Alina, Banterle, Marco, Heinrich, Joachim, Heude, Barbara, Holloway, John W., Hofman, Albert, Hyppönen, Elina, Inskip, Hazel, Kaplan, Lee M., Hedman, Asa K., Läärä, Esa, Prokisch, Holger, Grallert, Harald, Lakka, Timo A., Lawlor, Debbie A., Melbye, Mads, Ahluwalia, Tarunveer S., Marinelli, Marcella, Millwood, Iona Y., Palmer, Lyle J., Pennell, Craig E., Perry, John R., Ring, Susan M., Savolainen, Markku J., Rivadeneira, Fernando, Standl, Marie, Sunyer, Jordi, Tiesler, Carla M. T., Uitterlinden, Andre G., Schierding, William, O’Sullivan, Justin M., Prokopenko, Inga, Herzig, Karl-Heinz, Smith, George Davey, O'Reilly, Paul, Felix, Janine F., Buxton, Jessica L., Blakemore, Alexandra I. F., Ong, Ken K., Jaddoe, Vincent W. V., Grant, Struan F. A., Sebert, Sylvain, McCarthy, Mark I., and Järvelin, Marjo-Riitta

Subjects
ddc
Published
2018

15. Genetic architecture of early childhood growth phenotypes gives insights into their link with later obesity

Author

De Silva, N. Maneka G., primary, Sebert, Sylvain, additional, Alves, Alexessander Couto, additional, Sovio, Ulla, additional, Das, Shikta, additional, Taal, Rob, additional, Warrington, Nicole M., additional, Lewin, Alexandra M., additional, Kaakinen, Marika, additional, Cousminer, Diana, additional, Thiering, Elisabeth, additional, Timpson, Nicholas J., additional, Karhunen, Ville, additional, Bond, Tom, additional, Estivill, Xavier, additional, Lindi, Virpi, additional, Bradfield, Jonathan P., additional, Geller, Frank, additional, Coin, Lachlan J.M., additional, Loh, Marie, additional, Barton, Sheila J., additional, Beilin, Lawrence J., additional, Bisgaard, Hans, additional, Bønnelykke, Klaus, additional, Alili, Rohia, additional, Hatoum, Ida J., additional, Schramm, Katharina, additional, Cartwright, Rufus, additional, Charles, Marie-Aline, additional, Salerno, Vincenzo, additional, Clément, Karine, additional, van Duijn, Cornelia M., additional, Moltchanova, Elena, additional, Eriksson, Johan G., additional, Elks, Cathy, additional, Feenstra, Bjarke, additional, Flexeder, Claudia, additional, Franks, Stephen, additional, Frayling, Timothy M., additional, Freathy, Rachel M., additional, Elliott, Paul, additional, Widén, Elisabeth, additional, Hakonarson, Hakon, additional, Hattersley, Andrew T., additional, Rodriguez, Alina, additional, Banterle, Marco, additional, Heinrich, Joachim, additional, Heude, Barbara, additional, Holloway, John W., additional, Hofman, Albert, additional, Hyppönen, Elina, additional, Inskip, Hazel, additional, Kaplan, Lee M., additional, Hedman, Asa K., additional, Läärä, Esa, additional, Prokisch, Holger, additional, Grallert, Harald, additional, Lakka, Timo A., additional, Lawlor, Debbie A., additional, Melbye, Mads, additional, Ahluwalia, Tarunveer S., additional, Marinelli, Marcella, additional, Millwood, Iona Y., additional, Palmer, Lyle J., additional, Pennell, Craig E., additional, Perry, John R., additional, Ring, Susan M., additional, Savolainen, Markku, additional, Stefansson, Kari, additional, Thorleifsson, Gudmar, additional, Rivadeneira, Fernando, additional, Standl, Marie, additional, Sunyer, Jordi, additional, Tiesler, Carla M.T., additional, Uitterlinden, Andre G., additional, Prokopenko, Inga, additional, Herzig, Karl-Heinz, additional, Smith, George Davey, additional, O'Reilly, Paul, additional, Felix, Janine F., additional, Buxton, Jessica L., additional, Blakemore, Alexandra I.F., additional, Ong, Ken K., additional, Grant, Struan F.A., additional, Jaddoe, Vincent W.V., additional, McCarthy, Mark I., additional, and Järvelin, Marjo-Riitta, additional

Published
2017
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16. Liver Function and Risk of Type 2 Diabetes: Bidirectional Mendelian Randomization Study.

Author

De Silva, N. Maneka G., Borges, Maria Carolina, Hingorani, Aroon D., Engmann, Jorgen, Shah, Tina, Xiaoshuai Zhang, Jian'an Luan, Langenberg, Claudia, Wong, Andrew, Kuh, Diana, Chambers, John C., Weihua Zhang, Jarvelin, Marjo-Ritta, Sebert, Sylvain, Auvinen, Juha, Gaunt, Tom R., Lawlor, Deborah A., Zhang, Xiaoshuai, Luan, Jian'an, and Zhang, Weihua

Subjects
*TYPE 2 diabetes, *LIVER, *FATTY liver, *ALANINE aminotransferase, *ASPARTATE aminotransferase
Abstract

Liver dysfunction and type 2 diabetes (T2D) are consistently associated. However, it is currently unknown whether liver dysfunction contributes to, results from, or is merely correlated with T2D due to confounding. We used Mendelian randomization to investigate the presence and direction of any causal relation between liver function and T2D risk including up to 64,094 T2D case and 607,012 control subjects. Several biomarkers were used as proxies of liver function (i.e., alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], and γ-glutamyl transferase [GGT]). Genetic variants strongly associated with each liver function marker were used to investigate the effect of liver function on T2D risk. In addition, genetic variants strongly associated with T2D risk and with fasting insulin were used to investigate the effect of predisposition to T2D and insulin resistance, respectively, on liver function. Genetically predicted higher circulating ALT and AST were related to increased risk of T2D. There was a modest negative association of genetically predicted ALP with T2D risk and no evidence of association between GGT and T2D risk. Genetic predisposition to higher fasting insulin, but not to T2D, was related to increased circulating ALT. Since circulating ALT and AST are markers of nonalcoholic fatty liver disease (NAFLD), these findings provide some support for insulin resistance resulting in NAFLD, which in turn increases T2D risk. [ABSTRACT FROM AUTHOR]

Published
2019
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17. Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight

Author

Tyrrell, Jessica, primary, Richmond, Rebecca C., additional, Palmer, Tom M., additional, Feenstra, Bjarke, additional, Rangarajan, Janani, additional, Metrustry, Sarah, additional, Cavadino, Alana, additional, Paternoster, Lavinia, additional, Armstrong, Loren L., additional, De Silva, N. Maneka G., additional, Wood, Andrew R., additional, Horikoshi, Momoko, additional, Geller, Frank, additional, Myhre, Ronny, additional, Bradfield, Jonathan P., additional, Kreiner-Møller, Eskil, additional, Huikari, Ville, additional, Painter, Jodie N., additional, Hottenga, Jouke-Jan, additional, Allard, Catherine, additional, Berry, Diane J., additional, Bouchard, Luigi, additional, Das, Shikta, additional, Evans, David M., additional, Hakonarson, Hakon, additional, Hayes, M. Geoffrey, additional, Heikkinen, Jani, additional, Hofman, Albert, additional, Knight, Bridget, additional, Lind, Penelope A., additional, McCarthy, Mark I., additional, McMahon, George, additional, Medland, Sarah E., additional, Melbye, Mads, additional, Morris, Andrew P., additional, Nodzenski, Michael, additional, Reichetzeder, Christoph, additional, Ring, Susan M., additional, Sebert, Sylvain, additional, Sengpiel, Verena, additional, Sørensen, Thorkild I. A., additional, Willemsen, Gonneke, additional, de Geus, Eco J. C., additional, Martin, Nicholas G., additional, Spector, Tim D., additional, Power, Christine, additional, Järvelin, Marjo-Riitta, additional, Bisgaard, Hans, additional, Grant, Struan F. A., additional, Nohr, Ellen A., additional, Jaddoe, Vincent W., additional, Jacobsson, Bo, additional, Murray, Jeffrey C., additional, Hocher, Berthold, additional, Hattersley, Andrew T., additional, Scholtens, Denise M., additional, Davey Smith, George, additional, Hivert, Marie-France, additional, Felix, Janine F., additional, Hyppönen, Elina, additional, Lowe, William L., additional, Frayling, Timothy M., additional, Lawlor, Debbie A., additional, and Freathy, Rachel M., additional

Published
2016
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18. ADH1B and ADH1C Genotype, Alcohol Consumption and Biomarkers of Liver Function:Findings from a Mendelian Randomization Study in 58,313 European Origin Danes

Author

Lawlor, Debbie A, Benn, Marianne, Zuccolo, Luisa, De Silva, N Maneka G, Tybjaerg-Hansen, Anne, Smith, George Davey, Nordestgaard, Børge G, Lawlor, Debbie A, Benn, Marianne, Zuccolo, Luisa, De Silva, N Maneka G, Tybjaerg-Hansen, Anne, Smith, George Davey, and Nordestgaard, Børge G

Abstract

BACKGROUND: The effect of alcohol consumption on liver function is difficult to determine because of reporting bias and potential residual confounding. Our aim was to determine this effect using genetic variants to proxy for the unbiased effect of alcohol.METHODS: We used variants in ADH1B and ADH1C genes as instrumental variables (IV) to estimate the causal effect of long-term alcohol consumption on alanine aminotransferase (ALT), γ-glutamyl-transferase (γ-GT), alkaline phosphatase (ALP), bilirubin and prothrombin action. Analyses were undertaken on 58,313 Danes (mean age 56).RESULTS: In both confounder adjusted multivariable and genetic-IV analyses greater alcohol consumption, amongst those who drank any alcohol, was associated with higher ALT [mean difference per doubling of alcohol consumption: 3.4% (95% CI: 3.1, 3.7) from multivariable analyses and 3.7% (-4.5, 11.9) from genetic-IV analyses] and γ-GT [8.2% (7.8, 8.5) and 6.8% (-2.8, 16.5)]. The point estimates from the two methods were very similar and statistically the results from the two methods were consistent with each other for effects with ALT and γ-GT (both pdiff>0.3). Results from the multivariable analyses suggested a weak inverse association of alcohol with ALP [-1.5% (-1 .7, -1.3)], which differed from the strong positive effect found in genetic-IV analyses [11.6% (6.8, 16.4)] (p diff<0.0001). In both multivariable and genetic-IV analyses associations with bilirubin and protrombin action were weak and close to the null.CONCLUSIONS: Our results suggest that greater consumption of alcohol is related to poorer liver function as indicated by higher ALT, γ-GT and ALP, but not to clotting or bilirubin.

Published
2014

20. Evaluation of Common Type 2 Diabetes Risk Variants in a South Asian Population of Sri Lankan Descent

Author

Hassanali, Neelam, primary, De Silva, N. Maneka G., additional, Robertson, Neil, additional, Rayner, N. William, additional, Barrett, Amy, additional, Bennett, Amanda J., additional, Groves, Christopher J., additional, Matthews, David R., additional, Katulanda, Prasad, additional, Frayling, Timothy M., additional, and McCarthy, Mark I., additional

Published
2014
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21. GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI

Author

Couto Alves, Alexessander, De Silva, N Maneka G, Karhunen, Ville, Sovio, Ulla, Das, Shikta, Taal, H Rob, Warrington, Nicole M, Lewin, Alexandra M, Kaakinen, Marika, Cousminer, Diana L, Thiering, Elisabeth, Timpson, Nicholas J, Bond, Tom A, Lowry, Estelle, Brown, Christopher D, Estivill, Xavier, Lindi, Virpi, Bradfield, Jonathan P, Geller, Frank, Speed, Doug, Coin, Lachlan JM, Loh, Marie, Barton, Sheila J, Beilin, Lawrence J, Bisgaard, Hans, Bønnelykke, Klaus, Alili, Rohia, Hatoum, Ida J, Schramm, Katharina, Cartwright, Rufus, Charles, Marie-Aline, Salerno, Vincenzo, Clément, Karine, Claringbould, Annique AJ, Van Duijn, Cornelia M, Moltchanova, Elena, Eriksson, Johan G, Elks, Cathy, Feenstra, Bjarke, Flexeder, Claudia, Franks, Stephen, Frayling, Timothy M, Freathy, Rachel M, Elliott, Paul, Widén, Elisabeth, Hakonarson, Hakon, Hattersley, Andrew T, Rodriguez, Alina, Banterle, Marco, Heinrich, Joachim, Heude, Barbara, Holloway, John W, Hofman, Albert, Hyppönen, Elina, Inskip, Hazel, Kaplan, Lee M, Hedman, Asa K, Läärä, Esa, Prokisch, Holger, Grallert, Harald, Lakka, Timo A, Lawlor, Debbie A, Melbye, Mads, Ahluwalia, Tarunveer S, Marinelli, Marcella, Millwood, Iona Y, Palmer, Lyle J, Pennell, Craig E, Perry, John R, Ring, Susan M, Savolainen, Markku J, Rivadeneira, Fernando, Standl, Marie, Sunyer, Jordi, Tiesler, Carla MT, Uitterlinden, Andre G, Schierding, William, O’Sullivan, Justin M, Prokopenko, Inga, Herzig, Karl-Heinz, Smith, George Davey, O'Reilly, Paul, Felix, Janine F, Buxton, Jessica L, Blakemore, Alexandra IF, Ong, Ken K, Jaddoe, Vincent WV, Grant, Struan FA, Sebert, Sylvain, McCarthy, Mark I, and Järvelin, Marjo-Riitta

Subjects
2. Zero hunger, Adult, Male, Pharmacogenomic Variants, Quantitative Trait Loci, Intracellular Signaling Peptides and Proteins, Infant, Genomics, Polymorphism, Single Nucleotide, Body Mass Index, Quantitative Trait, Heritable, Humans, Receptors, Leptin, Female, Genetic Predisposition to Disease, Longitudinal Studies, Growth Charts, Child, Genetic Association Studies, Adaptor Proteins, Signal Transducing, Genome-Wide Association Study
Abstract

Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.

22. Could vitamin D reduce obesity-associated inflammation? Observational and Mendelian randomization study

Author

Estelle Lowry, Elina Hyppönen, Heimo Viinamäki, Sylvain Sebert, Eeva Sliz, Dipender Gill, Shivaprakash Jagalur Mutt, Saranya Palaniswamy, Abbas Dehghan, Karl-Heinz Herzig, N. Maneka G. De Silva, Markku Timonen, Jari Jokelainen, Sirkka Keinänen-Kiukaanniemi, Marjo-Riitta Järvelin, Daniel I. Chasman, Toni Karhu, UNIVERSITY OF OULU, Palaniswamy, Saranya, Gill, Dipender, De Silva, N Maneka, Lowry, Estelle, Jokelainen, Jari, Karhu, Toni, Mutt, Shivaprakash J, Dehghan, Abbas, Sliz, Eeva, Chasman, Daniel I, Timonen, Markku, Viinamäki, Heimo, Keinänen-Kiukaanniemi, Sirkka, Hyppönen, Elina, Herzig, Karl Heinz, Sebert, Sylvain, and Järvelin, Marjo Riitta

Subjects
0301 basic medicine, Male, Chemokine, obesity, LOCI, Medicine (miscellaneous), PROTEIN, vitamin D, ADULTHOOD, Gastroenterology, 09 Engineering, law.invention, SUPPLEMENTATION, Body Mass Index, AcademicSubjects/MED00160, Cohort Studies, BMI, obesity, 0302 clinical medicine, Randomized controlled trial, law, CHOLECALCIFEROL, 11 Medical and Health Sciences, Randomized Controlled Trials as Topic, Nutrition and Dietetics, biology, 25(OH)D, Intercellular Adhesion Molecule-1, 3. Good health, Original Research Communications, C-Reactive Protein, Female, medicine.symptom, Life Sciences & Biomedicine, medicine.medical_specialty, BIRTH, 030209 endocrinology & metabolism, Inflammation, PROFILE, 03 medical and health sciences, AcademicSubjects/MED00060, BMI, Mediator, Nutritional Epidemiology and Public Health, Internal medicine, Mendelian randomization, medicine, Vitamin D and neurology, Humans, mediation, Science & Technology, OVERWEIGHT, Nutrition & Dietetics, business.industry, PATHWAYS, Mendelian Randomization Analysis, medicine.disease, Obesity, BODY-MASS INDEX, 030104 developmental biology, inflammation, biology.protein, Observational study, business, Genome-Wide Association Study
Abstract

BACKGROUND: Obesity is associated with inflammation but the role of vitamin D in this process is not clear. OBJECTIVES: We aimed to assess the associations between serum 25-hydroxyvitamin D [25(OH)D], BMI, and 16 inflammatory biomarkers, and to assess the role of vitamin D as a potential mediator in the association between higher BMI and inflammation. METHODS: Northern Finland Birth Cohort 1966 (NFBC1966) 31-y data on 3586 individuals were analyzed to examine the observational associations between BMI, 25(OH)D, and 16 inflammatory biomarkers. Multivariable regression analyses and 2-sample regression-based Mendelian randomization (MR) mediation analysis were performed to assess any role of vitamin D in mediating a causal effect of BMI on inflammatory biomarkers [soluble intercellular adhesion molecule 1 (sICAM-1), high sensitivity C-reactive protein (hs-CRP), and α1-acid glycoprotein (AGP)] for which observational associations were detected. For MR, genome-wide association study summary results ranging from 5163 to 806,834 individuals were used for biomarkers, 25(OH)D, and BMI. Findings were triangulated with a literature review of vitamin D supplementation trials. RESULTS: In NFBC1966, mean BMI (kg/m2) was 24.8 (95% CI: 24.7, 25.0) and mean 25(OH)D was 50.3 nmol/L (95% CI: 49.8, 50.7 nmol/L). Inflammatory biomarkers correlated as 4 independent clusters: interleukins, adhesion molecules, acute-phase proteins, and chemokines. BMI was positively associated with 9 inflammatory biomarkers and inversely with 25(OH)D (false discovery rate < 0.05). 25(OH)D was inversely associated with sICAM-1, hs-CRP, and AGP, which were positively associated with BMI. The MR analyses showed causal association of BMI on these 3 inflammatory biomarkers. There was no observational or MR evidence that circulating 25(OH)D concentrations mediated the association between BMI and these 3 inflammatory markers. Review of randomized controlled trials (RCTs) supported our findings showing no impact of vitamin D supplementation on inflammatory biomarkers. CONCLUSIONS: The findings from our observational study and causal MR analyses, together with data from RCTs, do not support a beneficial role of vitamin D supplementation on obesity-related inflammation. Refereed/Peer-reviewed

Published
2020
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23. GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI.

Author

Couto Alves A, De Silva NMG, Karhunen V, Sovio U, Das S, Taal HR, Warrington NM, Lewin AM, Kaakinen M, Cousminer DL, Thiering E, Timpson NJ, Bond TA, Lowry E, Brown CD, Estivill X, Lindi V, Bradfield JP, Geller F, Speed D, Coin LJM, Loh M, Barton SJ, Beilin LJ, Bisgaard H, Bønnelykke K, Alili R, Hatoum IJ, Schramm K, Cartwright R, Charles MA, Salerno V, Clément K, Claringbould AAJ, van Duijn CM, Moltchanova E, Eriksson JG, Elks C, Feenstra B, Flexeder C, Franks S, Frayling TM, Freathy RM, Elliott P, Widén E, Hakonarson H, Hattersley AT, Rodriguez A, Banterle M, Heinrich J, Heude B, Holloway JW, Hofman A, Hyppönen E, Inskip H, Kaplan LM, Hedman AK, Läärä E, Prokisch H, Grallert H, Lakka TA, Lawlor DA, Melbye M, Ahluwalia TS, Marinelli M, Millwood IY, Palmer LJ, Pennell CE, Perry JR, Ring SM, Savolainen MJ, Rivadeneira F, Standl M, Sunyer J, Tiesler CMT, Uitterlinden AG, Schierding W, O'Sullivan JM, Prokopenko I, Herzig KH, Smith GD, O'Reilly P, Felix JF, Buxton JL, Blakemore AIF, Ong KK, Jaddoe VWV, Grant SFA, Sebert S, McCarthy MI, and Järvelin MR

Subjects
Adaptor Proteins, Signal Transducing genetics, Adult, Child, Female, Genetic Predisposition to Disease, Genomics, Growth Charts, Humans, Infant, Intracellular Signaling Peptides and Proteins, Longitudinal Studies, Male, Pharmacogenomic Variants, Polymorphism, Single Nucleotide, Receptors, Leptin genetics, Body Mass Index, Genetic Association Studies, Genome-Wide Association Study, Quantitative Trait Loci, Quantitative Trait, Heritable
Abstract

Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).)

Published
2019
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