Author: "Ken K Ong" - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"Ken K Ong"' showing total 524 results

Start Over Author "Ken K Ong"

524 results on '"Ken K Ong"'

1. Maternal obesity increases hypothalamic miR-505-5p expression in mouse offspring leading to altered fatty acid sensing and increased intake of high-fat food.

Author: Laura Dearden, Isadora C Furigo, Lucas C Pantaleão, L W P Wong, Denise S Fernandez-Twinn, Juliana de Almeida-Faria, Katherine A Kentistou, Maria V Carreira, Guillaume Bidault, Antonio Vidal-Puig, Ken K Ong, John R B Perry, Jose Donato, and Susan E Ozanne
Subjects: Biology (General), QH301-705.5
Abstract: In utero exposure to maternal obesity programs increased obesity risk. Animal models show that programmed offspring obesity is preceded by hyperphagia, but the mechanisms that mediate these changes are unknown. Using a mouse model of maternal obesity, we observed increased intake of a high-fat diet (HFD) in offspring of obese mothers that precedes the development of obesity. Through small RNA sequencing, we identified programmed overexpression of hypothalamic miR-505-5p that is established in the fetus, lasts to adulthood and is maintained in hypothalamic neural progenitor cells cultured in vitro. Metabolic hormones and long-chain fatty acids associated with obesity increase miR-505-5p expression in hypothalamic neurons in vitro. We demonstrate that targets of miR-505-5p are enriched in fatty acid metabolism pathways and overexpression of miR-505-5p decreased neuronal fatty acid metabolism in vitro. miR-505-5p targets are associated with increased BMI in human genetic studies. Intra-cerebroventricular injection of miR-505-5p in wild-type mice increased HFD intake, mimicking the phenotype observed in offspring exposed to maternal obesity. Conversely, maternal exercise intervention in an obese mouse pregnancy rescued the programmed increase of hypothalamic miR-505-5p in offspring of obese dams and reduced HFD intake to control offspring levels. This study identifies a novel mechanism by which maternal obesity programs obesity in offspring via increased intake of high-fat foods.
Published: 2024
Full Text: View/download PDF

2. Using genetic variation to disentangle the complex relationship between food intake and health outcomes.

Author: Nicola Pirastu, Ciara McDonnell, Eryk J Grzeszkowiak, Ninon Mounier, Fumiaki Imamura, Jordi Merino, Felix R Day, Jie Zheng, Nele Taba, Maria Pina Concas, Linda Repetto, Katherine A Kentistou, Antonietta Robino, Tõnu Esko, Peter K Joshi, Krista Fischer, Ken K Ong, Tom R Gaunt, Zoltán Kutalik, John R B Perry, and James F Wilson
Subjects: Genetics, QH426-470
Abstract: Diet is considered as one of the most important modifiable factors influencing human health, but efforts to identify foods or dietary patterns associated with health outcomes often suffer from biases, confounding, and reverse causation. Applying Mendelian randomization in this context may provide evidence to strengthen causality in nutrition research. To this end, we first identified 283 genetic markers associated with dietary intake in 445,779 UK Biobank participants. We then converted these associations into direct genetic effects on food exposures by adjusting them for effects mediated via other traits. The SNPs which did not show evidence of mediation were then used for MR, assessing the association between genetically predicted food choices and other risk factors, health outcomes. We show that using all associated SNPs without omitting those which show evidence of mediation, leads to biases in downstream analyses (genetic correlations, causal inference), similar to those present in observational studies. However, MR analyses using SNPs which have only a direct effect on the exposure on food exposures provided unequivocal evidence of causal associations between specific eating patterns and obesity, blood lipid status, and several other risk factors and health outcomes.
Published: 2022
Full Text: View/download PDF

3. Transforming Obesity Prevention for CHILDren (TOPCHILD) Collaboration: protocol for a systematic review with individual participant data meta-analysis of behavioural interventions for the prevention of early childhood obesity

Author: Finn Rasmussen, Hein Raat, Cristina Palacios, Barry J Taylor, Lisa Askie, Alison Hayes, Cindy-Lee Dennis, Karen Campbell, Wendy Smith, Luke Wolfenden, Sharleen O’Reilly, Eva Corpeleijn, Maria Bryant, Chris Rissel, Denise O’Connor, Paul Chadwick, Jessica Thomson, Anna Lene Seidler, Kylie E Hunter, Rachael W Taylor, Angie Barba, Kristy Robledo, Ken Ong, Carolina González Acero, Ana Pérez-Expósito, Kylie D Hesketh, Rebecca K Golley, David Espinoza, Ken K Ong, Sarah Taki, Rachael Taylor, Louise A Baur, Li Ming Wen, Seema Mihrshahi, Emily Oken, Barry Taylor, Ian Marschner, Junilla K Larsen, Kylie Hesketh, Rajalakshmi Lakshman, Amanda L Thompson, Sharleen L O'Reilly, Jonathan Williams, Charles Wood, Alison J Hayes, Kaumudi Joshipura, Hongping Xia, Lynne Daniels, Rebecca Byrne, Alison Karasz, Rebecca Golley, Kaumudi J Joshipura, Angela Webster, Nina Cecilie Øverby, Brittany J Johnson, Mason Aberoumand, Sol Libesman, Kristy P Robledo, Charles T Wood, Lukas P Staub, Michelle Sue-See, Ian C Marschner, Jessica L Thomson, Vera Verbestel, Sarah-Jeanne Salvy, Levie T Karssen, Finn E Rasmussen, Mary Jo Messito, Rachel S Gross, Ian M Paul, Heather M Wasser, Claudio Maffeis, Ata Ghaderi, Jinan C Banna, Maribel Campos Rivera, Ana B Pérez-Expósito, Jennifer S Savage, Margrethe Røed, Michael Goran, Kayla de la Haye, Stephanie Anzman-Frasca, Kylie Hunter, Brittany Johnson, Louise Baur, Lukas Staub, Shonna Yin, Lee Sanders, Amanda Thompson, Ana Maria Linares, Cathleen Odar Stough, Christine Helle, Eliana Perrin, Heather Wasser, Jinan Banna, Kayla dela Haye, Levie Karssen, Nina Øverby, Rachel Gross, Russell Rothman, Wendy A Smith, Alexander Fiks, Deborah Jacobvitz, Jennifer Savage Williams, Márcia Regina Vitolo, and Elizabeth Widen
Subjects: Medicine
Published: 2022
Full Text: View/download PDF

4. Associations between maternal iron supplementation in pregnancy and offspring growth and cardiometabolic risk outcomes in infancy and childhood.

Author: Clive J Petry, Laurentya Olga, Ieuan A Hughes, and Ken K Ong
Subjects: Medicine, Science
Abstract: It was previously observed that maternal iron supplementation in pregnancy was associated with increased offspring size and adiposity at birth, possibly mediated through increased risk of gestational diabetes. In this study we investigated potential long-term associations of maternal iron supplementation in pregnancy with offspring growth in infancy, and growth and cardiometabolic risk factors in mid-childhood to seek evidence of nutritional programming. Using a nested case-control format, markers of growth and adiposity were measured at 3, 12 and 24 months of age in 341 infants from the Cambridge Baby Growth Study whose mothers supplemented with iron in pregnancy and 222 infants whose mothers did not. Measures of growth, glucose tolerance (using a 30 minute 1.75 g glucose/kg body weight oral glucose tolerance test), insulin sensitivity (HOMA IR) and blood pressure were collected in 122 and 79 of these children, respectively, at around 9.5 years of age. In infancy adiposity-promoting associations with maternal iron supplementation in pregnancy were evident at 3 months of age (e.g. mean difference in skinfold thickness: β = +0.15 mm, p = 0.02, in n = 341 whose mothers supplemented versus 222 that did not; waist circumference: β = +0.7 cm, p = 0.04, in n = 159 and 78, respectively) but differences lessened after this time (e.g. 3-12 month change in mean difference in skinfold thickness: β = -0.2 mm, p = 0.03, in n = 272 and 178, respectively). At ~9.5 years of age children whose mothers supplemented with iron in pregnancy had lower mean arterial blood pressures (β = -1.0 mmHg, p = 0.03, in n = 119 and 78, respectively). There were no apparent differences in markers of growth or other cardiometabolic factors. These results suggest that most of the associations of maternal iron supplementation in pregnancy on growth and adiposity evident at birth disappear during infancy, but there may be some evidence of long-term nutritional programming of blood pressure in mid-childhood.
Published: 2022
Full Text: View/download PDF

5. Associations of autozygosity with a broad range of human phenotypes

Author: David W Clark, Yukinori Okada, Kristjan H S Moore, Dan Mason, Nicola Pirastu, Ilaria Gandin, Hannele Mattsson, Catriona L K Barnes, Kuang Lin, Jing Hua Zhao, Patrick Deelen, Rebecca Rohde, Claudia Schurmann, Xiuqing Guo, Franco Giulianini, Weihua Zhang, Carolina Medina-Gomez, Robert Karlsson, Yanchun Bao, Traci M Bartz, Clemens Baumbach, Ginevra Biino, Matthew J Bixley, Marco Brumat, Jin-Fang Chai, Tanguy Corre, Diana L Cousminer, Annelot M Dekker, David A Eccles, Kristel R van Eijk, Christian Fuchsberger, He Gao, Marine Germain, Scott D Gordon, Hugoline G de Haan, Sarah E Harris, Edith Hofer, Alicia Huerta-Chagoya, Catherine Igartua, Iris E Jansen, Yucheng Jia, Tim Kacprowski, Torgny Karlsson, Marcus E Kleber, Shengchao Alfred Li, Ruifang Li-Gao, Anubha Mahajan, Koichi Matsuda, Karina Meidtner, Weihua Meng, May E Montasser, Peter J van der Most, Matthias Munz, Teresa Nutile, Teemu Palviainen, Gauri Prasad, Rashmi B Prasad, Tallapragada Divya Sri Priyanka, Federica Rizzi, Erika Salvi, Bishwa R Sapkota, Daniel Shriner, Line Skotte, Melissa C Smart, Albert Vernon Smith, Ashley van der Spek, Cassandra N Spracklen, Rona J Strawbridge, Salman M Tajuddin, Stella Trompet, Constance Turman, Niek Verweij, Clara Viberti, Lihua Wang, Helen R Warren, Robyn E Wootton, Lisa R Yanek, Jie Yao, Noha A Yousri, Wei Zhao, Adebowale A Adeyemo, Saima Afaq, Carlos Alberto Aguilar-Salinas, Masato Akiyama, Matthew L Albert, Matthew A Allison, Maris Alver, Tin Aung, Fereidoun Azizi, Amy R Bentley, Heiner Boeing, Eric Boerwinkle, Judith B Borja, Gert J de Borst, Erwin P Bottinger, Linda Broer, Harry Campbell, Stephen Chanock, Miao-Li Chee, Guanjie Chen, Yii-Der I Chen, Zhengming Chen, Yen-Feng Chiu, Massimiliano Cocca, Francis S Collins, Maria Pina Concas, Janie Corley, Giovanni Cugliari, Rob M van Dam, Anna Damulina, Maryam S Daneshpour, Felix R Day, Graciela E Delgado, Klodian Dhana, Alexander S F Doney, Marcus Dörr, Ayo P Doumatey, Nduna Dzimiri, S Sunna Ebenesersdóttir, Joshua Elliott, Paul Elliott, Ralf Ewert, Janine F Felix, Krista Fischer, Barry I Freedman, Giorgia Girotto, Anuj Goel, Martin Gögele, Mark O Goodarzi, Mariaelisa Graff, Einat Granot-Hershkovitz, Francine Grodstein, Simonetta Guarrera, Daniel F Gudbjartsson, Kamran Guity, Bjarni Gunnarsson, Yu Guo, Saskia P Hagenaars, Christopher A Haiman, Avner Halevy, Tamara B Harris, Mehdi Hedayati, David A van Heel, Makoto Hirata, Imo Höfer, Chao Agnes Hsiung, Jinyan Huang, Yi-Jen Hung, M Arfan Ikram, Anuradha Jagadeesan, Pekka Jousilahti, Yoichiro Kamatani, Masahiro Kanai, Nicola D Kerrison, Thorsten Kessler, Kay-Tee Khaw, Chiea Chuen Khor, Dominique P V de Kleijn, Woon-Puay Koh, Ivana Kolcic, Peter Kraft, Bernhard K Krämer, Zoltán Kutalik, Johanna Kuusisto, Claudia Langenberg, Lenore J Launer, Deborah A Lawlor, I-Te Lee, Wen-Jane Lee, Markus M Lerch, Liming Li, Jianjun Liu, Marie Loh, Stephanie J London, Stephanie Loomis, Yingchang Lu, Jian’an Luan, Reedik Mägi, Ani W Manichaikul, Paolo Manunta, Gísli Másson, Nana Matoba, Xue W Mei, Christa Meisinger, Thomas Meitinger, Massimo Mezzavilla, Lili Milani, Iona Y Millwood, Yukihide Momozawa, Amy Moore, Pierre-Emmanuel Morange, Hortensia Moreno-Macías, Trevor A Mori, Alanna C Morrison, Taulant Muka, Yoshinori Murakami, Alison D Murray, Renée de Mutsert, Josyf C Mychaleckyj, Mike A Nalls, Matthias Nauck, Matt J Neville, Ilja M Nolte, Ken K Ong, Lorena Orozco, Sandosh Padmanabhan, Gunnar Pálsson, James S Pankow, Cristian Pattaro, Alison Pattie, Ozren Polasek, Neil Poulter, Peter P Pramstaller, Lluis Quintana-Murci, Katri Räikkönen, Sarju Ralhan, Dabeeru C Rao, Wouter van Rheenen, Stephen S Rich, Paul M Ridker, Cornelius A Rietveld, Antonietta Robino, Frank J A van Rooij, Daniela Ruggiero, Yasaman Saba, Charumathi Sabanayagam, Maria Sabater-Lleal, Cinzia Felicita Sala, Veikko Salomaa, Kevin Sandow, Helena Schmidt, Laura J Scott, William R Scott, Bahareh Sedaghati-Khayat, Bengt Sennblad, Jessica van Setten, Peter J Sever, Wayne H-H Sheu, Yuan Shi, Smeeta Shrestha, Sharvari Rahul Shukla, Jon K Sigurdsson, Timo Tonis Sikka, Jai Rup Singh, Blair H Smith, Alena Stančáková, Alice Stanton, John M Starr, Lilja Stefansdottir, Leon Straker, Patrick Sulem, Gardar Sveinbjornsson, Morris A Swertz, Adele M Taylor, Kent D Taylor, Natalie Terzikhan, Yih-Chung Tham, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Annika Tillander, Russell P Tracy, Teresa Tusié-Luna, Ioanna Tzoulaki, Simona Vaccargiu, Jagadish Vangipurapu, Jan H Veldink, Veronique Vitart, Uwe Völker, Eero Vuoksimaa, Salma M Wakil, Melanie Waldenberger, Gurpreet S Wander, Ya Xing Wang, Nicholas J Wareham, Sarah Wild, Chittaranjan S Yajnik, Jian-Min Yuan, Lingyao Zeng, Liang Zhang, Jie Zhou, Najaf Amin, Folkert W Asselbergs, Stephan J L Bakker, Diane M Becker, Benjamin Lehne, David A Bennett, Leonard H van den Berg, Sonja I Berndt, Dwaipayan Bharadwaj, Lawrence F Bielak, Murielle Bochud, Mike Boehnke, Claude Bouchard, Jonathan P Bradfield, Jennifer A Brody, Archie Campbell, Shai Carmi, Mark J Caulfield, David Cesarini, John C Chambers, Giriraj Ratan Chandak, Ching-Yu Cheng, Marina Ciullo, Marilyn Cornelis, Daniele Cusi, George Davey Smith, Ian J Deary, Rajkumar Dorajoo, Cornelia M van Duijn, David Ellinghaus, Jeanette Erdmann, Johan G Eriksson, Evangelos Evangelou, Michele K Evans, Jessica D Faul, Bjarke Feenstra, Mary Feitosa, Sylvain Foisy, Andre Franke, Yechiel Friedlander, Paolo Gasparini, Christian Gieger, Clicerio Gonzalez, Philippe Goyette, Struan F A Grant, Lyn R Griffiths, Leif Groop, Vilmundur Gudnason, Ulf Gyllensten, Hakon Hakonarson, Anders Hamsten, Pim van der Harst, Chew-Kiat Heng, Andrew A Hicks, Hagit Hochner, Heikki Huikuri, Steven C Hunt, Vincent W V Jaddoe, Philip L De Jager, Magnus Johannesson, Åsa Johansson, Jost B Jonas, J Wouter Jukema, Juhani Junttila, Jaakko Kaprio, Sharon L. R. Kardia, Fredrik Karpe, Meena Kumari, Markku Laakso, Sander W van der Laan, Jari Lahti, Matthias Laudes, Rodney A Lea, Wolfgang Lieb, Thomas Lumley, Nicholas G Martin, Winfried März, Giuseppe Matullo, Mark I McCarthy, Sarah E Medland, Tony R Merriman, Andres Metspalu, Brian F Meyer, Karen L Mohlke, Grant W Montgomery, Dennis Mook-Kanamori, Patricia B Munroe, Kari E North, Dale R Nyholt, Jeffery R O’connell, Carole Ober, Albertine J Oldehinkel, Walter Palmas, Colin Palmer, Gerard G Pasterkamp, Etienne Patin, Craig E Pennell, Louis Perusse, Patricia A Peyser, Mario Pirastu, Tinca J. C. Polderman, David J Porteous, Danielle Posthuma, Bruce M Psaty, John D Rioux, Fernando Rivadeneira, Charles Rotimi, Jerome I Rotter, Igor Rudan, Hester M Den Ruijter, Dharambir K Sanghera, Naveed Sattar, Reinhold Schmidt, Matthias B Schulze, Heribert Schunkert, Robert A Scott, Alan R Shuldiner, Xueling Sim, Neil Small, Jennifer A Smith, Nona Sotoodehnia, E-Shyong Tai, Alexander Teumer, Nicholas J Timpson, Daniela Toniolo, David-Alexandre Tregouet, Tiinamaija Tuomi, Peter Vollenweider, Carol A Wang, David R Weir, John B Whitfield, Cisca Wijmenga, Tien-Yin Wong, John Wright, Jingyun Yang, Lei Yu, Babette S Zemel, Alan B Zonderman, Markus Perola, Patrik K. E. Magnusson, André G Uitterlinden, Jaspal S Kooner, Daniel I Chasman, Ruth J. F. Loos, Nora Franceschini, Lude Franke, Chris S Haley, Caroline Hayward, Robin G Walters, John R. B. Perry, Tōnu Esko, Agnar Helgason, Kari Stefansson, Peter K Joshi, Michiaki Kubo, and James F Wilson
Subjects: Science
Abstract: Inbreeding depression has been observed in many different species, but in humans a systematic analysis has been difficult so far. Here, analysing more than 1.3 million individuals, the authors show that a genomic inbreeding coefficient (FROH) is associated with disadvantageous outcomes in 32 out of 100 traits tested.
Published: 2019
Full Text: View/download PDF

6. Duration of obesity exposure between ages 10 and 40 years and its relationship with cardiometabolic disease risk factors: A cohort study.

Author: Tom Norris, Tim J Cole, David Bann, Mark Hamer, Rebecca Hardy, Leah Li, Ken K Ong, George B Ploubidis, Russell Viner, and William Johnson
Subjects: Medicine
Abstract: BackgroundIndividuals with obesity do not represent a homogeneous group in terms of cardiometabolic risk. Using 3 nationally representative British birth cohorts, we investigated whether the duration of obesity was related to heterogeneity in cardiometabolic risk.Methods and findingsWe used harmonised body mass index (BMI) and cardiometabolic disease risk factor data from 20,746 participants (49.1% male and 97.2% white British) enrolled in 3 British birth cohort studies: the 1946 National Survey of Health and Development (NSHD), the 1958 National Child Development Study (NCDS), and the 1970 British Cohort Study (BCS70). Within each cohort, individual life course BMI trajectories were created between 10 and 40 years of age, and from these, age of obesity onset, duration spent obese (range 0 to 30 years), and cumulative obesity severity were derived. Obesity duration was examined in relation to a number of cardiometabolic disease risk factors collected in mid-adulthood: systolic (SBP) and diastolic blood pressure (DBP), high-density-lipoprotein cholesterol (HDL-C), and glycated haemoglobin (HbA1c). A greater obesity duration was associated with worse values for all cardiometabolic disease risk factors. The strongest association with obesity duration was for HbA1c: HbA1c levels in those with obesity for ConclusionsGiven that the obesity epidemic is characterised by a much earlier onset of obesity and consequently a greater lifetime exposure, our findings suggest that health policy recommendations aimed at preventing early obesity onset, and therefore reducing lifetime exposure, may help reduce the risk of diabetes, independently of obesity severity. However, to test the robustness of our observed associations, triangulation of evidence from different epidemiological approaches (e.g., mendelian randomization and negative control studies) should be obtained.
Published: 2020
Full Text: View/download PDF

7. Association of puberty timing with type 2 diabetes: A systematic review and meta-analysis.

Author: Tuck Seng Cheng, Felix R Day, Rajalakshmi Lakshman, and Ken K Ong
Subjects: Medicine
Abstract: BackgroundEmerging studies have investigated the association between puberty timing, particularly age at menarche (AAM), and type 2 diabetes. However, whether this association is independent of adiposity is unclear. We aimed to systematically review published evidence on the association between puberty timing and type 2 diabetes (T2D) or impaired glucose tolerance (IGT), with and without adjustment for adiposity, and to estimate the potential contribution of puberty timing to the burden of T2D in the United Kingdom (UK).Methods and findingsWe searched PubMed, Medline, and Embase databases for publications until February 2019 on the timing of any secondary sexual characteristic in boys or girls in relation to T2D/IGT. Inverse-variance-weighted random-effects meta-analysis was used to pool reported estimates, and meta-regression was used to explore sources of heterogeneity. Twenty-eight observational studies were identified. All assessed AAM in women (combined N = 1,228,306); only 1 study additionally included men. In models without adjustment for adult adiposity, T2D/IGT risk was lower per year later AAM (relative risk [RR] = 0.91, 95% CI 0.89-0.93, p < 0.001, 11 estimates, n = 833,529, I2 = 85.4%) and higher for early versus later menarche (RR = 1.39, 95% CI 1.25-1.55, p < 0.001, 23 estimates, n = 1,185,444, I2 = 87.8%). Associations were weaker but still evident in models adjusted for adiposity (AAM: RR = 0.97 per year, 95% CI 0.95-0.98, p < 0.001, 12 estimates, n = 852,268, I2 = 51.8%; early menarche: RR = 1.19, 95% CI 1.11-1.28, p < 0.001, 21 estimates, n = 890,583, I2 = 68.1%). Associations were stronger among white than Asian women, and in populations with earlier average AAM. The estimated population attributable risk of T2D in white UK women due to early menarche unadjusted and adjusted for adiposity was 12.6% (95% CI 11.0-14.3) and 5.1% (95% CI 3.6-6.7), respectively. Findings in this study are limited by residual and unmeasured confounding, and self-reported AAM.ConclusionsEarlier AAM is consistently associated with higher T2D/IGT risk, independent of adiposity. More importantly, this research has identified that a substantial proportion of T2D in women is related to early menarche, which would be expected to increase in light of global secular trends towards earlier puberty timing. These findings highlight the need to identify the underlying mechanisms linking early menarche to T2D/IGT risk.
Published: 2020
Full Text: View/download PDF

8. Associations of stunting in early childhood with cardiometabolic risk factors in adulthood.

Author: Emanuella De Lucia Rolfe, Giovanny Vinícius Araújo de França, Carolina Avila Vianna, Denise P Gigante, J Jaime Miranda, John S Yudkin, Bernardo Lessa Horta, and Ken K Ong
Subjects: Medicine, Science
Abstract: Early life stunting may have long-term effects on body composition, resulting in obesity-related comorbidities. We tested the hypothesis that individuals stunted in early childhood may be at higher cardiometabolic risk later in adulthood. 1753 men and 1781 women participating in the 1982 Pelotas (Brazil) birth cohort study had measurements of anthropometry, body composition, lipids, glucose, blood pressure, and other cardiometabolic traits at age 30 years. Early stunting was defined as height-for-age Z-score at age 2 years below -2 against the World Health Organization growth standards. Linear regression models were performed controlling for sex, maternal race/ethnicity, family income at birth, and birthweight. Analyses were stratified by sex when p-interaction
Published: 2018
Full Text: View/download PDF

9. Validity of ultrasonography to assess hepatic steatosis compared to magnetic resonance spectroscopy as a criterion method in older adults.

Author: Emanuella De Lucia Rolfe, Soren Brage, Alison Sleigh, Francis Finucane, Simon J Griffin, Nick J Wareham, Ken K Ong, and Nita G Forouhi
Subjects: Medicine, Science
Abstract: BACKGROUND:The rising prevalence of obesity has made hepatic steatosis an increasingly common issue. Ultrasound is generally used in clinical practice to assess steatosis, but its accuracy has been inconsistent across studies. We aimed to determine the validity of ultrasound to diagnose hepatic steatosis when compared to the criterion method proton magnetic resonance spectroscopy (MRS) in older individuals. METHODS:A total of 72 healthy white European individuals (n = 42 men; n = 30 women aged 67-76 years) participating in the Hertfordshire Birth Cohort Physical Activity trial had hepatic steatosis assessed by ultrasound and MRS. The ultrasound scans were graded as normal, mild, moderate and severe steatosis, while hepatic fat content above 5.5% by MRS was used as a cut-off for steatosis. RESULTS:18 participants (25%) had a level of hepatic fat measured by MRS consistent with diagnosis of steatosis. The sensitivity and specificity of ultrasound in diagnosing hepatic steatosis (mild/moderate/severe vs normal) were 96% (95% CI: 87-99.6%) and 94% (95% CI: 73-100%) respectively, although overlap in MRS hepatic fat content was observed between the ultrasound categories. CONCLUSIONS:Ultrasound is a valid method for detecting the presence or absence of hepatic steatosis in older adults and can be used as an alternative tool in both clinical investigations and epidemiological studies, when other imaging techniques are not feasible.
Published: 2018
Full Text: View/download PDF

10. Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis.

Author: Eleanor Wheeler, Aaron Leong, Ching-Ti Liu, Marie-France Hivert, Rona J Strawbridge, Clara Podmore, Man Li, Jie Yao, Xueling Sim, Jaeyoung Hong, Audrey Y Chu, Weihua Zhang, Xu Wang, Peng Chen, Nisa M Maruthur, Bianca C Porneala, Stephen J Sharp, Yucheng Jia, Edmond K Kabagambe, Li-Ching Chang, Wei-Min Chen, Cathy E Elks, Daniel S Evans, Qiao Fan, Franco Giulianini, Min Jin Go, Jouke-Jan Hottenga, Yao Hu, Anne U Jackson, Stavroula Kanoni, Young Jin Kim, Marcus E Kleber, Claes Ladenvall, Cecile Lecoeur, Sing-Hui Lim, Yingchang Lu, Anubha Mahajan, Carola Marzi, Mike A Nalls, Pau Navarro, Ilja M Nolte, Lynda M Rose, Denis V Rybin, Serena Sanna, Yuan Shi, Daniel O Stram, Fumihiko Takeuchi, Shu Pei Tan, Peter J van der Most, Jana V Van Vliet-Ostaptchouk, Andrew Wong, Loic Yengo, Wanting Zhao, Anuj Goel, Maria Teresa Martinez Larrad, Dörte Radke, Perttu Salo, Toshiko Tanaka, Erik P A van Iperen, Goncalo Abecasis, Saima Afaq, Behrooz Z Alizadeh, Alain G Bertoni, Amelie Bonnefond, Yvonne Böttcher, Erwin P Bottinger, Harry Campbell, Olga D Carlson, Chien-Hsiun Chen, Yoon Shin Cho, W Timothy Garvey, Christian Gieger, Mark O Goodarzi, Harald Grallert, Anders Hamsten, Catharina A Hartman, Christian Herder, Chao Agnes Hsiung, Jie Huang, Michiya Igase, Masato Isono, Tomohiro Katsuya, Chiea-Chuen Khor, Wieland Kiess, Katsuhiko Kohara, Peter Kovacs, Juyoung Lee, Wen-Jane Lee, Benjamin Lehne, Huaixing Li, Jianjun Liu, Stephane Lobbens, Jian'an Luan, Valeriya Lyssenko, Thomas Meitinger, Tetsuro Miki, Iva Miljkovic, Sanghoon Moon, Antonella Mulas, Gabriele Müller, Martina Müller-Nurasyid, Ramaiah Nagaraja, Matthias Nauck, James S Pankow, Ozren Polasek, Inga Prokopenko, Paula S Ramos, Laura Rasmussen-Torvik, Wolfgang Rathmann, Stephen S Rich, Neil R Robertson, Michael Roden, Ronan Roussel, Igor Rudan, Robert A Scott, William R Scott, Bengt Sennblad, David S Siscovick, Konstantin Strauch, Liang Sun, Morris Swertz, Salman M Tajuddin, Kent D Taylor, Yik-Ying Teo, Yih Chung Tham, Anke Tönjes, Nicholas J Wareham, Gonneke Willemsen, Tom Wilsgaard, Aroon D Hingorani, EPIC-CVD Consortium, EPIC-InterAct Consortium, Lifelines Cohort Study, Josephine Egan, Luigi Ferrucci, G Kees Hovingh, Antti Jula, Mika Kivimaki, Meena Kumari, Inger Njølstad, Colin N A Palmer, Manuel Serrano Ríos, Michael Stumvoll, Hugh Watkins, Tin Aung, Matthias Blüher, Michael Boehnke, Dorret I Boomsma, Stefan R Bornstein, John C Chambers, Daniel I Chasman, Yii-Der Ida Chen, Yduan-Tsong Chen, Ching-Yu Cheng, Francesco Cucca, Eco J C de Geus, Panos Deloukas, Michele K Evans, Myriam Fornage, Yechiel Friedlander, Philippe Froguel, Leif Groop, Myron D Gross, Tamara B Harris, Caroline Hayward, Chew-Kiat Heng, Erik Ingelsson, Norihiro Kato, Bong-Jo Kim, Woon-Puay Koh, Jaspal S Kooner, Antje Körner, Diana Kuh, Johanna Kuusisto, Markku Laakso, Xu Lin, Yongmei Liu, Ruth J F Loos, Patrik K E Magnusson, Winfried März, Mark I McCarthy, Albertine J Oldehinkel, Ken K Ong, Nancy L Pedersen, Mark A Pereira, Annette Peters, Paul M Ridker, Charumathi Sabanayagam, Michele Sale, Danish Saleheen, Juha Saltevo, Peter Eh Schwarz, Wayne H H Sheu, Harold Snieder, Timothy D Spector, Yasuharu Tabara, Jaakko Tuomilehto, Rob M van Dam, James G Wilson, James F Wilson, Bruce H R Wolffenbuttel, Tien Yin Wong, Jer-Yuarn Wu, Jian-Min Yuan, Alan B Zonderman, Nicole Soranzo, Xiuqing Guo, David J Roberts, Jose C Florez, Robert Sladek, Josée Dupuis, Andrew P Morris, E-Shyong Tai, Elizabeth Selvin, Jerome I Rotter, Claudia Langenberg, Inês Barroso, and James B Meigs
Subjects: Medicine
Abstract: BackgroundGlycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.Methods & findingsUsing genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 × 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.ConclusionsAs G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.
Published: 2017
Full Text: View/download PDF

11. Correction: Genome-wide physical activity interactions in adiposity - A meta-analysis of 200,452 adults.

Author: Mariaelisa Graff, Robert A Scott, Anne E Justice, Kristin L Young, Mary F Feitosa, Llilda Barata, Thomas W Winkler, Audrey Y Chu, Anubha Mahajan, David Hadley, Luting Xue, Tsegaselassie Workalemahu, Nancy L Heard-Costa, Marcel den Hoed, Tarunveer S Ahluwalia, Qibin Qi, Julius S Ngwa, Frida Renström, Lydia Quaye, John D Eicher, James E Hayes, Marilyn Cornelis, Zoltan Kutalik, Elise Lim, Jian'an Luan, Jennifer E Huffman, Weihua Zhang, Wei Zhao, Paula J Griffin, Toomas Haller, Shafqat Ahmad, Pedro M Marques-Vidal, Stephanie Bien, Loic Yengo, Alexander Teumer, Albert Vernon Smith, Meena Kumari, Marie Neergaard Harder, Johanne Marie Justesen, Marcus E Kleber, Mette Hollensted, Kurt Lohman, Natalia V Rivera, John B Whitfield, Jing Hua Zhao, Heather M Stringham, Leo-Pekka Lyytikäinen, Charlotte Huppertz, Gonneke Willemsen, Wouter J Peyrot, Ying Wu, Kati Kristiansson, Ayse Demirkan, Myriam Fornage, Maija Hassinen, Lawrence F Bielak, Gemma Cadby, Toshiko Tanaka, Reedik Mägi, Peter J van der Most, Anne U Jackson, Jennifer L Bragg-Gresham, Veronique Vitart, Jonathan Marten, Pau Navarro, Claire Bellis, Dorota Pasko, Åsa Johansson, Søren Snitker, Yu-Ching Cheng, Joel Eriksson, Unhee Lim, Mette Aadahl, Linda S Adair, Najaf Amin, Beverley Balkau, Juha Auvinen, John Beilby, Richard N Bergman, Sven Bergmann, Alain G Bertoni, John Blangero, Amélie Bonnefond, Lori L Bonnycastle, Judith B Borja, Søren Brage, Fabio Busonero, Steve Buyske, Harry Campbell, Peter S Chines, Francis S Collins, Tanguy Corre, George Davey Smith, Graciela E Delgado, Nicole Dueker, Marcus Dörr, Tapani Ebeling, Gudny Eiriksdottir, Tõnu Esko, Jessica D Faul, Mao Fu, Kristine Færch, Christian Gieger, Sven Gläser, Jian Gong, Penny Gordon-Larsen, Harald Grallert, Tanja B Grammer, Niels Grarup, Gerard van Grootheest, Kennet Harald, Nicholas D Hastie, Aki S Havulinna, Dena Hernandez, Lucia Hindorff, Lynne J Hocking, Oddgeir L Holmens, Christina Holzapfel, Jouke Jan Hottenga, Jie Huang, Tao Huang, Jennie Hui, Cornelia Huth, Nina Hutri-Kähönen, Alan L James, John-Olov Jansson, Min A Jhun, Markus Juonala, Leena Kinnunen, Heikki A Koistinen, Ivana Kolcic, Pirjo Komulainen, Johanna Kuusisto, Kirsti Kvaløy, Mika Kähönen, Timo A Lakka, Lenore J Launer, Benjamin Lehne, Cecilia M Lindgren, Mattias Lorentzon, Robert Luben, Michel Marre, Yuri Milaneschi, Keri L Monda, Grant W Montgomery, Marleen H M De Moor, Antonella Mulas, Martina Müller-Nurasyid, A W Musk, Reija Männikkö, Satu Männistö, Narisu Narisu, Matthias Nauck, Jennifer A Nettleton, Ilja M Nolte, Albertine J Oldehinkel, Matthias Olden, Ken K Ong, Sandosh Padmanabhan, Lavinia Paternoster, Jeremiah Perez, Markus Perola, Annette Peters, Ulrike Peters, Patricia A Peyser, Inga Prokopenko, Hannu Puolijoki, Olli T Raitakari, Tuomo Rankinen, Laura J Rasmussen-Torvik, Rajesh Rawal, Paul M Ridker, Lynda M Rose, Igor Rudan, Cinzia Sarti, Mark A Sarzynski, Kai Savonen, William R Scott, Serena Sanna, Alan R Shuldiner, Steve Sidney, Günther Silbernagel, Blair H Smith, Jennifer A Smith, Harold Snieder, Alena Stančáková, Barbara Sternfeld, Amy J Swift, Tuija Tammelin, Sian-Tsung Tan, Barbara Thorand, Dorothée Thuillier, Liesbeth Vandenput, Henrik Vestergaard, Jana V van Vliet-Ostaptchouk, Marie-Claude Vohl, Uwe Völker, Gérard Waeber, Mark Walker, Sarah Wild, Andrew Wong, Alan F Wright, M Carola Zillikens, Niha Zubair, Christopher A Haiman, Loic Lemarchand, Ulf Gyllensten, Claes Ohlsson, Albert Hofman, Fernando Rivadeneira, André G Uitterlinden, Louis Pérusse, James F Wilson, Caroline Hayward, Ozren Polasek, Francesco Cucca, Kristian Hveem, Catharina A Hartman, Anke Tönjes, Stefania Bandinelli, Lyle J Palmer, Sharon L R Kardia, Rainer Rauramaa, Thorkild I A Sørensen, Jaakko Tuomilehto, Veikko Salomaa, Brenda W J H Penninx, Eco J C de Geus, Dorret I Boomsma, Terho Lehtimäki, Massimo Mangino, Markku Laakso, Claude Bouchard, Nicholas G Martin, Diana Kuh, Yongmei Liu, Allan Linneberg, Winfried März, Konstantin Strauch, Mika Kivimäki, Tamara B Harris, Vilmundur Gudnason, Henry Völzke, Lu Qi, Marjo-Riitta Järvelin, John C Chambers, Jaspal S Kooner, Philippe Froguel, Charles Kooperberg, Peter Vollenweider, Göran Hallmans, Torben Hansen, Oluf Pedersen, Andres Metspalu, Nicholas J Wareham, Claudia Langenberg, David R Weir, David J Porteous, Eric Boerwinkle, Daniel I Chasman, CHARGE Consortium, EPIC-InterAct Consortium, PAGE Consortium, Gonçalo R Abecasis, Inês Barroso, Mark I McCarthy, Timothy M Frayling, Jeffrey R O'Connell, Cornelia M van Duijn, Michael Boehnke, Iris M Heid, Karen L Mohlke, David P Strachan, Caroline S Fox, Ching-Ti Liu, Joel N Hirschhorn, Robert J Klein, Andrew D Johnson, Ingrid B Borecki, Paul W Franks, Kari E North, L Adrienne Cupples, Ruth J F Loos, and Tuomas O Kilpeläinen
Subjects: Genetics, QH426-470
Abstract: [This corrects the article DOI: 10.1371/journal.pgen.1006528.].
Published: 2017
Full Text: View/download PDF

12. Ranking and characterization of established BMI and lipid associated loci as candidates for gene-environment interactions.

Author: Dmitry Shungin, Wei Q Deng, Tibor V Varga, Jian'an Luan, Evelin Mihailov, Andres Metspalu, GIANT Consortium, Andrew P Morris, Nita G Forouhi, Cecilia Lindgren, Patrik K E Magnusson, Nancy L Pedersen, Göran Hallmans, Audrey Y Chu, Anne E Justice, Mariaelisa Graff, Thomas W Winkler, Lynda M Rose, Claudia Langenberg, L Adrienne Cupples, Paul M Ridker, Nicholas J Wareham, Ken K Ong, Ruth J F Loos, Daniel I Chasman, Erik Ingelsson, Tuomas O Kilpeläinen, Robert A Scott, Reedik Mägi, Guillaume Paré, and Paul W Franks
Subjects: Genetics, QH426-470
Abstract: Phenotypic variance heterogeneity across genotypes at a single nucleotide polymorphism (SNP) may reflect underlying gene-environment (G×E) or gene-gene interactions. We modeled variance heterogeneity for blood lipids and BMI in up to 44,211 participants and investigated relationships between variance effects (Pv), G×E interaction effects (with smoking and physical activity), and marginal genetic effects (Pm). Correlations between Pv and Pm were stronger for SNPs with established marginal effects (Spearman's ρ = 0.401 for triglycerides, and ρ = 0.236 for BMI) compared to all SNPs. When Pv and Pm were compared for all pruned SNPs, only BMI was statistically significant (Spearman's ρ = 0.010). Overall, SNPs with established marginal effects were overrepresented in the nominally significant part of the Pv distribution (Pbinomial
Published: 2017
Full Text: View/download PDF

13. Genome-wide physical activity interactions in adiposity - A meta-analysis of 200,452 adults.

Author: Mariaelisa Graff, Robert A Scott, Anne E Justice, Kristin L Young, Mary F Feitosa, Llilda Barata, Thomas W Winkler, Audrey Y Chu, Anubha Mahajan, David Hadley, Luting Xue, Tsegaselassie Workalemahu, Nancy L Heard-Costa, Marcel den Hoed, Tarunveer S Ahluwalia, Qibin Qi, Julius S Ngwa, Frida Renström, Lydia Quaye, John D Eicher, James E Hayes, Marilyn Cornelis, Zoltan Kutalik, Elise Lim, Jian'an Luan, Jennifer E Huffman, Weihua Zhang, Wei Zhao, Paula J Griffin, Toomas Haller, Shafqat Ahmad, Pedro M Marques-Vidal, Stephanie Bien, Loic Yengo, Alexander Teumer, Albert Vernon Smith, Meena Kumari, Marie Neergaard Harder, Johanne Marie Justesen, Marcus E Kleber, Mette Hollensted, Kurt Lohman, Natalia V Rivera, John B Whitfield, Jing Hua Zhao, Heather M Stringham, Leo-Pekka Lyytikäinen, Charlotte Huppertz, Gonneke Willemsen, Wouter J Peyrot, Ying Wu, Kati Kristiansson, Ayse Demirkan, Myriam Fornage, Maija Hassinen, Lawrence F Bielak, Gemma Cadby, Toshiko Tanaka, Reedik Mägi, Peter J van der Most, Anne U Jackson, Jennifer L Bragg-Gresham, Veronique Vitart, Jonathan Marten, Pau Navarro, Claire Bellis, Dorota Pasko, Åsa Johansson, Søren Snitker, Yu-Ching Cheng, Joel Eriksson, Unhee Lim, Mette Aadahl, Linda S Adair, Najaf Amin, Beverley Balkau, Juha Auvinen, John Beilby, Richard N Bergman, Sven Bergmann, Alain G Bertoni, John Blangero, Amélie Bonnefond, Lori L Bonnycastle, Judith B Borja, Søren Brage, Fabio Busonero, Steve Buyske, Harry Campbell, Peter S Chines, Francis S Collins, Tanguy Corre, George Davey Smith, Graciela E Delgado, Nicole Dueker, Marcus Dörr, Tapani Ebeling, Gudny Eiriksdottir, Tõnu Esko, Jessica D Faul, Mao Fu, Kristine Færch, Christian Gieger, Sven Gläser, Jian Gong, Penny Gordon-Larsen, Harald Grallert, Tanja B Grammer, Niels Grarup, Gerard van Grootheest, Kennet Harald, Nicholas D Hastie, Aki S Havulinna, Dena Hernandez, Lucia Hindorff, Lynne J Hocking, Oddgeir L Holmens, Christina Holzapfel, Jouke Jan Hottenga, Jie Huang, Tao Huang, Jennie Hui, Cornelia Huth, Nina Hutri-Kähönen, Alan L James, John-Olov Jansson, Min A Jhun, Markus Juonala, Leena Kinnunen, Heikki A Koistinen, Ivana Kolcic, Pirjo Komulainen, Johanna Kuusisto, Kirsti Kvaløy, Mika Kähönen, Timo A Lakka, Lenore J Launer, Benjamin Lehne, Cecilia M Lindgren, Mattias Lorentzon, Robert Luben, Michel Marre, Yuri Milaneschi, Keri L Monda, Grant W Montgomery, Marleen H M De Moor, Antonella Mulas, Martina Müller-Nurasyid, A W Musk, Reija Männikkö, Satu Männistö, Narisu Narisu, Matthias Nauck, Jennifer A Nettleton, Ilja M Nolte, Albertine J Oldehinkel, Matthias Olden, Ken K Ong, Sandosh Padmanabhan, Lavinia Paternoster, Jeremiah Perez, Markus Perola, Annette Peters, Ulrike Peters, Patricia A Peyser, Inga Prokopenko, Hannu Puolijoki, Olli T Raitakari, Tuomo Rankinen, Laura J Rasmussen-Torvik, Rajesh Rawal, Paul M Ridker, Lynda M Rose, Igor Rudan, Cinzia Sarti, Mark A Sarzynski, Kai Savonen, William R Scott, Serena Sanna, Alan R Shuldiner, Steve Sidney, Günther Silbernagel, Blair H Smith, Jennifer A Smith, Harold Snieder, Alena Stančáková, Barbara Sternfeld, Amy J Swift, Tuija Tammelin, Sian-Tsung Tan, Barbara Thorand, Dorothée Thuillier, Liesbeth Vandenput, Henrik Vestergaard, Jana V van Vliet-Ostaptchouk, Marie-Claude Vohl, Uwe Völker, Gérard Waeber, Mark Walker, Sarah Wild, Andrew Wong, Alan F Wright, M Carola Zillikens, Niha Zubair, Christopher A Haiman, Loic Lemarchand, Ulf Gyllensten, Claes Ohlsson, Albert Hofman, Fernando Rivadeneira, André G Uitterlinden, Louis Pérusse, James F Wilson, Caroline Hayward, Ozren Polasek, Francesco Cucca, Kristian Hveem, Catharina A Hartman, Anke Tönjes, Stefania Bandinelli, Lyle J Palmer, Sharon L R Kardia, Rainer Rauramaa, Thorkild I A Sørensen, Jaakko Tuomilehto, Veikko Salomaa, Brenda W J H Penninx, Eco J C de Geus, Dorret I Boomsma, Terho Lehtimäki, Massimo Mangino, Markku Laakso, Claude Bouchard, Nicholas G Martin, Diana Kuh, Yongmei Liu, Allan Linneberg, Winfried März, Konstantin Strauch, Mika Kivimäki, Tamara B Harris, Vilmundur Gudnason, Henry Völzke, Lu Qi, Marjo-Riitta Järvelin, John C Chambers, Jaspal S Kooner, Philippe Froguel, Charles Kooperberg, Peter Vollenweider, Göran Hallmans, Torben Hansen, Oluf Pedersen, Andres Metspalu, Nicholas J Wareham, Claudia Langenberg, David R Weir, David J Porteous, Eric Boerwinkle, Daniel I Chasman, CHARGE Consortium, EPIC-InterAct Consortium, PAGE Consortium, Gonçalo R Abecasis, Inês Barroso, Mark I McCarthy, Timothy M Frayling, Jeffrey R O'Connell, Cornelia M van Duijn, Michael Boehnke, Iris M Heid, Karen L Mohlke, David P Strachan, Caroline S Fox, Ching-Ti Liu, Joel N Hirschhorn, Robert J Klein, Andrew D Johnson, Ingrid B Borecki, Paul W Franks, Kari E North, L Adrienne Cupples, Ruth J F Loos, and Tuomas O Kilpeläinen
Subjects: Genetics, QH426-470
Abstract: Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.
Published: 2017
Full Text: View/download PDF

14. Genomic ancestry and education level independently influence abdominal fat distributions in a Brazilian admixed population.

Author: Giovanny Vinícius Araújo de França, Emanuella De Lucia Rolfe, Bernardo Lessa Horta, Denise Petrucci Gigante, John S Yudkin, Ken K Ong, and Cesar Gomes Victora
Subjects: Medicine, Science
Abstract: We aimed to identify the independent associations of genomic ancestry and education level with abdominal fat distributions in the 1982 Pelotas birth cohort study, Brazil. In 2,890 participants (1,409 men and 1,481 women), genomic ancestry was assessed using genotype data on 370,539 genome-wide variants to quantify ancestral proportions in each individual. Years of completed education was used to indicate socio-economic position. Visceral fat depth and subcutaneous abdominal fat thickness were measured by ultrasound at age 29-31y; these measures were adjusted for BMI to indicate abdominal fat distributions. Linear regression models were performed, separately by sex. Admixture was observed between European (median proportion 85.3), African (6.6), and Native American (6.3) ancestries, with a strong inverse correlation between the African and European ancestry scores (ρ = -0.93; p
Published: 2017
Full Text: View/download PDF

15. Correction: The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.

Author: Thomas W Winkler, Anne E Justice, Mariaelisa Graff, Llilda Barata, Mary F Feitosa, Su Chu, Jacek Czajkowski, Tõnu Esko, Tove Fall, Tuomas O Kilpeläinen, Yingchang Lu, Reedik Mägi, Evelin Mihailov, Tune H Pers, Sina Rüeger, Alexander Teumer, Georg B Ehret, Teresa Ferreira, Nancy L Heard-Costa, Juha Karjalainen, Vasiliki Lagou, Anubha Mahajan, Michael D Neinast, Inga Prokopenko, Jeannette Simino, Tanya M Teslovich, Rick Jansen, Harm-Jan Westra, Charles C White, Devin Absher, Tarunveer S Ahluwalia, Shafqat Ahmad, Eva Albrecht, Alexessander Couto Alves, Jennifer L Bragg-Gresham, Anton J M de Craen, Joshua C Bis, Amélie Bonnefond, Gabrielle Boucher, Gemma Cadby, Yu-Ching Cheng, Charleston W K Chiang, Graciela Delgado, Ayse Demirkan, Nicole Dueker, Niina Eklund, Gudny Eiriksdottir, Joel Eriksson, Bjarke Feenstra, Krista Fischer, Francesca Frau, Tessel E Galesloot, Frank Geller, Anuj Goel, Mathias Gorski, Tanja B Grammer, Stefan Gustafsson, Saskia Haitjema, Jouke-Jan Hottenga, Jennifer E Huffman, Anne U Jackson, Kevin B Jacobs, Åsa Johansson, Marika Kaakinen, Marcus E Kleber, Jari Lahti, Irene Mateo Leach, Benjamin Lehne, Youfang Liu, Ken Sin Lo, Mattias Lorentzon, Jian'an Luan, Pamela A F Madden, Massimo Mangino, Barbara McKnight, Carolina Medina-Gomez, Keri L Monda, May E Montasser, Gabriele Müller, Martina Müller-Nurasyid, Ilja M Nolte, Kalliope Panoutsopoulou, Laura Pascoe, Lavinia Paternoster, Nigel W Rayner, Frida Renström, Federica Rizzi, Lynda M Rose, Kathy A Ryan, Perttu Salo, Serena Sanna, Hubert Scharnagl, Jianxin Shi, Albert Vernon Smith, Lorraine Southam, Alena Stančáková, Valgerdur Steinthorsdottir, Rona J Strawbridge, Yun Ju Sung, Ioanna Tachmazidou, Toshiko Tanaka, Gudmar Thorleifsson, Stella Trompet, Natalia Pervjakova, Jonathan P Tyrer, Liesbeth Vandenput, Sander W van der Laan, Nathalie van der Velde, Jessica van Setten, Jana V van Vliet-Ostaptchouk, Niek Verweij, Efthymia Vlachopoulou, Lindsay L Waite, Sophie R Wang, Zhaoming Wang, Sarah H Wild, Christina Willenborg, James F Wilson, Andrew Wong, Jian Yang, Loïc Yengo, Laura M Yerges-Armstrong, Lei Yu, Weihua Zhang, Jing Hua Zhao, Ehm A Andersson, Stephan J L Bakker, Damiano Baldassarre, Karina Banasik, Matteo Barcella, Cristina Barlassina, Claire Bellis, Paola Benaglio, John Blangero, Matthias Blüher, Fabrice Bonnet, Lori L Bonnycastle, Heather A Boyd, Marcel Bruinenberg, Aron S Buchman, Harry Campbell, Yii-Der Ida Chen, Peter S Chines, Simone Claudi-Boehm, John Cole, Francis S Collins, Eco J C de Geus, Lisette C P G M de Groot, Maria Dimitriou, Jubao Duan, Stefan Enroth, Elodie Eury, Aliki-Eleni Farmaki, Nita G Forouhi, Nele Friedrich, Pablo V Gejman, Bruna Gigante, Nicola Glorioso, Alan S Go, Omri Gottesman, Jürgen Gräßler, Harald Grallert, Niels Grarup, Yu-Mei Gu, Linda Broer, Annelies C Ham, Torben Hansen, Tamara B Harris, Catharina A Hartman, Maija Hassinen, Nicholas Hastie, Andrew T Hattersley, Andrew C Heath, Anjali K Henders, Dena Hernandez, Hans Hillege, Oddgeir Holmen, Kees G Hovingh, Jennie Hui, Lise L Husemoen, Nina Hutri-Kähönen, Pirro G Hysi, Thomas Illig, Philip L De Jager, Shapour Jalilzadeh, Torben Jørgensen, J Wouter Jukema, Markus Juonala, Stavroula Kanoni, Maria Karaleftheri, Kay Tee Khaw, Leena Kinnunen, Steven J Kittner, Wolfgang Koenig, Ivana Kolcic, Peter Kovacs, Nikolaj T Krarup, Wolfgang Kratzer, Janine Krüger, Diana Kuh, Meena Kumari, Theodosios Kyriakou, Claudia Langenberg, Lars Lannfelt, Chiara Lanzani, Vaneet Lotay, Lenore J Launer, Karin Leander, Jaana Lindström, Allan Linneberg, Yan-Ping Liu, Stéphane Lobbens, Robert Luben, Valeriya Lyssenko, Satu Männistö, Patrik K Magnusson, Wendy L McArdle, Cristina Menni, Sigrun Merger, Lili Milani, Grant W Montgomery, Andrew P Morris, Narisu Narisu, Mari Nelis, Ken K Ong, Aarno Palotie, Louis Pérusse, Irene Pichler, Maria G Pilia, Anneli Pouta, Myriam Rheinberger, Rasmus Ribel-Madsen, Marcus Richards, Kenneth M Rice, Treva K Rice, Carlo Rivolta, Veikko Salomaa, Alan R Sanders, Mark A Sarzynski, Salome Scholtens, Robert A Scott, William R Scott, Sylvain Sebert, Sebanti Sengupta, Bengt Sennblad, Thomas Seufferlein, Angela Silveira, P Eline Slagboom, Jan H Smit, Thomas H Sparsø, Kathleen Stirrups, Ronald P Stolk, Heather M Stringham, Morris A Swertz, Amy J Swift, Ann-Christine Syvänen, Sian-Tsung Tan, Barbara Thorand, Anke Tönjes, Angelo Tremblay, Emmanouil Tsafantakis, Peter J van der Most, Uwe Völker, Marie-Claude Vohl, Judith M Vonk, Melanie Waldenberger, Ryan W Walker, Roman Wennauer, Elisabeth Widén, Gonneke Willemsen, Tom Wilsgaard, Alan F Wright, M Carola Zillikens, Suzanne C van Dijk, Natasja M van Schoor, Folkert W Asselbergs, Paul I W de Bakker, Jacques S Beckmann, John Beilby, David A Bennett, Richard N Bergman, Sven Bergmann, Carsten A Böger, Bernhard O Boehm, Eric Boerwinkle, Dorret I Boomsma, Stefan R Bornstein, Erwin P Bottinger, Claude Bouchard, John C Chambers, Stephen J Chanock, Daniel I Chasman, Francesco Cucca, Daniele Cusi, George Dedoussis, Jeanette Erdmann, Johan G Eriksson, Denis A Evans, Ulf de Faire, Martin Farrall, Luigi Ferrucci, Ian Ford, Lude Franke, Paul W Franks, Philippe Froguel, Ron T Gansevoort, Christian Gieger, Henrik Grönberg, Vilmundur Gudnason, Ulf Gyllensten, Per Hall, Anders Hamsten, Pim van der Harst, Caroline Hayward, Markku Heliövaara, Christian Hengstenberg, Andrew A Hicks, Aroon Hingorani, Albert Hofman, Frank Hu, Heikki V Huikuri, Kristian Hveem, Alan L James, Joanne M Jordan, Antti Jula, Mika Kähönen, Eero Kajantie, Sekar Kathiresan, Lambertus A L M Kiemeney, Mika Kivimaki, Paul B Knekt, Heikki A Koistinen, Jaspal S Kooner, Seppo Koskinen, Johanna Kuusisto, Winfried Maerz, Nicholas G Martin, Markku Laakso, Timo A Lakka, Terho Lehtimäki, Guillaume Lettre, Douglas F Levinson, Lars Lind, Marja-Liisa Lokki, Pekka Mäntyselkä, Mads Melbye, Andres Metspalu, Braxton D Mitchell, Frans L Moll, Jeffrey C Murray, Arthur W Musk, Markku S Nieminen, Inger Njølstad, Claes Ohlsson, Albertine J Oldehinkel, Ben A Oostra, Lyle J Palmer, James S Pankow, Gerard Pasterkamp, Nancy L Pedersen, Oluf Pedersen, Brenda W Penninx, Markus Perola, Annette Peters, Ozren Polašek, Peter P Pramstaller, Bruce M Psaty, Lu Qi, Thomas Quertermous, Olli T Raitakari, Tuomo Rankinen, Rainer Rauramaa, Paul M Ridker, John D Rioux, Fernando Rivadeneira, Jerome I Rotter, Igor Rudan, Hester M den Ruijter, Juha Saltevo, Naveed Sattar, Heribert Schunkert, Peter E H Schwarz, Alan R Shuldiner, Juha Sinisalo, Harold Snieder, Thorkild I A Sørensen, Tim D Spector, Jan A Staessen, Bandinelli Stefania, Unnur Thorsteinsdottir, Michael Stumvoll, Jean-Claude Tardif, Elena Tremoli, Jaakko Tuomilehto, André G Uitterlinden, Matti Uusitupa, André L M Verbeek, Sita H Vermeulen, Jorma S Viikari, Veronique Vitart, Henry Völzke, Peter Vollenweider, Gérard Waeber, Mark Walker, Henri Wallaschofski, Nicholas J Wareham, Hugh Watkins, Eleftheria Zeggini, arcOGEN Consortium, CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, MAGIC Consortium, Aravinda Chakravarti, Deborah J Clegg, L Adrienne Cupples, Penny Gordon-Larsen, Cashell E Jaquish, D C Rao, Goncalo R Abecasis, Themistocles L Assimes, Inês Barroso, Sonja I Berndt, Michael Boehnke, Panos Deloukas, Caroline S Fox, Leif C Groop, David J Hunter, Erik Ingelsson, Robert C Kaplan, Mark I McCarthy, Karen L Mohlke, Jeffrey R O'Connell, David Schlessinger, David P Strachan, Kari Stefansson, Cornelia M van Duijn, Joel N Hirschhorn, Cecilia M Lindgren, Iris M Heid, Kari E North, Ingrid B Borecki, Zoltán Kutalik, and Ruth J F Loos
Subjects: Genetics, QH426-470
Abstract: [This corrects the article DOI: 10.1371/journal.pgen.1005378.].
Published: 2016
Full Text: View/download PDF

16. The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.

Author: Thomas W Winkler, Anne E Justice, Mariaelisa Graff, Llilda Barata, Mary F Feitosa, Su Chu, Jacek Czajkowski, Tõnu Esko, Tove Fall, Tuomas O Kilpeläinen, Yingchang Lu, Reedik Mägi, Evelin Mihailov, Tune H Pers, Sina Rüeger, Alexander Teumer, Georg B Ehret, Teresa Ferreira, Nancy L Heard-Costa, Juha Karjalainen, Vasiliki Lagou, Anubha Mahajan, Michael D Neinast, Inga Prokopenko, Jeannette Simino, Tanya M Teslovich, Rick Jansen, Harm-Jan Westra, Charles C White, Devin Absher, Tarunveer S Ahluwalia, Shafqat Ahmad, Eva Albrecht, Alexessander Couto Alves, Jennifer L Bragg-Gresham, Anton J M de Craen, Joshua C Bis, Amélie Bonnefond, Gabrielle Boucher, Gemma Cadby, Yu-Ching Cheng, Charleston W K Chiang, Graciela Delgado, Ayse Demirkan, Nicole Dueker, Niina Eklund, Gudny Eiriksdottir, Joel Eriksson, Bjarke Feenstra, Krista Fischer, Francesca Frau, Tessel E Galesloot, Frank Geller, Anuj Goel, Mathias Gorski, Tanja B Grammer, Stefan Gustafsson, Saskia Haitjema, Jouke-Jan Hottenga, Jennifer E Huffman, Anne U Jackson, Kevin B Jacobs, Åsa Johansson, Marika Kaakinen, Marcus E Kleber, Jari Lahti, Irene Mateo Leach, Benjamin Lehne, Youfang Liu, Ken Sin Lo, Mattias Lorentzon, Jian'an Luan, Pamela A F Madden, Massimo Mangino, Barbara McKnight, Carolina Medina-Gomez, Keri L Monda, May E Montasser, Gabriele Müller, Martina Müller-Nurasyid, Ilja M Nolte, Kalliope Panoutsopoulou, Laura Pascoe, Lavinia Paternoster, Nigel W Rayner, Frida Renström, Federica Rizzi, Lynda M Rose, Kathy A Ryan, Perttu Salo, Serena Sanna, Hubert Scharnagl, Jianxin Shi, Albert Vernon Smith, Lorraine Southam, Alena Stančáková, Valgerdur Steinthorsdottir, Rona J Strawbridge, Yun Ju Sung, Ioanna Tachmazidou, Toshiko Tanaka, Gudmar Thorleifsson, Stella Trompet, Natalia Pervjakova, Jonathan P Tyrer, Liesbeth Vandenput, Sander W van der Laan, Nathalie van der Velde, Jessica van Setten, Jana V van Vliet-Ostaptchouk, Niek Verweij, Efthymia Vlachopoulou, Lindsay L Waite, Sophie R Wang, Zhaoming Wang, Sarah H Wild, Christina Willenborg, James F Wilson, Andrew Wong, Jian Yang, Loïc Yengo, Laura M Yerges-Armstrong, Lei Yu, Weihua Zhang, Jing Hua Zhao, Ehm A Andersson, Stephan J L Bakker, Damiano Baldassarre, Karina Banasik, Matteo Barcella, Cristina Barlassina, Claire Bellis, Paola Benaglio, John Blangero, Matthias Blüher, Fabrice Bonnet, Lori L Bonnycastle, Heather A Boyd, Marcel Bruinenberg, Aron S Buchman, Harry Campbell, Yii-Der Ida Chen, Peter S Chines, Simone Claudi-Boehm, John Cole, Francis S Collins, Eco J C de Geus, Lisette C P G M de Groot, Maria Dimitriou, Jubao Duan, Stefan Enroth, Elodie Eury, Aliki-Eleni Farmaki, Nita G Forouhi, Nele Friedrich, Pablo V Gejman, Bruna Gigante, Nicola Glorioso, Alan S Go, Omri Gottesman, Jürgen Gräßler, Harald Grallert, Niels Grarup, Yu-Mei Gu, Linda Broer, Annelies C Ham, Torben Hansen, Tamara B Harris, Catharina A Hartman, Maija Hassinen, Nicholas Hastie, Andrew T Hattersley, Andrew C Heath, Anjali K Henders, Dena Hernandez, Hans Hillege, Oddgeir Holmen, Kees G Hovingh, Jennie Hui, Lise L Husemoen, Nina Hutri-Kähönen, Pirro G Hysi, Thomas Illig, Philip L De Jager, Shapour Jalilzadeh, Torben Jørgensen, J Wouter Jukema, Markus Juonala, Stavroula Kanoni, Maria Karaleftheri, Kay Tee Khaw, Leena Kinnunen, Steven J Kittner, Wolfgang Koenig, Ivana Kolcic, Peter Kovacs, Nikolaj T Krarup, Wolfgang Kratzer, Janine Krüger, Diana Kuh, Meena Kumari, Theodosios Kyriakou, Claudia Langenberg, Lars Lannfelt, Chiara Lanzani, Vaneet Lotay, Lenore J Launer, Karin Leander, Jaana Lindström, Allan Linneberg, Yan-Ping Liu, Stéphane Lobbens, Robert Luben, Valeriya Lyssenko, Satu Männistö, Patrik K Magnusson, Wendy L McArdle, Cristina Menni, Sigrun Merger, Lili Milani, Grant W Montgomery, Andrew P Morris, Narisu Narisu, Mari Nelis, Ken K Ong, Aarno Palotie, Louis Pérusse, Irene Pichler, Maria G Pilia, Anneli Pouta, Myriam Rheinberger, Rasmus Ribel-Madsen, Marcus Richards, Kenneth M Rice, Treva K Rice, Carlo Rivolta, Veikko Salomaa, Alan R Sanders, Mark A Sarzynski, Salome Scholtens, Robert A Scott, William R Scott, Sylvain Sebert, Sebanti Sengupta, Bengt Sennblad, Thomas Seufferlein, Angela Silveira, P Eline Slagboom, Jan H Smit, Thomas H Sparsø, Kathleen Stirrups, Ronald P Stolk, Heather M Stringham, Morris A Swertz, Amy J Swift, Ann-Christine Syvänen, Sian-Tsung Tan, Barbara Thorand, Anke Tönjes, Angelo Tremblay, Emmanouil Tsafantakis, Peter J van der Most, Uwe Völker, Marie-Claude Vohl, Judith M Vonk, Melanie Waldenberger, Ryan W Walker, Roman Wennauer, Elisabeth Widén, Gonneke Willemsen, Tom Wilsgaard, Alan F Wright, M Carola Zillikens, Suzanne C van Dijk, Natasja M van Schoor, Folkert W Asselbergs, Paul I W de Bakker, Jacques S Beckmann, John Beilby, David A Bennett, Richard N Bergman, Sven Bergmann, Carsten A Böger, Bernhard O Boehm, Eric Boerwinkle, Dorret I Boomsma, Stefan R Bornstein, Erwin P Bottinger, Claude Bouchard, John C Chambers, Stephen J Chanock, Daniel I Chasman, Francesco Cucca, Daniele Cusi, George Dedoussis, Jeanette Erdmann, Johan G Eriksson, Denis A Evans, Ulf de Faire, Martin Farrall, Luigi Ferrucci, Ian Ford, Lude Franke, Paul W Franks, Philippe Froguel, Ron T Gansevoort, Christian Gieger, Henrik Grönberg, Vilmundur Gudnason, Ulf Gyllensten, Per Hall, Anders Hamsten, Pim van der Harst, Caroline Hayward, Markku Heliövaara, Christian Hengstenberg, Andrew A Hicks, Aroon Hingorani, Albert Hofman, Frank Hu, Heikki V Huikuri, Kristian Hveem, Alan L James, Joanne M Jordan, Antti Jula, Mika Kähönen, Eero Kajantie, Sekar Kathiresan, Lambertus A L M Kiemeney, Mika Kivimaki, Paul B Knekt, Heikki A Koistinen, Jaspal S Kooner, Seppo Koskinen, Johanna Kuusisto, Winfried Maerz, Nicholas G Martin, Markku Laakso, Timo A Lakka, Terho Lehtimäki, Guillaume Lettre, Douglas F Levinson, Lars Lind, Marja-Liisa Lokki, Pekka Mäntyselkä, Mads Melbye, Andres Metspalu, Braxton D Mitchell, Frans L Moll, Jeffrey C Murray, Arthur W Musk, Markku S Nieminen, Inger Njølstad, Claes Ohlsson, Albertine J Oldehinkel, Ben A Oostra, Lyle J Palmer, James S Pankow, Gerard Pasterkamp, Nancy L Pedersen, Oluf Pedersen, Brenda W Penninx, Markus Perola, Annette Peters, Ozren Polašek, Peter P Pramstaller, Bruce M Psaty, Lu Qi, Thomas Quertermous, Olli T Raitakari, Tuomo Rankinen, Rainer Rauramaa, Paul M Ridker, John D Rioux, Fernando Rivadeneira, Jerome I Rotter, Igor Rudan, Hester M den Ruijter, Juha Saltevo, Naveed Sattar, Heribert Schunkert, Peter E H Schwarz, Alan R Shuldiner, Juha Sinisalo, Harold Snieder, Thorkild I A Sørensen, Tim D Spector, Jan A Staessen, Bandinelli Stefania, Unnur Thorsteinsdottir, Michael Stumvoll, Jean-Claude Tardif, Elena Tremoli, Jaakko Tuomilehto, André G Uitterlinden, Matti Uusitupa, André L M Verbeek, Sita H Vermeulen, Jorma S Viikari, Veronique Vitart, Henry Völzke, Peter Vollenweider, Gérard Waeber, Mark Walker, Henri Wallaschofski, Nicholas J Wareham, Hugh Watkins, Eleftheria Zeggini, CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, MAGIC Consortium, Aravinda Chakravarti, Deborah J Clegg, L Adrienne Cupples, Penny Gordon-Larsen, Cashell E Jaquish, D C Rao, Goncalo R Abecasis, Themistocles L Assimes, Inês Barroso, Sonja I Berndt, Michael Boehnke, Panos Deloukas, Caroline S Fox, Leif C Groop, David J Hunter, Erik Ingelsson, Robert C Kaplan, Mark I McCarthy, Karen L Mohlke, Jeffrey R O'Connell, David Schlessinger, David P Strachan, Kari Stefansson, Cornelia M van Duijn, Joel N Hirschhorn, Cecilia M Lindgren, Iris M Heid, Kari E North, Ingrid B Borecki, Zoltán Kutalik, and Ruth J F Loos
Subjects: Genetics, QH426-470
Abstract: Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR
Published: 2015
Full Text: View/download PDF

17. A central role for GRB10 in regulation of islet function in man.

Author: Inga Prokopenko, Wenny Poon, Reedik Mägi, Rashmi Prasad B, S Albert Salehi, Peter Almgren, Peter Osmark, Nabila Bouatia-Naji, Nils Wierup, Tove Fall, Alena Stančáková, Adam Barker, Vasiliki Lagou, Clive Osmond, Weijia Xie, Jari Lahti, Anne U Jackson, Yu-Ching Cheng, Jie Liu, Jeffrey R O'Connell, Paul A Blomstedt, Joao Fadista, Sami Alkayyali, Tasnim Dayeh, Emma Ahlqvist, Jalal Taneera, Cecile Lecoeur, Ashish Kumar, Ola Hansson, Karin Hansson, Benjamin F Voight, Hyun Min Kang, Claire Levy-Marchal, Vincent Vatin, Aarno Palotie, Ann-Christine Syvänen, Andrea Mari, Michael N Weedon, Ruth J F Loos, Ken K Ong, Peter Nilsson, Bo Isomaa, Tiinamaija Tuomi, Nicholas J Wareham, Michael Stumvoll, Elisabeth Widen, Timo A Lakka, Claudia Langenberg, Anke Tönjes, Rainer Rauramaa, Johanna Kuusisto, Timothy M Frayling, Philippe Froguel, Mark Walker, Johan G Eriksson, Charlotte Ling, Peter Kovacs, Erik Ingelsson, Mark I McCarthy, Alan R Shuldiner, Kristi D Silver, Markku Laakso, Leif Groop, and Valeriya Lyssenko
Subjects: Genetics, QH426-470
Abstract: Variants in the growth factor receptor-bound protein 10 (GRB10) gene were in a GWAS meta-analysis associated with reduced glucose-stimulated insulin secretion and increased risk of type 2 diabetes (T2D) if inherited from the father, but inexplicably reduced fasting glucose when inherited from the mother. GRB10 is a negative regulator of insulin signaling and imprinted in a parent-of-origin fashion in different tissues. GRB10 knock-down in human pancreatic islets showed reduced insulin and glucagon secretion, which together with changes in insulin sensitivity may explain the paradoxical reduction of glucose despite a decrease in insulin secretion. Together, these findings suggest that tissue-specific methylation and possibly imprinting of GRB10 can influence glucose metabolism and contribute to T2D pathogenesis. The data also emphasize the need in genetic studies to consider whether risk alleles are inherited from the mother or the father.
Published: 2014
Full Text: View/download PDF

18. Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits.

Author: Joshua C Randall, Thomas W Winkler, Zoltán Kutalik, Sonja I Berndt, Anne U Jackson, Keri L Monda, Tuomas O Kilpeläinen, Tõnu Esko, Reedik Mägi, Shengxu Li, Tsegaselassie Workalemahu, Mary F Feitosa, Damien C Croteau-Chonka, Felix R Day, Tove Fall, Teresa Ferreira, Stefan Gustafsson, Adam E Locke, Iain Mathieson, Andre Scherag, Sailaja Vedantam, Andrew R Wood, Liming Liang, Valgerdur Steinthorsdottir, Gudmar Thorleifsson, Emmanouil T Dermitzakis, Antigone S Dimas, Fredrik Karpe, Josine L Min, George Nicholson, Deborah J Clegg, Thomas Person, Jon P Krohn, Sabrina Bauer, Christa Buechler, Kristina Eisinger, DIAGRAM Consortium, Amélie Bonnefond, Philippe Froguel, MAGIC Investigators, Jouke-Jan Hottenga, Inga Prokopenko, Lindsay L Waite, Tamara B Harris, Albert Vernon Smith, Alan R Shuldiner, Wendy L McArdle, Mark J Caulfield, Patricia B Munroe, Henrik Grönberg, Yii-Der Ida Chen, Guo Li, Jacques S Beckmann, Toby Johnson, Unnur Thorsteinsdottir, Maris Teder-Laving, Kay-Tee Khaw, Nicholas J Wareham, Jing Hua Zhao, Najaf Amin, Ben A Oostra, Aldi T Kraja, Michael A Province, L Adrienne Cupples, Nancy L Heard-Costa, Jaakko Kaprio, Samuli Ripatti, Ida Surakka, Francis S Collins, Jouko Saramies, Jaakko Tuomilehto, Antti Jula, Veikko Salomaa, Jeanette Erdmann, Christian Hengstenberg, Christina Loley, Heribert Schunkert, Claudia Lamina, H Erich Wichmann, Eva Albrecht, Christian Gieger, Andrew A Hicks, Asa Johansson, Peter P Pramstaller, Sekar Kathiresan, Elizabeth K Speliotes, Brenda Penninx, Anna-Liisa Hartikainen, Marjo-Riitta Jarvelin, Ulf Gyllensten, Dorret I Boomsma, Harry Campbell, James F Wilson, Stephen J Chanock, Martin Farrall, Anuj Goel, Carolina Medina-Gomez, Fernando Rivadeneira, Karol Estrada, André G Uitterlinden, Albert Hofman, M Carola Zillikens, Martin den Heijer, Lambertus A Kiemeney, Andrea Maschio, Per Hall, Jonathan Tyrer, Alexander Teumer, Henry Völzke, Peter Kovacs, Anke Tönjes, Massimo Mangino, Tim D Spector, Caroline Hayward, Igor Rudan, Alistair S Hall, Nilesh J Samani, Antony Paul Attwood, Jennifer G Sambrook, Joseph Hung, Lyle J Palmer, Marja-Liisa Lokki, Juha Sinisalo, Gabrielle Boucher, Heikki Huikuri, Mattias Lorentzon, Claes Ohlsson, Niina Eklund, Johan G Eriksson, Cristina Barlassina, Carlo Rivolta, Ilja M Nolte, Harold Snieder, Melanie M Van der Klauw, Jana V Van Vliet-Ostaptchouk, Pablo V Gejman, Jianxin Shi, Kevin B Jacobs, Zhaoming Wang, Stephan J L Bakker, Irene Mateo Leach, Gerjan Navis, Pim van der Harst, Nicholas G Martin, Sarah E Medland, Grant W Montgomery, Jian Yang, Daniel I Chasman, Paul M Ridker, Lynda M Rose, Terho Lehtimäki, Olli Raitakari, Devin Absher, Carlos Iribarren, Hanneke Basart, Kees G Hovingh, Elina Hyppönen, Chris Power, Denise Anderson, John P Beilby, Jennie Hui, Jennifer Jolley, Hendrik Sager, Stefan R Bornstein, Peter E H Schwarz, Kati Kristiansson, Markus Perola, Jaana Lindström, Amy J Swift, Matti Uusitupa, Mustafa Atalay, Timo A Lakka, Rainer Rauramaa, Jennifer L Bolton, Gerry Fowkes, Ross M Fraser, Jackie F Price, Krista Fischer, Kaarel Krjutå Kov, Andres Metspalu, Evelin Mihailov, Claudia Langenberg, Jian'an Luan, Ken K Ong, Peter S Chines, Sirkka M Keinanen-Kiukaanniemi, Timo E Saaristo, Sarah Edkins, Paul W Franks, Göran Hallmans, Dmitry Shungin, Andrew David Morris, Colin N A Palmer, Raimund Erbel, Susanne Moebus, Markus M Nöthen, Sonali Pechlivanis, Kristian Hveem, Narisu Narisu, Anders Hamsten, Steve E Humphries, Rona J Strawbridge, Elena Tremoli, Harald Grallert, Barbara Thorand, Thomas Illig, Wolfgang Koenig, Martina Müller-Nurasyid, Annette Peters, Bernhard O Boehm, Marcus E Kleber, Winfried März, Bernhard R Winkelmann, Johanna Kuusisto, Markku Laakso, Dominique Arveiler, Giancarlo Cesana, Kari Kuulasmaa, Jarmo Virtamo, John W G Yarnell, Diana Kuh, Andrew Wong, Lars Lind, Ulf de Faire, Bruna Gigante, Patrik K E Magnusson, Nancy L Pedersen, George Dedoussis, Maria Dimitriou, Genovefa Kolovou, Stavroula Kanoni, Kathleen Stirrups, Lori L Bonnycastle, Inger Njølstad, Tom Wilsgaard, Andrea Ganna, Emil Rehnberg, Aroon Hingorani, Mika Kivimaki, Meena Kumari, Themistocles L Assimes, Inês Barroso, Michael Boehnke, Ingrid B Borecki, Panos Deloukas, Caroline S Fox, Timothy Frayling, Leif C Groop, Talin Haritunians, David Hunter, Erik Ingelsson, Robert Kaplan, Karen L Mohlke, Jeffrey R O'Connell, David Schlessinger, David P Strachan, Kari Stefansson, Cornelia M van Duijn, Gonçalo R Abecasis, Mark I McCarthy, Joel N Hirschhorn, Lu Qi, Ruth J F Loos, Cecilia M Lindgren, Kari E North, and Iris M Heid
Subjects: Genetics, QH426-470
Abstract: Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR
Published: 2013
Full Text: View/download PDF

19. Variability in the heritability of body mass index: a systematic review and meta-regression

Author: Cathy E Elks, Marcel eDen Hoed, Jing Hua eZhao, Stephen J Sharp, Nicholas J Wareham, Ruth J.F. Loos, and Ken K Ong
Subjects: heritability, twin study, Body Mass Index, family study, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Evidence for a major role of genetic factors in the determination of body mass index (BMI) comes from studies of related individuals. However, heritability estimates for BMI vary widely between studies and the reasons for this remain unclear. While some variation is natural due to differences between populations and settings, study design factors may also explain some of the heterogeneity. We performed a systematic review that identified eighty-eight independent estimates of BMI heritability from twin studies (total 140,525 twins) and twenty-seven estimates from family studies (42,968 family members). BMI heritability estimates from twin studies ranged from 0.47 to 0.90 (5th/50th/95th centiles: 0.58/0.75/0.87) and were generally higher than those from family studies (range: 0.24-0.81; 5th/50th/95th centiles: 0.25/0.46/0.68). Meta-regression of the results from twin studies showed that BMI heritability estimates were 0.07 (P=0.001) higher in children than in adults; estimates increased with mean age among childhood studies (+0.012 per year, P=0.002), but decreased with mean age in adult studies (-0.002 per year, P=0.002). Heritability estimates derived from AE twin models (which assume no contribution of shared environment) were 0.12 higher than those from ACE models (P
Published: 2012
Full Text: View/download PDF

20. Breastfeeding and infant temperament at age three months.

Author: Blandine de Lauzon-Guillain, Katrien Wijndaele, Matthew Clark, Carlo L Acerini, Ieuan A Hughes, David B Dunger, Jonathan C Wells, and Ken K Ong
Subjects: Medicine, Science
Abstract: BACKGROUND & METHODS:To examine the relationship between breastfeeding and maternally-rated infant temperament at age 3 months, 316 infants in the prospective Cambridge Baby Growth Study, UK had infant temperament assessed at age 3 months by mothers using the Revised Infant Behavior Questionnaire, which produces scores for three main dimensions of temperament derived from 14 subscales. Infant temperament scores were related to mode of infant milk feeding at age 3 months (breast only; formula milk only; or mixed) with adjustment for infant's age at assessment and an index of deprivation. RESULTS:Infant temperament dimension scores differed across the three infant feeding groups, but appeared to be comparable between exclusive breast-fed and mixed-fed infants. Compared to formula milk-fed infants, exclusive breast-fed and mixed-fed infants were rated as having lower impulsivity and positive responses to stimulation (adjusted mean [95% CI] "Surgency/Extraversion" in formula-fed vs. mixed-fed vs. breast-fed groups: 4.3 [4.2-4.5] vs. 4.0 [3.8-4.1] vs. 4.0 [3.9-4.1]; p-heterogeneity = 0.0006), lower ability to regulate their own emotions ("Orienting/Regulation": 5.1 [5.0-5.2], vs. 4.9 [4.8-5.1] vs. 4.9 [4.8-5.0]; p = 0.01), and higher emotional instability ("Negative affectivity": 2.8 [2.6-2.9] vs. 3.0 [2.8-3.1] vs. 3.0 [2.9-3.1]; p = 0.03). CONCLUSIONS:Breast and mixed-fed infants were rated by their mothers as having more challenging temperaments in all three dimensions; particular subscales included greater distress, less smiling, laughing, and vocalisation, and lower soothability. Increased awareness of the behavioural dynamics of breastfeeding, a better expectation of normal infant temperament and support to cope with difficult infant temperament could potentially help to promote successful breastfeeding.
Published: 2012
Full Text: View/download PDF

21. Genetic markers of obesity risk: stronger associations with body composition in overweight compared to normal-weight children.

Author: Andreas Beyerlein, Rüdiger von Kries, Andrew R Ness, and Ken K Ong
Subjects: Medicine, Science
Abstract: Genetic factors are important determinants of overweight. We examined whether there are differential effect sizes depending on children's body composition.We analysed data of n = 4,837 children recorded in the Avon Longitudinal Study of Parents and Children (ALSPAC), applying quantile regression with sex- and age-specific standard deviation scores (SDS) of body mass index (BMI) or with body fat mass index and fat-free mass index at 9 years as outcome variables and an "obesity-risk-allele score" based on eight genetic variants known to be associated with childhood BMI as the explanatory variable.The quantile regression coefficients increased with increasing child's BMI-SDS and fat mass index percentiles, indicating larger effects of the genetic factors at higher percentiles. While the associations with BMI-SDS were of similar size in medium and high BMI quantiles (40th percentile and above), effect sizes with fat mass index increased over the whole fat mass index distribution. For example, the fat mass index of a normal-weight (50th percentile) child was increased by 0.13 kg/m(2) (95% confidence interval (CI): 0.09, 0.16) per additional allele, compared to 0.24 kg/m(2) per allele (95% CI: 0.15, 0.32) in children at the 90th percentile. The genetic associations with fat-free mass index were weaker and the quantile regression effects less pronounced than those on fat mass index.Genetic risk factors for childhood overweight appear to have greater effects on fatter children. Interaction of known genetic factors with environmental or unknown genetic factors might provide a potential explanation of these findings.
Published: 2011
Full Text: View/download PDF

22. Genetic markers of adult obesity risk are associated with greater early infancy weight gain and growth.

Author: Cathy E Elks, Ruth J F Loos, Stephen J Sharp, Claudia Langenberg, Susan M Ring, Nicholas J Timpson, Andrew R Ness, George Davey Smith, David B Dunger, Nicholas J Wareham, and Ken K Ong
Subjects: Medicine
Abstract: BackgroundGenome-wide studies have identified several common genetic variants that are robustly associated with adult obesity risk. Exploration of these genotype associations in children may provide insights into the timing of weight changes leading to adult obesity.Methods and findingsChildren from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort were genotyped for ten genetic variants previously associated with adult BMI. Eight variants that showed individual associations with childhood BMI (in/near: FTO, MC4R, TMEM18, GNPDA2, KCTD15, NEGR1, BDNF, and ETV5) were used to derive an "obesity-risk-allele score" comprising the total number of risk alleles (range: 2-15 alleles) in each child with complete genotype data (n = 7,146). Repeated measurements of weight, length/height, and body mass index from birth to age 11 years were expressed as standard deviation scores (SDS). Early infancy was defined as birth to age 6 weeks, and early infancy failure to thrive was defined as weight gain between below the 5th centile, adjusted for birth weight. The obesity-risk-allele score showed little association with birth weight (regression coefficient: 0.01 SDS per allele; 95% CI 0.00-0.02), but had an apparently much larger positive effect on early infancy weight gain (0.119 SDS/allele/year; 0.023-0.216) than on subsequent childhood weight gain (0.004 SDS/allele/year; 0.004-0.005). The obesity-risk-allele score was also positively associated with early infancy length gain (0.158 SDS/allele/year; 0.032-0.284) and with reduced risk of early infancy failure to thrive (odds ratio = 0.92 per allele; 0.86-0.98; p = 0.009).ConclusionsThe use of robust genetic markers identified greater early infancy gains in weight and length as being on the pathway to adult obesity risk in a contemporary birth cohort.
Published: 2010
Full Text: View/download PDF

23. Infant motor development predicts sports participation at age 14 years: northern Finland birth cohort of 1966.

Author: Charlotte L Ridgway, Ken K Ong, Tuija H Tammelin, Stephen Sharp, Ulf Ekelund, and Marjo-Riitta Jarvelin
Subjects: Medicine, Science
Abstract: BackgroundMotor proficiency is positively associated with physical activity levels. The aim of this study is to investigate associations between the timing of infant motor development and subsequent sports participation during adolescence.MethodsProspective observational study. The study population consisted of 9,009 individuals from the Northern Finland Birth Cohort 1966. Motor development was assessed by parental report at age 1 year, using age at walking with support and age at standing unaided. At follow up aged 14 years, data were collected on the school grade awarded for physical education (PE). Self report was used to collect information on the frequency of sports participation and number of different sports reported.Principal findingsEarlier infant motor development was associated with improved school PE grade, for age at walking supported (pConclusionsEarlier infant motor development may predict higher levels of physical activity as indicated by higher school PE grade, participation in a greater number of different types of sports and increased frequency of sports participation. Identification of young children with slower motor development may allow early targeted interventions to improve motor skills and thereby increase physical activity in later life.
Published: 2009
Full Text: View/download PDF

24. Earlier mother's age at menarche predicts rapid infancy growth and childhood obesity.

Author: Ken K Ong, Kate Northstone, Jonathan C K Wells, Carol Rubin, Andy R Ness, Jean Golding, and David B Dunger
Subjects: Medicine
Abstract: BackgroundEarly menarche tends to be preceded by rapid infancy weight gain and is associated with increased childhood and adult obesity risk. As age at menarche is a heritable trait, we hypothesised that age at menarche in the mother may in turn predict her children's early growth and obesity risk.Methods and findingsWe tested associations between mother's age at menarche, mother's adult body size and obesity risk, and her children's growth and obesity risk in 6,009 children from the UK population-based Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort who had growth and fat mass at age 9 y measured by dual-energy X-ray absorptiometry. A subgroup of 914 children also had detailed infancy and childhood growth data. In the mothers, earlier menarche was associated with shorter adult height (by 0.64 cm/y), increased weight (0.92 kg/y), and body mass index (BMI, 0.51 kg/m2/y; all p < 0.001). In contrast, in her children, earlier mother's menarche predicted taller height at 9 y (by 0.41 cm/y) and greater weight (0.80 kg/y), BMI (0.29 kg/m2/y), and fat mass index (0.22 kg/m2/year; all p < 0.001). Children in the earliest mother's menarche quintile (< or =11 y) were more obese than the oldest quintile (> or =15 y) (OR, 2.15, 95% CI 1.46 to 3.17; p < 0.001, adjusted for mother's education and BMI). In the subgroup, children in the earliest quintile showed faster gains in weight (p < 0.001) and height (p < 0.001) only from birth to 2 y, but not from 2 to 9 y (p = 0.3-0.8).ConclusionsEarlier age at menarche may be a transgenerational marker of a faster growth tempo, characterised by rapid weight gain and growth, particularly during infancy, and leading to taller childhood stature, but likely earlier maturation and therefore shorter adult stature. This growth pattern confers increased childhood and adult obesity risks.
Published: 2007
Full Text: View/download PDF

25. Leptin and IGF-1 in Infancy Are Associated With Variants in DHCR7 and CYP2R1 That Relate With Type 1 Diabetes and 25OHD

Author: Antigoni Eleftheriou, Ken K Ong, Ieuan A Hughes, and Clive J Petry
Subjects: Endocrinology, Endocrinology, Diabetes and Metabolism, Biochemistry (medical), Clinical Biochemistry, Biochemistry
Abstract: Context Vitamin D has been variably implicated in risk of developing type 1 diabetes based on cohorts of at-risk individuals. Emergent type 1 diabetes in childhood is putatively preceded by altered growth. Objective We explored whether polymorphisms in vitamin D metabolism genes modify risk of type 1 diabetes via effects on growth in a prospective, population-based cohort of infants. Methods The Cambridge Baby Growth Study enrolled newborns from Cambridgeshire, UK, for follow-up in infancy. In 612 infants, we genotyped single nucleotide polymorphisms in vitamin D metabolism genes that relate with type 1 diabetes: rs10741657 and rs12794714 in CYP2R1, rs12785878 in DHCR7, and rs10877012 in CYP27B1. Multivariate linear regression analyses tested associations between genotypes and anthropometric indices (weight, length, and skinfold thickness) or growth-related hormones (C-peptide, IGF-1, and leptin) in infancy. Results Birth weight showed borderline associations with the diabetes risk–increasing alleles in CYP2R1, rs10741657 (β = −.11, P = .02) and rs12794714 (β = −.09, P = .04). The risk-increasing allele rs12794714 was also associated with higher IGF-1 levels at age 24 months (β = .30, P = .01). At age 3 months, the risk-increasing allele rs12785878 in DHCR7, known to negatively associate with 25-hydroxyvitamin D levels, showed a positive association with leptin levels (β = .23, P = .009), which was pronounced in girls (P = .004) vs boys (P = .7). Conclusion The vitamin D metabolism genes DHCR7 and CYP2R1 might influence infancy leptin and IGF-1 levels respectively. These findings open the possibility for a developmental role of vitamin D that is mediated by growth-related hormones with implications for the onset of type 1 diabetes autoimmunity.
Published: 2023

26. A Multiparametric Anti-Aging CRISPR Screen Uncovers a Role for BAF in Protein Translation

Author: Sophia Y. Breusegem, Jack Houghton, Raquel Romero-Bueno, Adrián Fragoso-Luna, Katherine A. Kentistou, Ken K. Ong, Anne F. J. Janssen, Nicholas A. Bright, Christian G. Riedel, John R. B. Perry, Peter Askjaer, and Delphine Larrieu
Abstract: Progeria syndromes are very rare, incurable premature aging conditions recapitulating most aging features. Here, we report the first whole genome, multiparametric CRISPR anti-aging screen, identifying 43 new genes that can reverse multiple aging phenotypes in progeria. The screen was implemented in fibroblasts from Néstor- Guillermo Progeria Syndrome (NGPS) patients, carrying a homozygous p.Ala12Thr mutation in barrier-to-autointegration factor (BAF A12T). The hits were enriched for genes involved in protein translation, protein and RNA transport and osteoclast formation. We further confirmed that BAF A12T drives increased protein translation and translational errors that could directly contribute to premature aging in patients. This work has highlighted the power of multiparametric whole genome synthetic rescue screens to identify new anti-aging genes and uncover novel biology behind progeria-associated cellular dysfunction.One-Sentence SummaryA whole genome multiparametric screen in progeria identifies new pathways that can reverse cellular aging phenotypes.
Published: 2023

27. MC3R links nutritional state to childhood growth and the timing of puberty

Author: Anthony P. Coll, MN Bedenbaugh, DT Porter, David H. Rowitch, John R. B. Perry, D A van Heel, X Dai, Rachel N. Lippert, Debra Rimmington, A. L. Gonçalves Soares, Felix R. Day, Duckett K, Patrick Sweeney, Zhaoyang Xu, Ahsan Nabi Khan, Hilary C. Martin, John Tadross, Roger D. Cone, Brian Y.H. Lam, Klj Ellacott, Richard B. Simerly, J Rosmaninho-Salgado, Alice E. Williamson, Gkc Dowsett, Sarah Finer, Irene Cimino, Giles S.H. Yeo, Audrey Melvin, Kara Rainbow, Claudia Langenberg, Stephen O'Rahilly, Nicholas J. Wareham, Katherine Ridley, Richard C. Trembath, Staffan Holmqvist, Sophie Buller, N J Timpson, Kaitlin H Wade, Ken K. Ong, and Elena G. Bochukova
Subjects: Male, medicine.medical_specialty, Time Factors, Calorie, Adolescent, media_common.quotation_subject, Hypothalamus, Nutritional Status, Estrous Cycle, Nutrient sensing, Biology, Weight Gain, Article, Mice, Child Development, Central melanocortin system, Internal medicine, medicine, Animals, Humans, Sexual maturity, Obesity, Sexual Maturation, Insulin-Like Growth Factor I, Child, media_common, Aged, 80 and over, Menarche, Multidisciplinary, Homozygote, Puberty, Appetite, Melanocortins, Melanocortin 4 receptor, Phenotype, medicine.anatomical_structure, Endocrinology, Lean body mass, Female, Melanocortin, Receptor, Melanocortin, Type 3
Abstract: The state of somatic energy stores in metazoans is communicated to the brain, which regulates key aspects of behaviour, growth, nutrient partitioning and development1. The central melanocortin system acts through melanocortin 4 receptor (MC4R) to control appetite, food intake and energy expenditure2. Here we present evidence that MC3R regulates the timing of sexual maturation, the rate of linear growth and the accrual of lean mass, which are all energy-sensitive processes. We found that humans who carry loss-of-function mutations in MC3R, including a rare homozygote individual, have a later onset of puberty. Consistent with previous findings in mice, they also had reduced linear growth, lean mass and circulating levels of IGF1. Mice lacking Mc3r had delayed sexual maturation and an insensitivity of reproductive cycle length to nutritional perturbation. The expression of Mc3r is enriched in hypothalamic neurons that control reproduction and growth, and expression increases during postnatal development in a manner that is consistent with a role in the regulation of sexual maturation. These findings suggest a bifurcating model of nutrient sensing by the central melanocortin pathway with signalling through MC4R controlling the acquisition and retention of calories, whereas signalling through MC3R primarily regulates the disposition of calories into growth, lean mass and the timing of sexual maturation. MC3R deficiency is associated with a delay in the onset of puberty, and a reduction in growth and lean mass.
Published: 2021

28. Meta-analysis of epigenome-wide association studies of carotid intima-media thickness

Author: Shih-Jen Hwang, Jordana T. Bell, Olli T. Raitakari, Mikko Hurme, Joanna M. Wardlaw, W. David Hill, Joshua C. Bis, Traci M. Bartz, Anton J.M. Roks, John M. Starr, Wolfgang Koenig, M. Arfan Ikram, Eliana Portilla-Fernandez, Alexander Teumer, Annette Peters, Mika Kähönen, Ian J. Deary, Maryam Kavousi, Nona Sotoodehnia, Joachim Thiery, Jennifer A. Brody, Melanie Waldenberger, Ulf Schminke, Abbas Dehghan, Hans J. Grabe, Roby Joehanes, Symen Ligthart, Daniel Levy, Bruce M. Psaty, A.H. Jan Danser, Wolfgang Rathmann, Henry Völzke, Andrew Wong, Mohsen Ghanbari, Jochen Seissler, Terho Lehtimäki, Ken K. Ong, Jane Maddock, Rory P. Wilson, Christopher J. O'Donnell, Cornelia Then, Christine Meisinger, Pashupati P. Mishra, Sahar Ghasemi, Marcus Dörr, Portilla-Fernández, Eliana [0000-0003-4105-8586], Ong, Kenneth [0000-0003-4689-7530], Apollo - University of Cambridge Repository, Tampere University, Department of Clinical Chemistry, Clinical Medicine, Department of Clinical Physiology and Nuclear Medicine, BioMediTech, Epidemiology, and Internal Medicine
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Epidemiology, Differentially methylated regions, Aryl hydrocarbon receptor repressor, Coronary Artery Disease, 030204 cardiovascular system & hematology, Carotid Intima-Media Thickness, Coronary artery disease, 03 medical and health sciences, Epigenome, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Risk Factors, Internal medicine, Mendelian randomization, Medicine, Vascular outcomes, Humans, ddc:610, cardiovascular diseases, Stroke, Cardiovascular risk factors, Epigenome-wide association studies, DNA methylation, business.industry, medicine.disease, humanities, 3142 Public health care science, environmental and occupational health, ddc, 030104 developmental biology, Cross-Sectional Studies, CpG site, Intima-media thickness, cardiovascular system, Common carotid intima-media thickness, business, Meta-Analysis
Abstract: Funder: Nederlandse Organisatie voor Wetenschappelijk Onderzoek; doi: http://dx.doi.org/10.13039/501100003246, Funder: ZonMw; doi: http://dx.doi.org/10.13039/501100001826, Funder: Research Institute for Diseases in the Elderly, Funder: Ministerie van Onderwijs, Cultuur en Wetenschap; doi: http://dx.doi.org/10.13039/501100003245, Funder: Health Promotion Administration, Ministry of Health and Welfare; doi: http://dx.doi.org/10.13039/100013227, Funder: Municipality of Rotterdam, Common carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta = -0.0264, p value = 3.5 × 10-8) in the discovery panel and was replicated in replication panel (beta = -0.07, p value = 0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value = 1.4 × 10-13). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.
Published: 2021

29. Early weight gain influences duration of breast feeding: prospective cohort study

Author: Laurentya Olga, Janna A van Diepen, Gabriele Gross, David B Dunger, Ken K Ong, Ong, Ken K [0000-0003-4689-7530], and Apollo - University of Cambridge Repository
Subjects: growth, Infant, Newborn, Infant, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Weight Gain, paediatrics, Cohort Studies, Breast Feeding, Pediatrics, Perinatology and Child Health, child health, Humans, Birth Weight, epidemiology, Female, Prospective Studies
Abstract: ObjectiveWhile several studies have shown that milk formula feeding is associated with faster infant weight gain compared with exclusively breast feeding (EBF), we explored the possible reverse association that infant weight gain influences the duration of EBF.DesignProspective birth cohort study (Cambridge Baby Growth Breastfeeding Study) born 2015–2018.SettingCambridge, UK.ParticipantsFull-term, singleton, normal birthweight infants who received EBF for 2–5 completed weeks (n=54), 6–11 weeks (n=14) or 12 or more weeks (n=80).InterventionWeight gain from birth to 2 and 6 weeks.Main outcome and measureDuration of EBF.ResultsFaster infant weight gain during EBF predicted longer duration of EBF. Among all 148 infants, each +1 unit gain in weight SD score (SDS) between birth and 2 weeks (while all infants received EBF) reduced the likelihood of stopping EBF between 2 and 5 weeks by ~70% (OR 0.32; 95% CI 0.12 to 0.77; adjusted for sex, gestational age at birth, birth weight and mother’s age, prepregnancy BMI and education). Similarly, among infants EBF for 6 or more weeks (n=94), each +1 unit gain in weight SDS between birth and 6 weeks reduced the likelihood of stopping EBF between 6 and 11 weeks by ~80% (OR 0.18; 95% CI 0.05 to 0.63).ConclusionsSlower early infant weight gain was consistently associated with subsequent earlier discontinuation of EBF. We conjecture that broader recognition of the wide range of normal infant growth might encourage parents to not stop EBF earlier than they intended.
Published: 2022

30. Damaging missense variants in IGF1R implicate a role for IGF-1 resistance in the etiology of type 2 diabetes

Author: Eugene J. Gardner, Katherine A. Kentistou, Stasa Stankovic, Samuel Lockhart, Eleanor Wheeler, Felix R. Day, Nicola D. Kerrison, Nicholas J. Wareham, Claudia Langenberg, Stephen O'Rahilly, Ken K. Ong, John R.B. Perry, Gardner, EJ [0000-0001-9671-1533], and Apollo - University of Cambridge Repository
Subjects: UK Biobank, IGF1, Genetics, Mendelian randomization, exome-wide association study, type 2 diabetes, Biochemistry, Genetics and Molecular Biology (miscellaneous)
Abstract: Type 2 diabetes (T2D) is a heritable metabolic disorder. While population studies have identified hundreds of common genetic variants associated with T2D, the role of rare (frequency < 0.1%) protein-coding variation is less clear. We performed exome sequence analysis in 418,436 (n = 32,374 T2D cases) individuals in the UK Biobank. We identified previously reported genes (GCK, GIGYF1, HNF1A) in addition to missense variants in ZEB2 (n = 31 carriers; odds ratio [OR] = 5.5 [95% confidence interval = 2.5-12.0]; p = 6.4 × 10-7), MLXIPL (n = 245; OR = 2.3 [1.6-3.2]; p = 3.2 × 10-7), and IGF1R (n = 394; OR = 2.4 [1.8-3.2]; p = 1.3 × 10-10). Carriers of damaging missense variants within IGF1R were also shorter (-2.2 cm [-1.8 to -2.7]; p = 1.2 × 10-19) and had higher circulating insulin-like growth factor-1 (IGF-1) protein levels (2.3 nmol/L [1.7-2.9]; p = 2.8 × 10-14), indicating relative IGF-1 resistance. A likely causal role of IGF-1 resistance was supported by Mendelian randomization analyses using common variants. These results increase understanding of the genetic architecture of T2D and highlight the growth hormone/IGF-1 axis as a potential therapeutic target.
Published: 2022
Full Text: View/download PDF

31. The Year in Science & Medicine

Author: Christa E. Fluck and Ken K. Ong
Subjects: General Economics, Econometrics and Finance
Published: 2022

32. Editors Choice

Author: Ken K Ong and Christa E Fluck
Subjects: General Economics, Econometrics and Finance
Published: 2022

33. Preface

Author: Christa E Fluck and Ken K Ong
Subjects: General Economics, Econometrics and Finance
Published: 2022

34. Detection and characterization of male sex chromosome abnormalities in the UK Biobank study

Author: Yajie Zhao, Eugene J. Gardner, Marcus A. Tuke, Huairen Zhang, Maik Pietzner, Mine Koprulu, Raina Y. Jia, Katherine S. Ruth, Andrew R. Wood, Robin N. Beaumont, Jessica Tyrrell, Samuel E. Jones, Hana Lango Allen, Felix R. Day, Claudia Langenberg, Timothy M. Frayling, Michael N. Weedon, John R.B. Perry, Ken K. Ong, Anna Murray, Zhao, Yajie [0000-0002-2747-0219], Lango Allen, Hana [0000-0002-7803-8688], Langenberg, Claudia [0000-0002-5017-7344], Ong, Kenneth [0000-0003-4689-7530], Apollo - University of Cambridge Repository, Institute for Molecular Medicine Finland, Helsinki Institute of Life Science HiLIFE, Joint Activities, and University of Helsinki
Subjects: Male, Disorders of sexual development, 1184 Genetics, developmental biology, physiology, Thrombosis, Type 2 diabetes, XYY, KLINEFELTER-SYNDROME, United Kingdom, Endocrinology, Klinefelter Syndrome, Diabetes Mellitus, Type 2, XYY Karyotype, 47,XYY, Humans, 3111 Biomedicine, Genetics (clinical), Sex Chromosome Aberrations, Biological Specimen Banks
Abstract: Purpose: The study aimed to systematically ascertain male sex chromosome abnormalities, 47,XXY (Klinefelter syndrome [KS]) and 47,XYY, and characterize their risks of adverse health outcomes. Methods: We analyzed genotyping array or exome sequence data in 207,067 men of European ancestry aged 40 to 70 years from the UK Biobank and related these to extensive routine health record data. Results: Only 49 of 213 (23%) of men whom we identified with KS and only 1 of 143 (0.7%) with 47,XYY had a diagnosis of abnormal karyotype on their medical records or self-report. We observed expected associations for KS with reproductive dysfunction (late puberty: risk ratio [RR] = 2.7; childlessness: RR = 4.2; testosterone concentration: RR = -3.8 nmol/L, all P < 2 x 10(-8)), whereas XYY men appeared to have normal reproductive function. Despite this difference, we identified several higher disease risks shared across both KS and 47,XYY, including type 2 diabetes (RR = 3.0 and 2.6, respectively), venous thrombosis (RR = 6.4 and 7.4, respectively), pulmonary embolism (RR = 3.3 and 3.7, respectively), and chronic obstructive pulmonary disease (RR = 4.4 and 4.6, respectively) (all P Conclusion: KS and 47,XYY were mostly unrecognized but conferred substantially higher risks for metabolic, vascular, and respiratory diseases, which were only partially explained by higher levels of body mass index, deprivation, and smoking. (C) 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics.
Published: 2022

35. Longitudinal associations between prepubertal childhood total energy and macronutrient intakes and subsequent puberty timing in UK boys and girls

Author: Nita G. Forouhi, Stephen J. Sharp, Soren Brage, Ken K. Ong, Pauline M Emmett, Tuck Seng Cheng, Cheng, Tuck Seng [0000-0003-4442-7332], Brage, Soren [0000-0002-1265-7355], Forouhi, Nita [0000-0002-5041-248X], Ong, Kenneth [0000-0003-4689-7530], and Apollo - University of Cambridge Repository
Subjects: Male, Longitudinal study, Random intercepts model, Medicine (miscellaneous), 030209 endocrinology & metabolism, Body fat percentage, Nutrient density, Eating, 03 medical and health sciences, 0302 clinical medicine, Humans, Medicine, Sex organ, Longitudinal Studies, 030212 general & internal medicine, Prospective study, Total energy, Puberty timing, Child, Prospective cohort study, Menarche, Nutrition and Dietetics, business.industry, Dietary intake, Protein, Puberty, Original Contribution, ALSPAC, United Kingdom, Female, business, Demography, Puberty onset
Abstract: Funder: the NIHR Biomedical Research Centre Cambridge: Nutrition, Diet, and Lifestyle Research Theme; Grant(s): IS-BRC-1215-20014, PURPOSE: Early puberty is associated with adverse health outcomes. To identify potential modifiable factors for puberty timing, we examined the associations of prepubertal childhood macronutrient intakes with puberty timing in boys and girls. METHODS: In the Avon Longitudinal Study of Parents and Children, macronutrient intakes at age 6 years were predicted using random intercepts linear regression models of dietary data at 3, 4, 7 (assessed by food frequency questionnaires) and 7.5 years (by 3-day food diaries). Timings of puberty onset (Tanner stage 2 genital or breast (B2) development) and puberty completion (voice breaking (VB) or menarche) were calculated from annual parental and child reports at 8-17 years. Age at peak height velocity (PHV) was derived from repeated height measurements at 5-20 years. Linear regression models were fit to estimate the associations of total energy (TEI) and macronutrient intakes (carbohydrate, fat, protein) with puberty timing traits, adjusting for maternal and infant characteristics. RESULTS: Among 3811 boys, higher TEI, but no macronutrient, was associated with earlier VB. Among 3919 girls, higher TEI was associated with earlier ages at B2, PHV, and menarche. Higher protein intake but not carbohydrate or fat intake (in energy partition models) and substitution of dietary protein for carbohydrate (in nutrient density and residual models) was associated with earlier B2, PHV, and menarche in girls. Findings were not attenuated on additional adjustment for body fat percentage during adolescence. CONCLUSIONS: These findings suggest habitual total energy intakes in children, and protein intakes in girls, as potential modifiable determinants of puberty timing.
Published: 2021

36. A one-year study of human milk oligosaccharide profiles in the milk of healthy UK mothers and their relationship to maternal FUT2 genotype

Author: Daniela Barile, Laurentya Olga, Randall C. Robinson, David B. Dunger, Maciej Chichlowski, Sierra D. Durham, Ken K. Ong, Durham, Sierra D [0000-0002-4184-7756], and Apollo - University of Cambridge Repository
Subjects: Genotype, FUT2, medicine.medical_treatment, Breastfeeding, Mothers, Oligosaccharides, Physiology, breastmilk, Biology, Breast milk, Polymorphism, Single Nucleotide, Biochemistry, secretor, Genotype-phenotype distinction, Polymorphism (computer science), Lactation, medicine, Humans, Milk Banks, Milk, Human, Prebiotic, high-performance anion-exchange chromatography, Fucosyltransferases, United Kingdom, Breast Feeding, medicine.anatomical_structure, human milk oligosaccharides, Female
Abstract: Human milk oligosaccharides (HMOs) are indigestible carbohydrates with prebiotic, pathogen decoy and immunomodulatory activities that are theorized to substantially impact infant health. The objective of this study was to monitor HMO concentrations over 1 year to develop a long-term longitudinal dataset. HMO concentrations in the breast milk of healthy lactating mothers of the Cambridge Baby Growth and Breastfeeding Study (CBGS-BF) were measured at birth, 2 weeks, 6 weeks, 3 months, 6 months and 12 months postpartum. HMO quantification was conducted by high-performance anion-exchange chromatography with pulsed amperometric detection using a newly validated “dilute-and-shoot” method. This technique minimizes sample losses and expedites throughput, making it particularly suitable for the analysis of large sample sets. Varying patterns of individual HMO concentrations were observed with changes in lactation timepoint and maternal secretor status, with the most prominent temporal changes occurring during the first 3 months. These data provide valuable information for the development of human milk banks in view of targeted distribution of donor milk based on infant age. Maternal FUT2 genotype was determined based on identification at single-nucleotide polymorphism rs516246 and compared with the genotype expected based on phenotypic markers in the HMO profile. Surprisingly, two mothers genotyped as secretors produced milk that displayed very low levels of 2′-fucosylated moieties. This unexpected discrepancy between genotype and phenotype suggests that differential enzyme expression may cause substantial variation in HMO profiles between genotypically similar mothers, and current genotypic methods of secretor status determination may require validation with HMO markers from milk analysis.
Published: 2021

37. Adverse Effects of Early Puberty Timing in Girls and Potential Solutions

Author: Tuck Seng Cheng, Ken K. Ong, Frank M. Biro, Ong, Kenneth [0000-0003-4689-7530], and Apollo - University of Cambridge Repository
Subjects: Adult, Adolescent, Diabetes Mellitus, Type 2, Pediatrics, Perinatology and Child Health, Puberty, Iatrogenic Disease, Obstetrics and Gynecology, Humans, Puberty, Precocious, Female, General Medicine, Hormones
Abstract: Given the global secular declining trends of the age at puberty and its relevant mechanisms, as illustrated in the first part of this series, the present part will discuss the public health implications of early puberty and potential clinical and public health measures. Although the major effect of earlier maturation impacts adolescents' mental health and likelihood of engaging in risky behaviors, there are also effects in adulthood on cardiometabolic health, especially type 2 diabetes, and an increased risk of certain cancers, especially hormone-related cancers such as breast cancer. The paper ends with recommendations for clinical management, especially for girls who should receive further evaluation, as well as recommendations for the patient and her family and public health considerations.
Published: 2022
Full Text: View/download PDF

38. Maternal obesity programs hypothalamic miR-505-5p expression in mouse offspring and impacts hypothalamic fatty acid sensing

Author: Isadora C. Furigo, Lucas C. Pantaleão, Juliana de Almeida-Faria, Katherine A. Kentistou, Maria V. Carreira, Ken K. Ong, John R. B. Perry, Jose Donato, Laura Dearden, and Susan E. Ozanne
Abstract: In utero exposure to maternal obesity programs a susceptibility to develop obesity. Animal models have shown that offspring obesity is often preceded by increased food intake, however, the mechanisms that mediate these changes are not understood. Using a mouse model of maternal diet-induced obesity we observed increased intake specifically of a high-fat pellet in adult offspring of obese mothers. Through small RNA sequencing, we identified programmed overexpression of miR-505-5p in the hypothalamus of offspring of obese mothers that is established in the fetus, and confirmed in vitro that fatty acid exposure increases expression of miR-505-5p. Pulsed SILAC analysis demonstrated protein targets of miR-505-5p are enriched in pathways involved in fatty acid metabolism. These include key components of neuronal fatty acid sensing, such as Cpt1a, that are implicated in BMI regulation in human genetic studies. Over-expression of miR-505-5p decreased neuronal fatty acid uptake and metabolism in vitro. Importantly, intra-cerebroventricular injection of a miR-505-5p mimic in mice resulted in increased high-fat pellet intake. Collectively these data suggest that maternal obesity induces over-expression of miR-505-5p in offspring hypothalamus, resulting in altered fatty acid sensing and increased intake of high-fat diet. This represents a novel mechanism by which maternal obesity programs obesity in offspring.
Published: 2022

39. Early childhood weight gain: Latent patterns and body composition outcomes

Author: George B. Ploubidis, Leah Li, Liina Mansukoski, Tom Norris, Ken K. Ong, Mark S. Gilthorpe, William Johnson, Rebecca Hardy, Laura D Howe, Mark Hamer, and Russell M Viner
Subjects: Gestational hypertension, Longitudinal study, Epidemiology, growth, Weight Gain, Body Mass Index, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, 030225 pediatrics, Diabetes mellitus, medicine, Humans, Longitudinal Studies, Obesity, Child, childhood, body composition, 030219 obstetrics & reproductive medicine, business.industry, Body Weight, weight, ALSPAC, medicine.disease, Confidence interval, Child, Preschool, Pediatrics, Perinatology and Child Health, Body Composition, Lean body mass, Female, medicine.symptom, business, Parity (mathematics), Body mass index, Weight gain, Demography
Abstract: BackgroundDespite early childhood weight gain being a key indicator of obesity risk, we do not have a good understanding of the different patterns that exist.ObjectivesTo identify and characterise distinct groups of children displaying similar early-life weight trajectories.MethodsA growth mixture model captured heterogeneity in weight trajectories between 0 and 60 months in 1390 children in the Avon Longitudinal Study of Parents and Children. Differences between the classes in characteristics and body size/composition at 9 years were investigated.ResultsThe best model had five classes. The “Normal” (45%) and “Normal after initial catch-down” (24%) classes were close to the 50th centile of a growth standard between 24 and 60 months. The “High-decreasing” (21%) and “Stable-high” (7%) classes peaked at the ~91st centile at 12-18 months, but while the former declined to the ~75th centile and comprised constitutionally big children, the latter did not. The “Rapidly increasing” (3%) class gained weight from below the 50th centile at 4 months to above the 91st centile at 60 months. By 9 years, their mean body mass index (BMI) placed them at the 98th centile. This class was characterised by the highest maternal BMI; highest parity; highest levels of gestational hypertension and diabetes; and the lowest socio-economic position. At 9 years, the “Rapidly increasing” class was estimated to have 68.2% (95% confidence interval [CI] 48.3, 88.1) more fat mass than the “Normal” class, but only 14.0% (95% CI 9.1, 18.9) more lean mass.ConclusionsCriteria used in growth monitoring practice are unlikely to consistently distinguish between the different patterns of weight gain reported here.
Published: 2021

40. Distinct Body Mass Index Trajectories to Young-Adulthood Obesity and Their Different Cardiometabolic Consequences

Author: Richard J. Silverwood, Mark S. Gilthorpe, Ken K. Ong, Leah Li, Emma O'Donnell, George B. Ploubidis, William Johnson, Liina Mansukoski, Rebecca Hardy, Laura D Howe, Alun D. Hughes, Mark Hamer, Russell M Viner, Tom Norris, Ong, Kenneth [0000-0003-4689-7530], and Apollo - University of Cambridge Repository
Subjects: Male, Gerontology, obesity, Pediatric Obesity, Time Factors, Health Status, Blood Pressure, 030204 cardiovascular system & hematology, Overweight, Ventricular Function, Left, 0302 clinical medicine, Insulin, Longitudinal Studies, Prospective Studies, Young adult, Child, ComputingMilieux_MISCELLANEOUS, Adiposity, Ventricular Remodeling, Age Factors, Lipids, adolescent growth, England, trajectory, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Female, medicine.symptom, Cardiology and Cardiovascular Medicine, cardiometabolic health, Adult, Adolescent, body mass index, 030209 endocrinology & metabolism, Risk Assessment, Article, Young Adult, 03 medical and health sciences, medicine, overweight, Humans, goals, growth mixture model, body composition, business.industry, Cardiometabolic Risk Factors, medicine.disease, Obesity, Body-Weight Trajectory, heterogeneity, business, Body mass index, Biomarkers
Abstract: Objective: Different body mass index (BMI) trajectories that result in obesity may have diverse health consequences, yet this heterogeneity is poorly understood. We aimed to identify distinct classes of individuals who share similar BMI trajectories and examine associations with cardiometabolic health. Approach and Results: Using data on 3549 participants in ALSPAC (Avon Longitudinal Study of Parents and Children), a growth mixture model was developed to capture heterogeneity in BMI trajectories between 7.5 and 24.5 years. Differences between identified classes in height growth curves, body composition trajectories, early-life characteristics, and a panel of cardiometabolic health measures at 24.5 years were investigated. The best mixture model had 6 classes. There were 2 normal-weight classes: normal weight (nonlinear; 35% of sample) and normal weight (linear; 21%). Two classes resulted in young-adulthood overweight: normal weight increasing to overweight (18%) and normal weight or overweight (16%). Two classes resulted in young-adulthood obesity: normal weight increasing to obesity (6%) and overweight or obesity (4%). The normal-weight-increasing-to-overweight class had more unfavorable levels of trunk fat, blood pressure, insulin, HDL (high-density lipoprotein) cholesterol, left ventricular mass, and E/e′ ratio compared with the always-normal-weight-or-overweight class, despite the average BMI trajectories for both classes converging at ≈26 kg/m 2 at 24.5 years. Similarly, the normal-weight-increasing-to-obesity class had a worse cardiometabolic profile than the always-overweight-or-obese class. Conclusions: Individuals with high and stable BMI across childhood may have lower cardiometabolic disease risk than individuals who do not become overweight or obese until late adolescence.
Published: 2021

41. Identification of methylation changes associated with positive and negative growth deviance in Gambian infants using a targeted methyl sequencing approach of genomic DNA

Author: Ken K. Ong, Nabeel A. Affara, Saikou Drammeh, Manu Kunaal Shrivastava, David B. Dunger, Benjamin M. Skinner, Carole A. Sargent, Kerry M. Harvey, María Laura Ríos Gómez, Sophie E. Moore, Andrew M. Prentice, Claire R. Quilter, Robin M. Bernstein, Julien Bauer, Andrew M. Doel, Bernstein, Robin M [0000-0001-8805-7527], and Apollo - University of Cambridge Repository
Subjects: Cancer Research, DNA methylation, Physiology, stunting, Promoter, Methylation, Biology, Biochemistry, Genetics and Molecular Biology (miscellaneous), Andrology, genomic DNA, Differentially methylated regions, lcsh:Biology (General), birthweight, Cord blood, Molecular Medicine, environmental exposures, lcsh:QH301-705.5, Reprogramming, Gene, Research Articles, Research Article
Abstract: Low birthweight and reduced height gain during infancy (stunting) may arise at least in part from adverse early life environments that trigger epigenetic reprogramming that may favor survival. We examined differential DNA methylation patterns using targeted methyl sequencing of regions regulating gene activity in groups of rural Gambian infants: (a) low and high birthweight (DNA from cord blood (n = 16 and n = 20, respectively), from placental trophoblast tissue (n = 21 and n = 20, respectively), and DNA from peripheral blood collected from infants at 12 months of age (n = 23 and n = 17, respectively)), and, (b) the top 10% showing rapid postnatal length gain (high, n = 20) and the bottom 10% showing slow postnatal length gain (low, n = 20) based on z score change between birth and 12 months of age (LAZ) (DNA from peripheral blood collected from infants at 12 months of age). Using BiSeq analysis to identify significant methylation marks, for birthweight, four differentially methylated regions (DMRs) were identified in trophoblast DNA, compared to 68 DMRs in cord blood DNA, and 54 DMRs in 12‐month peripheral blood DNA. Twenty‐five DMRs were observed to be associated with high and low length for age (LAZ) at 12 months. With the exception of five loci (associated with two different genes), there was no overlap between these groups of methylation marks. Of the 194 CpG methylation marks contained within DMRs, 106 were located to defined gene regulatory elements (promoters, CTCF‐binding sites, transcription factor‐binding sites, and enhancers), 58 to gene bodies (introns or exons), and 30 to intergenic DNA. Distinct methylation patterns associated with birthweight between comparison groups were observed in DNA collected at birth (at the end of intrauterine growth window) compared to those established by 12 months (near the infancy/childhood growth transition). The longitudinal differences in methylation patterns may arise from methylation adjustments, changes in cellular composition of blood or both that continue during the critical postnatal growth period, and in response to early nutritional and infectious environmental exposures with impacts on growth and longer‐term health outcomes.
Published: 2021

42. A Novel method for the identification and quantification of weight faltering

Author: Sophie E. Moore, James Dykes, Saikou Drammeh, Andrew M. Prentice, Robin M. Bernstein, Abdoulie Faal, Daniel J Naumenko, Fatou Sosseh, Andrew M. Doel, Zofia Stanley, G. Kesler O'Connor, Ken K. Ong, Nabeel A. Affara, David B. Dunger, Bernstein, Robin M [0000-0001-8805-7527], and Apollo - University of Cambridge Repository
Subjects: 0106 biological sciences, Every other day, wasting, First year of life, Growth faltering, Brief Communication, 010603 evolutionary biology, 01 natural sciences, Anthropology, Physical, Child Development, Negatively associated, Weight loss, medicine, Humans, 0601 history and archaeology, infancy, Wasting, Growth Disorders, the Gambia, Retrospective Studies, Models, Statistical, 060101 anthropology, Wasting Syndrome, business.industry, Body Weight, Longitudinal growth, stunting, Infant, Newborn, Infant, 06 humanities and the arts, Potential measurement, Failure to Thrive, growth faltering, Anthropology, Gambia, Anatomy, medicine.symptom, Brief Communications, business, Demography
Abstract: Objective We describe a new method for identifying and quantifying the magnitude and rate of short‐term weight faltering episodes, and assess how (a) these episodes relate to broader growth outcomes, and (b) different data collection intervals influence the quantification of weight faltering. Materials and methods We apply this method to longitudinal growth data collected every other day across the first year of life in Gambian infants (n = 124, males = 65, females = 59). Weight faltering episodes are identified from velocity peaks and troughs. Rate of weight loss and regain, maximum weight loss, and duration of each episode were calculated. We systematically reduced our dataset to mimic various potential measurement intervals, to assess how these intervals affect the ability to derive information about short‐term weight faltering episodes. We fit linear models to test whether metrics associated with growth faltering were associated with growth outcomes at 1 year, and generalized additive mixed models to determine whether different collection intervals influence episode identification and metrics. Results Three hundred weight faltering episodes from 119 individuals were identified. The number and magnitude of episodes negatively impacted growth outcomes at 1 year. As data collection interval increases, weight faltering episodes are missed and the duration of episodes is overestimated, resulting in the rate of weight loss and regain being underestimated. Conclusions This method identifies and quantifies short‐term weight faltering episodes, that are in turn negatively associated with growth outcomes. This approach offers a tool for investigators interested in understanding how short‐term weight faltering relates to longer‐term outcomes.
Published: 2021

43. Associations between maternal iron supplementation in pregnancy and offspring growth and cardiometabolic risk outcomes in infancy and childhood

Author: Clive J. Petry, Laurentya Olga, Ieuan A. Hughes, Ken K. Ong, Petry, Clive J [0000-0002-6642-9825], Ong, Ken K [0000-0003-4689-7530], Apollo - University of Cambridge Repository, Petry, Clive [0000-0002-6642-9825], and Ong, Kenneth [0000-0003-4689-7530]
Subjects: Medicine and health sciences, Multidisciplinary, Biology and life sciences, Iron, Infant, Newborn, Infant, Mothers, Glucose, Cardiovascular Diseases, Pregnancy, Dietary Supplements, Humans, Female, Obesity, People and places, Child, Research Article
Abstract: Funder: NIHR BioResource, It was previously observed that maternal iron supplementation in pregnancy was associated with increased offspring size and adiposity at birth, possibly mediated through increased risk of gestational diabetes. In this study we investigated potential long-term associations of maternal iron supplementation in pregnancy with offspring growth in infancy, and growth and cardiometabolic risk factors in mid-childhood to seek evidence of nutritional programming. Using a nested case-control format, markers of growth and adiposity were measured at 3, 12 and 24 months of age in 341 infants from the Cambridge Baby Growth Study whose mothers supplemented with iron in pregnancy and 222 infants whose mothers did not. Measures of growth, glucose tolerance (using a 30 minute 1.75 g glucose/kg body weight oral glucose tolerance test), insulin sensitivity (HOMA IR) and blood pressure were collected in 122 and 79 of these children, respectively, at around 9.5 years of age. In infancy adiposity-promoting associations with maternal iron supplementation in pregnancy were evident at 3 months of age (e.g. mean difference in skinfold thickness: β = +0.15 mm, p = 0.02, in n = 341 whose mothers supplemented versus 222 that did not; waist circumference: β = +0.7 cm, p = 0.04, in n = 159 and 78, respectively) but differences lessened after this time (e.g. 3-12 month change in mean difference in skinfold thickness: β = -0.2 mm, p = 0.03, in n = 272 and 178, respectively). At ~9.5 years of age children whose mothers supplemented with iron in pregnancy had lower mean arterial blood pressures (β = -1.0 mmHg, p = 0.03, in n = 119 and 78, respectively). There were no apparent differences in markers of growth or other cardiometabolic factors. These results suggest that most of the associations of maternal iron supplementation in pregnancy on growth and adiposity evident at birth disappear during infancy, but there may be some evidence of long-term nutritional programming of blood pressure in mid-childhood.
Published: 2022
Full Text: View/download PDF

44. Epigenome-wide association study of incident type 2 diabetes: a meta-analysis of five prospective European cohorts

Author: Eliza Fraszczyk, Annemieke M. W. Spijkerman, Yan Zhang, Stefan Brandmaier, Felix R. Day, Li Zhou, Paul Wackers, Martijn E. T. Dollé, Vincent W. Bloks, Xīn Gào, Christian Gieger, Jaspal Kooner, Jennifer Kriebel, H. Susan J. Picavet, Wolfgang Rathmann, Ben Schöttker, Marie Loh, W. M. Monique Verschuren, Jana V. van Vliet-Ostaptchouk, Nicholas J. Wareham, John C. Chambers, Ken K. Ong, Harald Grallert, Hermann Brenner, Mirjam Luijten, Harold Snieder, Day, Felix [0000-0003-3789-7651], Wareham, Nicholas [0000-0003-1422-2993], Ong, Kenneth [0000-0003-4689-7530], Apollo - University of Cambridge Repository, Center for Liver, Digestive and Metabolic Diseases (CLDM), and Life Course Epidemiology (LCE)
Subjects: Epigenome-wide association studies, DNA methylation, Endocrinology, Diabetes and Metabolism, Type 2 diabetes, Epigenesis, Genetic, Biomarkers, Dna Methylation, Epigenetics, Epigenome-wide Association Studies, Meta-analysis, Prediction, Prospective Studies, Type 2 Diabetes, Epigenome, Diabetes Mellitus, Type 2, Internal Medicine, Humans, CpG Islands, Genome-Wide Association Study
Abstract: Aims/hypothesis Type 2 diabetes is a complex metabolic disease with increasing prevalence worldwide. Improving the prediction of incident type 2 diabetes using epigenetic markers could help tailor prevention efforts to those at the highest risk. The aim of this study was to identify predictive methylation markers for incident type 2 diabetes by combining epigenome-wide association study (EWAS) results from five prospective European cohorts. Methods We conducted a meta-analysis of EWASs in blood collected 7–10 years prior to type 2 diabetes diagnosis. DNA methylation was measured with Illumina Infinium Methylation arrays. A total of 1250 cases and 1950 controls from five longitudinal cohorts were included: Doetinchem, ESTHER, KORA1, KORA2 and EPIC-Norfolk. Associations between DNA methylation and incident type 2 diabetes were examined using robust linear regression with adjustment for potential confounders. Inverse-variance fixed-effects meta-analysis of cohort-level individual CpG EWAS estimates was performed using METAL. The methylGSA R package was used for gene set enrichment analysis. Confirmation of genome-wide significant CpG sites was performed in a cohort of Indian Asians (LOLIPOP, UK). Results The meta-analysis identified 76 CpG sites that were differentially methylated in individuals with incident type 2 diabetes compared with control individuals (p values −7). Sixty-four out of 76 (84.2%) CpG sites were confirmed by directionally consistent effects and p values 1c) showed no improvement (AUC 0.757 vs 0.753). Gene set enrichment analysis of the full epigenome-wide results clearly showed enrichment of processes linked to insulin signalling, lipid homeostasis and inflammation. Conclusions/interpretation By combining results from five European cohorts, and thus significantly increasing study sample size, we identified 76 CpG sites associated with incident type 2 diabetes. Replication of 64 CpGs in an independent cohort of Indian Asians suggests that the association between DNA methylation levels and incident type 2 diabetes is robust and independent of ethnicity. Our data also indicate that BMI partly explains the association between DNA methylation and incident type 2 diabetes. Further studies are required to elucidate the underlying biological mechanisms and to determine potential causal roles of the differentially methylated CpG sites in type 2 diabetes development. Graphical abstract
Published: 2022

45. Damaging missense variants in

Author: Eugene J, Gardner, Katherine A, Kentistou, Stasa, Stankovic, Samuel, Lockhart, Eleanor, Wheeler, Felix R, Day, Nicola D, Kerrison, Nicholas J, Wareham, Claudia, Langenberg, Stephen, O'Rahilly, Ken K, Ong, and John R B, Perry
Abstract: Type 2 diabetes (T2D) is a heritable metabolic disorder. While population studies have identified hundreds of common genetic variants associated with T2D, the role of rare (frequency 0.1%) protein-coding variation is less clear. We performed exome sequence analysis in 418,436 (n = 32,374 T2D cases) individuals in the UK Biobank. We identified previously reported genes (
Published: 2022

46. Maternal Paracetamol Intake During Pregnancy—Impacts on Offspring Reproductive Development

Author: Rieko, Tadokoro-Cuccaro, Benjamin G, Fisher, Ajay, Thankamony, Ken K, Ong, and Ieuan A, Hughes
Subjects: digestive, oral, and skin physiology
Abstract: Paracetamol (acetaminophen) is the preferred antipyretic/analgesic for pregnant women as it is believed there are no adverse fetal effects at the recommended dose. However, emerging evidence suggests that intrauterine paracetamol exposure may be associated with certain urogenital/reproductive disorders in the offspring. In this mini-review, we describe human fetal sex development and possible pharmacological mechanisms by which paracetamol may disrupt this process, including reduced testicular production of testosterone and/or insulin-like peptide 3. We then review the available epidemiological literature on associations between maternal paracetamol exposure and offspring sexual development. Three epidemiological studies have reported associations between maternal paracetamol intake and increased risk of cryptorchidism, although five others have not. None have found associations with hypospadias or penile length. Two out of three studies have reported a shorter anogenital distance (a marker of androgen action during the masculinisation programming window, ∼8–14 weeks of gestation) in male infants antenatally exposed to paracetamol. One study has described a dose-dependent relationship between maternal paracetamol consumption and earlier female (but not male) attainment of puberty. Such epidemiological analyses are complicated by various factors, including method of paracetamol exposure assessment (usually retrospective self-report), variation in diagnostic accuracy, selection bias, confounding by clinical indication, and demographic/genetic differences between geographically separated populations. There is an urgent need for stronger evidence in this area, from both relevant experimental studies and large, carefully-designed prospective studies. In the meantime, a precautionary attitude to gestational paracetamol usage should be considered as the evidence for clinically significant reproductive effects in humans is limited.
Published: 2022

47. Damaging missense variants in IGF1R implicate a role for IGF-1 resistance in the aetiology of type 2 diabetes

Author: Eugene J. Gardner, Katherine A. Kentistou, Stasa Stankovic, Samuel Lockhart, Eleanor Wheeler, Felix R. Day, Nicola D. Kerrison, Nicholas J. Wareham, Claudia Langenberg, Stephen O’Rahilly, Ken K. Ong, and John R. B. Perry
Abstract: Type 2 diabetes (T2D) is a chronic metabolic disorder with a significant genetic component. While large-scale population studies have identified hundreds of common genetic variants associated with T2D susceptibility, the role of rare (minor allele frequency < 0.1%) protein coding variation is less clear. To this end, we performed a gene burden analysis of 18,691 genes in 418,436 (n=32,374 T2D cases) individuals sequenced by the UK Biobank (UKBB) study to assess the impact of rare genetic variants on T2D risk. Our analysis identified T2D associations at exome-wide significance (P < 6.9×10-7) with rare, damaging variants within previously identified genes including GCK, GIGYF1, HNF1A, and TNRC6B. In addition, individuals with rare, damaging missense variants in the genes ZEB2 (N=31 carriers; OR=5.5 [95% CI=2.5-12.0]; p=6.4×10-7), MLXIPL (N=245; OR=2.3 [1.6-3.2]; p=3.2×10-7), and IGF1R (N=394; OR=2.4 [1.8-3.2]; p=1.3×10-10) have higher risk of T2D. Carriers of damaging missense variants within IGF1R were also shorter (-2.2cm [-1.8-2.7]; p=1.2×10-19) and had higher circulating protein levels of insulin-like growth factor-1 (IGF-1; 2.3 nmol/L [1.7-2.9] p=2.8×10-14), indicating relative IGF-1 resistance. A likely causal role of IGF-1 resistance on T2D was further supported by Mendelian randomisation analyses using common variants. Our results increase our understanding of the genetic architecture of T2D and highlight a potential therapeutic benefit of targeting the Growth Hormone/IGF-1 axis.
Published: 2022

48. Newborn body composition and child cardiovascular risk markers: a prospective multi-ethnic Asian cohort study

Author: Yi Ying Ong, Mya-Thway Tint, Izzuddin M Aris, Wen Lun Yuan, Ling-Wei Chen, Marielle V Fortier, Jonathan Choo, Lieng Hsi Ling, Lynette Shek, Kok Hian Tan, Peter D Gluckman, Fabian Yap, Yap-Seng Chong, Keith M Godfrey, Mary F-F Chong, Shiao-Yng Chan, Johan G Eriksson, Mary E Wlodek, Emanuella De Lucia Rolfe, Ken K Ong, Navin Michael, Yung Seng Lee, Aris, Izzuddin M [0000-0002-9239-7476], Yuan, Wen Lun [0000-0002-7472-5042], Tan, Kok Hian [0000-0003-1945-0266], Yap, Fabian [0000-0003-1083-7958], Chong, Yap-Seng [0000-0002-7232-8473], Eriksson, Johan G [0000-0002-2516-2060], Michael, Navin [0000-0002-6170-2108], Lee, Yung Seng [0000-0002-1253-0557], and Apollo - University of Cambridge Repository
Subjects: Epidemiology, Blood Pressure, Pulse Wave Analysis, Carotid Intima-Media Thickness, Body Mass Index, Cohort Studies, Prehypertension, Pregnancy, Risk Factors, Humans, Birth Weight, Prospective Studies, Obesity, Child, Adiposity, cardiovascular, Infant, Newborn, General Medicine, birthweight, Cardiovascular Diseases, Heart Disease Risk Factors, Child, Preschool, Hypertension, Body Composition, Female, fetal growth
Abstract: Background Early epidemiological studies have associated low birthweight with increased cardiovascular risk. We aimed to examine whether the fat and fat-free components of birthweight have differing relationships with childhood cardiovascular risk markers. Methods In the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort, air displacement plethysmography was conducted within 24 h after delivery in 290 naturally conceived singletons. We investigated associations of newborn cohort-specific standardized z-score of fat mass, fat-free mass, body fat percentage and birthweight on child (at 6 years of age) carotid intima-media thickness, pulse wave velocity, blood pressure, prehypertension/hypertension (>110/70 mmHg) and standardized systolic and diastolic blood pressure (SBP and DBP) trajectories (at 3–6 years of age), taking account of maternal education, height, tobacco exposure, parity, ethnicity, child’s sex, gestational age, age at follow-up, and other maternal factors. Results Clear inverse associations were seen for blood pressure with z-score of fat mass [SBP, β (95% CI): −1.31 mmHg (−2.57, −0.06); DBP: −0.79 mmHg (−1.74, 0.15)] and body fat percentage [SBP: −1.46 mmHg (−2.73, −0.19); DBP: −0.80 mmHg (−1.75, 0.16)], but not with fat-free mass [SBP: 0.27 mmHg (−1.29, 1.83)]; DBP: −0.14 mmHg (−1.30, 1.03)]. Being in the lowest tertile of fat mass or body fat percentage was associated with higher blood pressure trajectories and prehypertension/hypertension risk [OR (95% CI), fat mass: 4.23 (1.41, 12.68); body fat percentage: 3.22 (1.09, 9.53)] without concomitantly higher overweight/obesity risk. Conclusions At birth, low adiposity was associated with increased childhood blood pressure. Low newborn adiposity might serve as a marker of poor fetal growth or suboptimal intrauterine conditions associated with hypertension risk later in life.
Published: 2022

49. Trends Toward Earlier Puberty Timing in Girls and Its Likely Mechanisms

Author: Tuck Seng Cheng, Ken K. Ong, Frank M. Biro, Ong, Kenneth [0000-0003-4689-7530], and Apollo - University of Cambridge Repository
Subjects: Adult, Biological Products, Pediatrics, Perinatology and Child Health, Puberty, Obstetrics and Gynecology, Humans, Puberty, Precocious, Female, General Medicine, Obesity, Body Mass Index
Abstract: This is the first of two installments examining early puberty in girls. The first paper will discuss secular trends in onset of puberty and the possible mechanisms to explain these developments. The potential etiologies examined will include the role of endocrine-disrupting chemicals and obesogens, the impact of body mass index and obesity, genetic and biologic pathways, and the influence of lifestyle behaviors. The second paper of the two-part series will examine the potential health impacts of early puberty on young and adult women and offer suggestions for clinical management and public health prevention.
Published: 2022

50. ImprintSeq, a novel tool to interrogate DNA methylation at human imprinted regions and diagnose multilocus imprinting disturbance

Author: Eguzkine Ochoa, Sunwoo Lee, Benoit Lan-Leung, Renuka P. Dias, Ken K. Ong, Jessica A. Radley, Gustavo Pérez de Nanclares, Rosa Martinez, Graeme Clark, Ezequiel Martin, Luis Castaño, Leonardo Bottolo, Eamonn R. Maher, Ong, Kenneth [0000-0003-4689-7530], Bottolo, Leonardo [0000-0002-6381-2327], Maher, Eamonn [0000-0002-6226-6918], and Apollo - University of Cambridge Repository
Subjects: Multilocus imprinting disturbance, Genomic Imprinting, Diagnostic assay, Humans, DNA Methylation, Child, Imprinting disorders, Methylation, Genetics (clinical)
Abstract: PURPOSE: Disruptions of genomic imprinting are associated with congenital imprinting disorders (CIDs) and other disease states, including cancer. CIDs are most often associated with altered methylation at imprinted differentially methylated regions (iDMRs). In some cases, multiple iDMRs are affected causing multilocus imprinting disturbances (MLIDs). The availability of accurate, quantitative, and scalable high-throughput methods to interrogate multiple iDMRs simultaneously would enhance clinical diagnostics and research. METHODS: We report the development of a custom targeted methylation sequencing panel that covered most relevant 63 iDMRs for CIDs and the detection of MLIDs. We tested it in 70 healthy controls and 147 individuals with CIDs. We distinguished loss and gain of methylation per differentially methylated region and classified high and moderate methylation alterations. RESULTS: Across a range of CIDs with a variety of molecular mechanisms, ImprintSeq performed at 98.4% sensitivity, 99.9% specificity, and 99.9% accuracy (when compared with previous diagnostic testing). ImprintSeq was highly sensitive for detecting MLIDs and enabled diagnostic criteria for MLID to be proposed. In a child with extreme MLID profile a probable genetic cause was identified. CONCLUSION: ImprintSeq provides a novel assay for clinical diagnostic and research studies of CIDs, MLIDs, and the role of disordered imprinting in human disease states.
Published: 2022

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Language

Publication Type

Journal

Database

Publisher

524 results on '"Ken K Ong"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources