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1. A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes

Author

Moltke, Ida, Grarup, Niels, Jørgensen, Marit E, Bjerregaard, Peter, Treebak, Jonas T, Fumagalli, Matteo, Korneliussen, Thorfinn S, Andersen, Marianne A, Nielsen, Thomas S, Krarup, Nikolaj T, Gjesing, Anette P, Zierath, Juleen R, Linneberg, Allan, Wu, Xueli, Sun, Guangqing, Jin, Xin, Al-Aama, Jumana, Wang, Jun, Borch-Johnsen, Knut, Pedersen, Oluf, Nielsen, Rasmus, Albrechtsen, Anders, and Hansen, Torben

Subjects
Biological Sciences, Genetics, Human Genome, Diabetes, 2.1 Biological and endogenous factors, Aetiology, Metabolic and endocrine, Adult, Blood Glucose, Codon, Nonsense, Diabetes Mellitus, Type 2, GTPase-Activating Proteins, Gene Frequency, Genetic Variation, Genome-Wide Association Study, Genotype, Greenland, Humans, Insulin, Insulin Resistance, Middle Aged, Muscle, Skeletal, General Science & Technology
Abstract

The Greenlandic population, a small and historically isolated founder population comprising about 57,000 inhabitants, has experienced a dramatic increase in type 2 diabetes (T2D) prevalence during the past 25 years. Motivated by this, we performed association mapping of T2D-related quantitative traits in up to 2,575 Greenlandic individuals without known diabetes. Using array-based genotyping and exome sequencing, we discovered a nonsense p.Arg684Ter variant (in which arginine is replaced by a termination codon) in the gene TBC1D4 with an allele frequency of 17%. Here we show that homozygous carriers of this variant have markedly higher concentrations of plasma glucose (β = 3.8 mmol l(-1), P = 2.5 × 10(-35)) and serum insulin (β = 165 pmol l(-1), P = 1.5 × 10(-20)) 2 hours after an oral glucose load compared with individuals with other genotypes (both non-carriers and heterozygous carriers). Furthermore, homozygous carriers have marginally lower concentrations of fasting plasma glucose (β = -0.18 mmol l(-1), P = 1.1 × 10(-6)) and fasting serum insulin (β = -8.3 pmol l(-1), P = 0.0014), and their T2D risk is markedly increased (odds ratio (OR) = 10.3, P = 1.6 × 10(-24)). Heterozygous carriers have a moderately higher plasma glucose concentration 2 hours after an oral glucose load than non-carriers (β = 0.43 mmol l(-1), P = 5.3 × 10(-5)). Analyses of skeletal muscle biopsies showed lower messenger RNA and protein levels of the long isoform of TBC1D4, and lower muscle protein levels of the glucose transporter GLUT4, with increasing number of p.Arg684Ter alleles. These findings are concomitant with a severely decreased insulin-stimulated glucose uptake in muscle, leading to postprandial hyperglycaemia, impaired glucose tolerance and T2D. The observed effect sizes are several times larger than any previous findings in large-scale genome-wide association studies of these traits and constitute further proof of the value of conducting genetic association studies outside the traditional setting of large homogeneous populations.

Published
2014

2. Whole-Exome Sequencing of 2,000 Danish Individuals and the Role of Rare Coding Variants in Type 2 Diabetes

Author

Lohmueller, Kirk E, Sparsø, Thomas, Li, Qibin, Andersson, Ehm, Korneliussen, Thorfinn, Albrechtsen, Anders, Banasik, Karina, Grarup, Niels, Hallgrimsdottir, Ingileif, Kiil, Kristoffer, Kilpeläinen, Tuomas O, Krarup, Nikolaj T, Pers, Tune H, Sanchez, Gaston, Hu, Youna, DeGiorgio, Michael, Jørgensen, Torben, Sandbæk, Annelli, Lauritzen, Torsten, Brunak, Søren, Kristiansen, Karsten, Li, Yingrui, Hansen, Torben, Wang, Jun, Nielsen, Rasmus, and Pedersen, Oluf

Subjects
Biological Sciences, Genetics, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Published
2014

3. Whole-Exome Sequencing of 2,000 Danish Individuals and the Role of Rare Coding Variants in Type 2 Diabetes

Author

Lohmueller, Kirk E, Sparsø, Thomas, Li, Qibin, Andersson, Ehm, Korneliussen, Thorfinn, Albrechtsen, Anders, Banasik, Karina, Grarup, Niels, Hallgrimsdottir, Ingileif, Kiil, Kristoffer, Kilpeläinen, Tuomas O, Krarup, Nikolaj T, Pers, Tune H, Sanchez, Gaston, Hu, Youna, DeGiorgio, Michael, Jørgensen, Torben, Sandbæk, Annelli, Lauritzen, Torsten, Brunak, Søren, Kristiansen, Karsten, Li, Yingrui, Hansen, Torben, Wang, Jun, Nielsen, Rasmus, and Pedersen, Oluf

Subjects
Human Genome, Genetic Testing, Diabetes, Biotechnology, Cardiovascular, Genetics, Autoimmune Disease, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Computational Biology, Denmark, Diabetes Mellitus, Type 2, Exome, Genetic Association Studies, Genetic Variation, Genotype, High-Throughput Nucleotide Sequencing, Humans, Models, Statistical, Open Reading Frames, Polymorphism, Single Nucleotide, White People, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

It has been hypothesized that, in aggregate, rare variants in coding regions of genes explain a substantial fraction of the heritability of common diseases. We sequenced the exomes of 1,000 Danish cases with common forms of type 2 diabetes (including body mass index > 27.5 kg/m(2) and hypertension) and 1,000 healthy controls to an average depth of 56×. Our simulations suggest that our study had the statistical power to detect at least one causal gene (a gene containing causal mutations) if the heritability of these common diseases was explained by rare variants in the coding regions of a limited number of genes. We applied a series of gene-based tests to detect such susceptibility genes. However, no gene showed a significant association with disease risk after we corrected for the number of genes analyzed. Thus, we could reject a model for the genetic architecture of type 2 diabetes where rare nonsynonymous variants clustered in a modest number of genes (fewer than 20) are responsible for the majority of disease risk.

Published
2013

4. The Arg82Cys Polymorphism of the Protein Nepmucin Implies a Role in HDL Metabolism

Author

Metz, Sophia, primary, Krarup, Nikolaj T, additional, Bryrup, Thomas, additional, Støy, Julie, additional, Andersson, Ehm A, additional, Christoffersen, Christina, additional, Neville, Matt J, additional, Christiansen, Malene R, additional, Jonsson, Anna E, additional, Witte, Daniel R, additional, Kampmann, Ulla, additional, Nielsen, Lars B, additional, Jørgensen, Niklas R, additional, Karpe, Fredrik, additional, Grarup, Niels, additional, Pedersen, Oluf, additional, Kilpeläinen, Tuomas O, additional, and Hansen, Torben, additional

Published
2022
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5. Arg82Cys Polymorphism of the Protein Nepmucin Implies a Role in HDL Metabolism.

Author

Metz, Sophia, Krarup, Nikolaj T, Bryrup, Thomas, Støy, Julie, Andersson, Ehm A, Christoffersen, Christina, Neville, Matt J, Christiansen, Malene R, Jonsson, Anna E, Witte, Daniel R, Kampmann, Ulla, Nielsen, Lars B, Jørgensen, Niklas R, Karpe, Fredrik, Grarup, Niels, Pedersen, Oluf, Kilpeläinen, Tuomas O, and Hansen, Torben

Subjects
HDL cholesterol, BLOOD lipids, METABOLISM, MEMBRANE proteins, BLOOD sugar
Abstract

Context Blood lipid levels are linked to the risk of cardiovascular disease and regulated by genetic factors. A low-frequency polymorphism Arg82Cys (rs72836561) in the membrane protein nepmucin, encoded by CD300LG , is associated with lower fasting concentration of high-density lipoprotein cholesterol (HDLc) and higher fasting triglycerides. However, whether the variant is linked to postprandial lipids and glycemic status remains elusive. Objective Here, we augment the genetic effect of Arg82Cys on fasting plasma concentrations of HDL subclasses, postprandial lipemia after a standardized high-fat meal, and glycemic status to further untangle its role in HDL metabolism. Methods We elucidated fasting associations with HDL subclasses in a population-based cohort study (Oxford BioBank, OBB), including 4522 healthy men and women. We investigated fasting and postprandial consequences on HDL metabolism in recall-by-genotype (RbG) studies (fasting: 20 carrier/20 noncarrier; postprandial: 7 carrier/17 noncarrier), and shed light on the synergistic interaction with glycemic status. Results A lower fasting plasma concentration of cholesterol in large HDL particles was found in healthy male carriers of the Cys82 polymorphism compared to noncarriers, both in the OBB (P  = .004) and RbG studies (P  = .005). In addition, the Cys82 polymorphism was associated with low fasting plasma concentrations of ApoA1 (P  = .008) in the OBB cohort. On the contrary, we did not find differences in postprandial lipemia or 2-hour plasma glucose levels. Conclusion Taken together, our results indicate an association between the Arg82Cys variant and a lower concentration of HDL particles and HDLc, especially in larger HDL subclasses, suggesting a link between nepmucin and HDLc metabolism or maturation. [ABSTRACT FROM AUTHOR]

Published
2022
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7. The minor C-allele of rs2014355 in ACADS is associated with reduced insulin release following an oral glucose load

Author

Pisinger Charlotta, Lauritzen Torsten, Sandbæk Annelli, Andersson Åsa, Sandholt Camilla H, Krarup Nikolaj T, Justesen Johanne M, Banasik Karina, Hornbak Malene, Witte Daniel R, Sørensen Thorkild IA, Pedersen Oluf, and Hansen Torben

Subjects
Internal medicine, RC31-1245, Genetics, QH426-470
Abstract

Abstract Background A genome-wide association study (GWAS) using metabolite concentrations as proxies for enzymatic activity, suggested that two variants: rs2014355 in the gene encoding short-chain acyl-coenzyme A dehydrogenase (ACADS) and rs11161510 in the gene encoding medium-chain acyl-coenzyme A dehydrogenase (ACADM) impair fatty acid β-oxidation. Chronic exposure to fatty acids due to an impaired β-oxidation may down-regulate the glucose-stimulated insulin release and result in an increased risk of type 2 diabetes (T2D). We aimed to investigate whether the two variants associate with altered insulin release following an oral glucose load or with T2D. Methods The variants were genotyped using KASPar® PCR SNP genotyping system and investigated for associations with estimates of insulin release and insulin sensitivity following an oral glucose tolerance test (OGTT) in a random sample of middle-aged Danish individuals (nACADS = 4,324; nACADM = 4,337). The T2D-case-control study involved a total of ~8,300 Danish individuals (nACADS = 8,313; nACADM = 8,344). Results In glucose-tolerant individuals the minor C-allele of rs2014355 of ACADS associated with reduced measures of serum insulin at 30 min following an oral glucose load (per allele effect (β) = -3.8% (-6.3%;-1.3%), P = 0.003), reduced incremental area under the insulin curve (β = -3.6% (-6.3%;-0.9%), P = 0.009), reduced acute insulin response (β = -2.2% (-4.2%;0.2%), P = 0.03), and with increased insulin sensitivity ISIMatsuda (β = 2.9% (0.5%;5.2%), P = 0.02). The C-allele did not associate with two other measures of insulin sensitivity or with a derived disposition index. The C-allele was not associated with T2D in the case-control analysis (OR 1.07, 95% CI 0.96-1.18, P = 0.21). rs11161510 of ACADM did not associate with any indices of glucose-stimulated insulin release or with T2D. Conclusions In glucose-tolerant individuals the minor C-allele of rs2014355 of ACADS was associated with reduced measures of glucose-stimulated insulin release during an OGTT, a finding which in part may be mediated through an impaired β-oxidation of fatty acids.

Published
2011
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8. The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study

Author

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

Subjects
ddc
Published
2015

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

Author

Winkler, Thomas W, Justice, Anne E, Graff, Mariaelisa, Barata, Llilda, Feitosa, Mary F, Chu, Su, Czajkowski, Jacek, Esko, Tõnu, Fall, Tove, Kilpeläinen, Tuomas O, Lu, Yingchang, Mägi, Reedik, Mihailov, Evelin, Pers, Tune H, Rüeger, Sina, Teumer, Alexander, Ehret, Georg B, Ferreira, Teresa, Heard-Costa, Nancy L, Karjalainen, Juha, Lagou, Vasiliki, Mahajan, Anubha, Neinast, Michael D, Prokopenko, Inga, Simino, Jeannette, Teslovich, Tanya M, Jansen, Rick, Westra, Harm-Jan, White, Charles C, Absher, Devin, Ahluwalia, Tarunveer S, Ahmad, Shafqat, Albrecht, Eva, Alves, Alexessander Couto, Bragg-Gresham, Jennifer L, de Craen, Anton JM, Bis, Joshua C, Bonnefond, Amélie, Boucher, Gabrielle, Cadby, Gemma, Cheng, Yu-Ching, Chiang, Charleston WK, Delgado, Graciela, Demirkan, Ayse, Dueker, Nicole, Eklund, Niina, Eiriksdottir, Gudny, Eriksson, Joel, Feenstra, Bjarke, Fischer, Krista, Frau, Francesca, Galesloot, Tessel E, Geller, Frank, Goel, Anuj, Gorski, Mathias, Grammer, Tanja B, Gustafsson, Stefan, Haitjema, Saskia, Hottenga, Jouke-Jan, Huffman, Jennifer E, Jackson, Anne U, Jacobs, Kevin B, Johansson, Åsa, Kaakinen, Marika, Kleber, Marcus E, Lahti, Jari, Mateo Leach, Irene, Lehne, Benjamin, Liu, Youfang, Lo, Ken Sin, Lorentzon, Mattias, Luan, Jian'an, Madden, Pamela AF, Mangino, Massimo, McKnight, Barbara, Medina-Gomez, Carolina, Monda, Keri L, Montasser, May E, Müller, Gabriele, Müller-Nurasyid, Martina, Nolte, Ilja M, Panoutsopoulou, Kalliope, Pascoe, Laura, Paternoster, Lavinia, Rayner, Nigel W, Renström, Frida, Rizzi, Federica, Rose, Lynda M, Ryan, Kathy A, Salo, Perttu, Sanna, Serena, Scharnagl, Hubert, Shi, Jianxin, Smith, Albert Vernon, Southam, Lorraine, Stančáková, Alena, Steinthorsdottir, Valgerdur, Strawbridge, Rona J, Sung, Yun Ju, Tachmazidou, Ioanna, Tanaka, Toshiko, Thorleifsson, Gudmar, Trompet, Stella, Pervjakova, Natalia, Tyrer, Jonathan P, Vandenput, Liesbeth, van der Laan, Sander W, van der Velde, Nathalie, van Setten, Jessica, van Vliet-Ostaptchouk, Jana V, Verweij, Niek, Vlachopoulou, Efthymia, Waite, Lindsay L, Wang, Sophie R, Wang, Zhaoming, Wild, Sarah H, Willenborg, Christina, Wilson, James F, Wong, Andrew, Yang, Jian, Yengo, Loïc, Yerges-Armstrong, Laura M, Yu, Lei, Zhang, Weihua, Zhao, Jing Hua, Andersson, Ehm A, Bakker, Stephan JL, Baldassarre, Damiano, Banasik, Karina, Barcella, Matteo, Barlassina, Cristina, Bellis, Claire, Benaglio, Paola, Blangero, John, Blüher, Matthias, Bonnet, Fabrice, Bonnycastle, Lori L, Boyd, Heather A, Bruinenberg, Marcel, Buchman, Aron S, Campbell, Harry, Chen, Yii-Der Ida, Chines, Peter S, Claudi-Boehm, Simone, Cole, John, Collins, Francis S, de Geus, Eco JC, de Groot, Lisette CPGM, Dimitriou, Maria, Duan, Jubao, Enroth, Stefan, Eury, Elodie, Farmaki, Aliki-Eleni, Forouhi, Nita G, Friedrich, Nele, Gejman, Pablo V, Gigante, Bruna, Glorioso, Nicola, Go, Alan S, Gottesman, Omri, Gräßler, Jürgen, Grallert, Harald, Grarup, Niels, Gu, Yu-Mei, Broer, Linda, Ham, Annelies C, Hansen, Torben, Harris, Tamara B, Hartman, Catharina A, Hassinen, Maija, Hastie, Nicholas, Hattersley, Andrew T, Heath, Andrew C, Henders, Anjali K, Hernandez, Dena, Hillege, Hans, Holmen, Oddgeir, Hovingh, Kees G, Hui, Jennie, Husemoen, Lise L, Hutri-Kähönen, Nina, Hysi, Pirro G, Illig, Thomas, De Jager, Philip L, Jalilzadeh, Shapour, Jørgensen, Torben, Jukema, J Wouter, Juonala, Markus, Kanoni, Stavroula, Karaleftheri, Maria, Khaw, Kay Tee, Kinnunen, Leena, Kittner, Steven J, Koenig, Wolfgang, Kolcic, Ivana, Kovacs, Peter, Krarup, Nikolaj T, Kratzer, Wolfgang, Krüger, Janine, Kuh, Diana, Kumari, Meena, Kyriakou, Theodosios, Langenberg, Claudia, Lannfelt, Lars, Lanzani, Chiara, Lotay, Vaneet, Launer, Lenore J, Leander, Karin, Lindström, Jaana, Linneberg, Allan, Liu, Yan-Ping, Lobbens, Stéphane, Luben, Robert, Lyssenko, Valeriya, Männistö, Satu, Magnusson, Patrik K, McArdle, Wendy L, Menni, Cristina, Merger, Sigrun, Milani, Lili, Montgomery, Grant W, Morris, Andrew P, Narisu, Narisu, Nelis, Mari, Ong, Ken K, Palotie, Aarno, Pérusse, Louis, Pichler, Irene, Pilia, Maria G, Pouta, Anneli, Rheinberger, Myriam, Ribel-Madsen, Rasmus, Richards, Marcus, Rice, Kenneth M, Rice, Treva K, Rivolta, Carlo, Salomaa, Veikko, Sanders, Alan R, Sarzynski, Mark A, Scholtens, Salome, Scott, Robert A, Scott, William R, Sebert, Sylvain, Sengupta, Sebanti, Sennblad, Bengt, Seufferlein, Thomas, Silveira, Angela, Slagboom, P Eline, Smit, Jan H, Sparsø, Thomas H, Stirrups, Kathleen, Stolk, Ronald P, Stringham, Heather M, Swertz, Morris A, Swift, Amy J, Syvänen, Ann-Christine, Tan, Sian-Tsung, Thorand, Barbara, Tönjes, Anke, Tremblay, Angelo, Tsafantakis, Emmanouil, van der Most, Peter J, Völker, Uwe, Vohl, Marie-Claude, Vonk, Judith M, Waldenberger, Melanie, Walker, Ryan W, Wennauer, Roman, Widén, Elisabeth, Willemsen, Gonneke, Wilsgaard, Tom, Wright, Alan F, Zillikens, M Carola, van Dijk, Suzanne C, van Schoor, Natasja M, Asselbergs, Folkert W, de Bakker, Paul IW, Beckmann, Jacques S, Beilby, John, Bennett, David 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Division of Statistical Genomics, Washington University School of Medicine, Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP), Estonian Genome and Medicine, University of Tartu, Institute of Molecular and Cell Biology, Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Institute of Metabolic Science, MRC, Brown University, Center for Biological Sequence Analysis [Lyngby], Technical University of Denmark [Lyngby] (DTU), King‘s College London, Groningen Bioinformatics Centre, GBB, University of Groningen [Groningen], University of Queensland [Brisbane], National Institut of Food Science and Technology, University of Agriculture, Department of Biostatistics and Center for Statistical Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Department of neurology, Leiden University Medical Center (LUMC), University of Washington [Seattle], Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Genetic Epidemiology Unit, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Deptartment of Medical Biochemistry and Microbiology, Uppsala University, Infectious diseases division, Department of internal medicine, Washington University in Saint Louis (WUSTL), Limnology, Ecology, Department of Ecology and Evolutionary Biology, University of California, Core Genotyping Facility, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Division of Cancer Epidemiology and Genetics, Institute of Health Sciences and Biocenter Oulu, University of Oulu, Department of Chemical Engineering Taiwan (DCET - NTHU), National Tsing Hua University [Hsinchu] (NTHU), University of Oxford [Oxford], Department of Epidemiology, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Human Genetics, The Wellcome Trust Sanger Institute [Cambridge], Departments of Epidemiology and Nutrition, Harvard School of Public Health, Department of Clinical Sciences, Lund University [Lund]-Lund University Diabetes Centre, Genetic Epidemiology and Clinical Research Group, Umea University Hospital, Department of Medicine, University of Eastern Finland-Kuopio University Hospital, Department of Medical Sciences, Department of Educational Psychology and Counseling, National Taiwan Normal University (NTNU), Laboratory for Cardiovascular Genomics and Informatics [Yokohama] (RIKEN IMS), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN)-RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), deCODE Genetics, deCODE genetics [Reykjavik], Interuniversity Cardiology Institute Netherlands, Molecular Genetics Section, University of Groningen [Groningen]-University Medical Centre Groningen, Kidney Center, University Medical Center Groningen [Groningen] (UMCG), The University of Texas Health Science Center at Houston (UTHealth), Texas Biomedical Research Institute [San Antonio, TX], Medical Department III, Universität Leipzig [Leipzig], Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Dept. of Epidemiology Research, Statens Serum Institut [Copenhagen], GNS Science, Blackett Laboratory, Imperial College London, Medstar Research Institute, University of Rochester [USA], MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, Institute of Epidemiology [Neuherberg] (EPI), German Research Center for Environmental Health - Helmholtz Center München (GmbH), Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Dept Biochem & Mol Biol, Pennsylvania State University (Penn State), Penn State System-Penn State System, Genomic Research Laboratory, Service of Infectious Disease, Hôpitaux Universitaires de Genève (HUG), Epidemiology, University Medical Centre Groningen, Unit for Molecular Epidemiology, German Research Center for Environmental Health-Helmholtz-Zentrum München (HZM), Program in Translational NeuroPsychiatric Genomics, Brigham and Women's Hospital [Boston], Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Research Centre for Prevention and Health (RCPH), Department of Public Health [Copenhagen], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)-Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)-Capital Region of Denmark, University of Copenhagen = Københavns Universitet (KU), Faculty of Medicine, Institute of Public Health, Aalborg University [Denmark] (AAU), Department of Nutrition-Dietetics, Harokopio University of Athens, Department of Medical Statistics, Epidemiology and Medical Informatics, University of Zagreb, MRC National Survey of Health and Development, MRC Unit for Lifelong Health and Ageing, Department of Epidemiology and Public Health, University College of London [London] (UCL), Department of Public health and Caring Sciences, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden, Research Center for Prevention and Health, Glostrup Hospital, Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Cambridge Institute of Public Health, University of Cambridge [UK] (CAM), Chronic Disease Epidemiology and Prevention Unit, National Institute for Health and Welfare [Helsinki], Queensland Institute of Medical Research, Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Head of Medical Sequencing, Department of Biostatistics, University of Washington, Department of Chronic Disease Prevention, Molecular Epidemiology, Department of Genetics, Université Laval [Québec] (ULaval), Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Netherlands Genomics Initiative, Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), Department of Internal Medicine, Université de Lausanne (UNIL), Carl Gustav Carus University Hospital, Loughborough University, Genomics and Bioinformatics Platform, Fondazione Filarete, Department of Medicine, Surgery, and Dentistry, University of Milano, Medizinische Klinik II, Universität zu Lübeck [Lübeck], Department of Genomic Medicine, University of Manchester [Manchester], The Wellcome Trust Centre for Human Genetics [Oxford], National Institutes of Health [Bethesda] (NIH), Department of Nephrology, University Medical Center, University of Groningen, Helmholtz-Zentrum München (HZM), Icelandic Heart Association, Kopavogur, Iceland., Faculty of Medicine, University of Iceland [Reykjavik], Genetics and Pathology, Department of child and adolescent psychiatry, Universität Duisburg-Essen [Essen], Department of Internal Medicine II, Division of Respirology, University of Regensburg, Regensburg, Germany, Universität Regensburg (UR), Franz-Volhard-Centrum für Klinische Forschung, ECRC, Department of Clinical Physiology, University of Tampere [Finland]-Tampere University Hospital, Finnish Institute of Occupational Health of Helsinki, Department of Clinical Chemistry, Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Department of Oncology, University of Tampere Medical School, University of Tampere, Department of Physiology, University of Eastern Finland-Institute of Biomedicine, Department of Medicine, Montreal, Developmental Brain and Behaviour Unit, University of Southampton, Division of Gastroenterology and Hepatology, Department of Immunology, Mayo Clinic, Centre for Bone and Arthritis Research, Institute of Medicine-University of Gothenburg (GU), Interdisciplinary Center for Psychiatric Epidemiology, Experimental Cardiology Laboratory, University Medical Center [Utrecht], Peter MacCallum Cancer Center, Faculty of Health Sciences, Aarhus University [Aarhus], Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Department of Health Services, University of Washington, Group Health Research Institute, Group Health Cooperative, Department of Epidemiology, University of Washington, Department of Medicine, University of Washington, Cardiovascular Health Research Unit, University of Washington, The Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku University Hospital (TYKS), Erasmus Medical Centre, Cedars-Sinai Medical Center, Department of Pathological Biochemistry, Royal Infirmary, Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology, University Medical Center Groningen, Department of Pediatrics, Augusta University - Medical College of Georgia, University System of Georgia (USG)-University System of Georgia (USG), Institute of Preventive Medicine, Copenhagen University Hospital-Bispebjerg and Frederiksberg Hospitals, Maastricht University [Maastricht], Department of Public Health, South Ostrobothnia Central Hospital, Department of Clinical and Preventive Medicine, Danube-University Krems, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Department of Epidemiology & Biostatistics, Radboud University Medical Center [Nijmegen], Institute for Community Medicine, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), MRC epidemiology Unit, Framingham Heart Study, National Heart, Lung, and Blood Institute [Bethesda] (NHLBI)-Boston University [Boston] (BU), Metabolic Disease Group, University of Cambridge Metabolic Research Laboratories, Department of Genetics and Biotechnology, Wellcome Trust, Divisions of Genetics and Endocrinology and Program in Genomics, Boston Children's Hospital, Metabolism Initiative and Program in Medical and Population Genetics, Endocrinology and Metabolism, The Churchill Hospital-Oxford Centre for Diabetes, Department of Epidemiology and Preventive Medicine, Regensburg University Medical Center, University of North Carolina System (UNC)-University of North Carolina System (UNC)-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, Department of Medical Genetics, Epidemiology Unit, Addenbrooke's Hospital-Medical Research Council (MRC), P30 AG010161/AG/NIA NIH HHS/United States, Psychiatry, Epidemiology and Data Science, NCA - Neurobiology of mental health, EMGO - Lifestyle, overweight and diabetes, APH - Amsterdam Public Health, AMS - Amsterdam Movement Sciences, Geriatrics, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Other departments, Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Lifestyle, Overweight and Diabetes, RS: CARIM - R3 - Vascular biology, MUMC+: DA BV AIOS Radiologie (9), Epidemiologie, Orthopedie, Institute for Molecular Medicine Finland, Helsinki Collegium for Advanced Studies, Behavioural Sciences, University of Helsinki, Transplantation Laboratory, Medicum, Research Programs Unit, Research Programme of Molecular Medicine, Aarno Palotie / Principal Investigator, Elisabeth Ingrid Maria Widen / Principal Investigator, Clinicum, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Children's Hospital, Lastentautien yksikkö, Marja-Liisa Lokki / Principal Investigator, Kardiologian yksikkö, Leif Groop Research Group, Quantitative Genetics, Developmental Psychology Research Group, Genomics of Neurological and Neuropsychiatric Disorders, Genomic Discoveries and Clinical Translation, Ehret, Georg Benedikt, Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Universiteit Leiden-Universiteit Leiden, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), University of California (UC), University of Oxford, Lund University [Lund], Universität Leipzig, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Helmholtz Zentrum München = German Research Center for Environmental Health, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH)-Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH)-Capital Region of Denmark, University of Copenhagen = Københavns Universitet (UCPH), Université de Lausanne = University of Lausanne (UNIL), Universität zu Lübeck = University of Lübeck [Lübeck], Universität Duisburg-Essen = University of Duisburg-Essen [Essen], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, University of Gothenburg (GU)-Institute of Medicine, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), Luan, Jian'an [0000-0003-3137-6337], Tyrer, Jonathan [0000-0003-3724-4757], Forouhi, Nita [0000-0002-5041-248X], Khaw, Kay-Tee [0000-0002-8802-2903], Langenberg, Claudia [0000-0002-5017-7344], Luben, Robert [0000-0002-5088-6343], Ong, Kenneth [0000-0003-4689-7530], Johnson, Kathleen [0000-0002-6823-3252], Wareham, Nicholas [0000-0003-1422-2993], Barroso, Ines [0000-0001-5800-4520], Apollo - University of Cambridge Repository, CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, MAGIC Consortium, Biochemistry, Surgery, Internal Medicine, Public Health, Medical Oncology, Pathology, Erasmus MC other, Child and Adolescent Psychiatry / Psychology, and Clinical Genetics

Subjects
0301 basic medicine, Netherlands Twin Register (NTR), Male, Cancer Research, endocrine system diseases, Biological pathways, QH426-470, Genome, Body Mass Index, Body Size, Genetics (clinical), ddc:616, Genetics & Heredity, Sex Characteristics, Loci, MAGIC Consortium, Mass index, Age Factors, Chromosome Mapping, Middle Aged, Genealogy, Self-reported height, Peripheral-blood, Scale (social sciences), ICBP Consortium, Female, Life Sciences & Biomedicine, Medical Genetics, Research Article, arcOGEN Consortium, musculoskeletal diseases, Adult, European Continental Ancestry Group, Natural menopause, Aged, Body Size/genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Waist-Hip Ratio, Biology, Body size, DIAGRAM Consortium, Age and sex, White People, Fat distribution, GLGC Consortium, 03 medical and health sciences, Life-course, Genetics, Weight-gain, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Medicinsk genetik, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0604 Genetics, Science & Technology, nutritional and metabolic diseases, Correction, 030104 developmental biology, GWAS meta-analysis, Global-BPGen Consortium, Common SNPS, CHARGE Consortium, 3111 Biomedicine, Developmental Biology
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, Author Summary Adult body size and body shape differ substantially between men and women and change over time. More than 100 genetic variants that influence body mass index (measure of body size) or waist-to-hip ratio (measure of body shape) have been identified. While there is evidence that some genetic loci affect body shape differently in men than in women, little is known about whether genetic effects differ in older compared to younger adults, and whether such changes differ between men and women. Therefore, we conducted a systematic genome-wide search, including 114 studies (>320,000 individuals), to specifically identify genetic loci with age- and or sex-dependent effects on body size and shape. We identified 15 loci of which the effect on BMI was different in older compared to younger adults, whereas we found no evidence for loci with different effects in men compared to women. The opposite was seen for body shape as we identified 44 loci of which the effect on waist-to-hip ratio differed between men and women, but no difference between younger and older adults were observed. Our observations may provide new insights into the biology that underlies weight change with age or the sexual dimorphism of body shape.

Published
2014

10. Bioinformatics-Driven Identification and Examination of Candidate Genes for Non-Alcoholic Fatty Liver Disease

Author

Banasik, Karina, primary, Justesen, Johanne M., additional, Hornbak, Malene, additional, Krarup, Nikolaj T., additional, Gjesing, Anette P., additional, Sandholt, Camilla H., additional, Jensen, Thomas S., additional, Grarup, Niels, additional, Andersson, Åsa, additional, Jørgensen, Torben, additional, Witte, Daniel R., additional, Sandbæk, Annelli, additional, Lauritzen, Torsten, additional, Thorens, Bernard, additional, Brunak, Søren, additional, Sørensen, Thorkild I. A., additional, Pedersen, Oluf, additional, and Hansen, Torben, additional

Published
2011
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11. The minor C-allele of rs2014355 in ACADSis associated with reduced insulin release following an oral glucose load

Author

Hornbak, Malene, primary, Banasik, Karina, additional, Justesen, Johanne M, additional, Krarup, Nikolaj T, additional, Sandholt, Camilla H, additional, Andersson, Åsa, additional, Sandbæk, Annelli, additional, Lauritzen, Torsten, additional, Pisinger, Charlotta, additional, Witte, Daniel R, additional, Sørensen, Thorkild IA, additional, Pedersen, Oluf, additional, and Hansen, Torben, additional

Published
2011
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12. The minor C-allele of rs2014355 in ACADS is associated with reduced insulin release following an oral glucose load.

Author

Hornbak, Malene, Banasik, Karina, Justesen, Johanne M., Krarup, Nikolaj T., Sandholt, Camilla H., Andersson, Äsa, Sandbæk, Annelli, Lauritzen, Torsten, Pisinger, Charlotta, Witte, Daniel R., Sørensen, Thorkild I. A., Pedersen, Oluf, and Hansen, Torben

Subjects
INSULIN, GLUCOSE, GENOMES, COENZYMES, TYPE 2 diabetes
Abstract

Background: A genome-wide association study (GWAS) using metabolite concentrations as proxies for enzymatic activity, suggested that two variants: rs2014355 in the gene encoding short-chain acyl-coenzyme A dehydrogenase (ACADS) and rs11161510 in the gene encoding medium-chain acyl-coenzyme A dehydrogenase (ACADM) impair fatty acid β-oxidation. Chronic exposure to fatty acids due to an impaired β-oxidation may down-regulate the glucose-stimulated insulin release and result in an increased risk of type 2 diabetes (T2D). We aimed to investigate whether the two variants associate with altered insulin release following an oral glucose load or with T2D. Methods: The variants were genotyped using KASPar® PCR SNP genotyping system and investigated for associations with estimates of insulin release and insulin sensitivity following an oral glucose tolerance test (OGTT) in a random sample of middle-aged Danish individuals (nACADS = 4,324; nACADM = 4,337). The T2D-case-control study involved a total of ∼8,300 Danish individuals (nACADS = 8,313; nACADM = 8,344). Results: In glucose-tolerant individuals the minor C-allele of rs2014355 of ACADS associated with reduced measures of serum insulin at 30 min following an oral glucose load (per allele effect (β) = -3.8% (-6.3%;-1.3%), P = 0.003), reduced incremental area under the insulin curve (β = -3.6% (-6.3%;-0.9%), P = 0.009), reduced acute insulin response (β = -2.2% (-4.2%;0.2%), P = 0.03), and with increased insulin sensitivity ISIMatsuda (β = 2.9% (0.5%;5.2%), P = 0.02). The C-allele did not associate with two other measures of insulin sensitivity or with a derived disposition index. The C-allele was not associated with T2D in the case-control analysis (OR 1.07, 95% CI 0.96-1.18, P = 0.21). rs11161510 of ACADM did not associate with any indices of glucose-stimulated insulin release or with T2D. Conclusions: In glucose-tolerant individuals the minor C-allele of rs2014355 of ACADS was associated with reduced measures of glucose-stimulated insulin release during an OGTT, a finding which in part may be mediated through an impaired β-oxidation of fatty acids. [ABSTRACT FROM AUTHOR]

Published
2011
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13. Correction: The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.

Author

Winkler TW, Justice AE, Graff M, Barata L, Feitosa MF, Chu S, Czajkowski J, Esko T, Fall T, Kilpeläinen TO, Lu Y, Mägi R, Mihailov E, Pers TH, Rüeger S, Teumer A, Ehret GB, Ferreira T, Heard-Costa NL, Karjalainen J, Lagou V, Mahajan A, Neinast MD, Prokopenko I, Simino J, Teslovich TM, Jansen R, Westra HJ, White CC, Absher D, Ahluwalia TS, Ahmad S, Albrecht E, Alves AC, Bragg-Gresham JL, de Craen AJ, Bis JC, Bonnefond A, Boucher G, Cadby G, Cheng YC, Chiang CW, Delgado G, Demirkan A, Dueker N, Eklund N, Eiriksdottir G, Eriksson J, Feenstra B, Fischer K, Frau F, Galesloot TE, Geller F, Goel A, Gorski M, Grammer TB, Gustafsson S, Haitjema S, Hottenga JJ, Huffman JE, Jackson AU, Jacobs KB, Johansson Å, Kaakinen M, Kleber ME, Lahti J, Mateo Leach I, Lehne B, Liu Y, Lo KS, Lorentzon M, Luan J, Madden PA, Mangino M, McKnight B, Medina-Gomez C, Monda KL, Montasser ME, Müller G, Müller-Nurasyid M, Nolte IM, Panoutsopoulou K, Pascoe L, Paternoster L, Rayner NW, Renström F, Rizzi F, Rose LM, Ryan KA, Salo P, Sanna S, Scharnagl H, Shi J, Smith AV, Southam L, Stančáková A, Steinthorsdottir V, Strawbridge RJ, Sung YJ, Tachmazidou I, Tanaka T, Thorleifsson G, Trompet S, Pervjakova N, Tyrer JP, Vandenput L, van der Laan SW, van der Velde N, van Setten J, van Vliet-Ostaptchouk JV, Verweij N, Vlachopoulou E, Waite LL, Wang SR, Wang Z, Wild SH, Willenborg C, Wilson JF, Wong A, Yang J, Yengo L, Yerges-Armstrong LM, Yu L, Zhang W, Zhao JH, Andersson EA, Bakker SJ, Baldassarre D, Banasik K, Barcella M, Barlassina C, Bellis C, Benaglio P, Blangero J, Blüher M, Bonnet F, Bonnycastle LL, Boyd HA, Bruinenberg M, Buchman AS, Campbell H, Chen YI, Chines PS, Claudi-Boehm S, Cole J, Collins FS, de Geus EJ, de Groot LC, Dimitriou M, Duan J, Enroth S, Eury E, Farmaki AE, Forouhi NG, Friedrich N, Gejman PV, Gigante B, Glorioso N, Go AS, Gottesman O, Gräßler J, Grallert H, Grarup N, Gu YM, Broer L, Ham AC, Hansen T, Harris TB, Hartman CA, Hassinen M, Hastie N, Hattersley AT, Heath AC, Henders AK, Hernandez D, Hillege H, Holmen O, Hovingh KG, Hui J, Husemoen LL, Hutri-Kähönen N, Hysi PG, Illig T, De Jager PL, Jalilzadeh S, Jørgensen T, Jukema JW, Juonala M, Kanoni S, Karaleftheri M, Khaw KT, Kinnunen L, Kittner SJ, Koenig W, Kolcic I, Kovacs P, Krarup NT, Kratzer W, Krüger J, Kuh D, Kumari M, Kyriakou T, Langenberg C, Lannfelt L, Lanzani C, Lotay V, Launer LJ, Leander K, Lindström J, Linneberg A, Liu YP, Lobbens S, Luben R, Lyssenko V, Männistö S, Magnusson PK, McArdle WL, Menni C, Merger S, Milani L, Montgomery GW, Morris AP, Narisu N, Nelis M, Ong KK, Palotie A, Pérusse L, Pichler I, Pilia MG, Pouta A, Rheinberger M, Ribel-Madsen R, Richards M, Rice KM, Rice TK, Rivolta C, Salomaa V, Sanders AR, Sarzynski MA, Scholtens S, Scott RA, Scott WR, Sebert S, Sengupta S, Sennblad B, Seufferlein T, Silveira A, Slagboom PE, Smit JH, Sparsø TH, Stirrups K, Stolk RP, Stringham HM, Swertz MA, Swift AJ, Syvänen AC, Tan ST, Thorand B, Tönjes A, Tremblay A, Tsafantakis E, van der Most PJ, Völker U, Vohl MC, Vonk JM, Waldenberger M, Walker RW, Wennauer R, Widén E, Willemsen G, Wilsgaard T, Wright AF, Zillikens MC, van Dijk SC, van Schoor NM, Asselbergs FW, de Bakker PI, Beckmann JS, Beilby J, Bennett DA, Bergman RN, Bergmann S, Böger CA, Boehm BO, Boerwinkle E, Boomsma DI, Bornstein SR, Bottinger EP, Bouchard C, Chambers JC, Chanock SJ, Chasman DI, Cucca F, Cusi D, Dedoussis G, Erdmann J, Eriksson JG, Evans DA, de Faire U, Farrall M, Ferrucci L, Ford I, Franke L, Franks PW, Froguel P, Gansevoort RT, Gieger C, Grönberg H, Gudnason V, Gyllensten U, Hall P, Hamsten A, van der Harst P, Hayward C, Heliövaara M, Hengstenberg C, Hicks AA, Hingorani A, Hofman A, Hu F, Huikuri HV, Hveem K, James AL, Jordan JM, Jula A, Kähönen M, Kajantie E, Kathiresan S, Kiemeney LA, Kivimaki M, Knekt PB, Koistinen HA, Kooner JS, Koskinen S, Kuusisto J, Maerz W, Martin NG, Laakso M, Lakka TA, Lehtimäki T, Lettre G, Levinson DF, Lind L, Lokki ML, Mäntyselkä P, Melbye M, Metspalu A, Mitchell BD, Moll FL, Murray JC, Musk AW, Nieminen MS, Njølstad I, Ohlsson C, Oldehinkel AJ, Oostra BA, Palmer LJ, Pankow JS, Pasterkamp G, Pedersen NL, Pedersen O, Penninx BW, Perola M, Peters A, Polašek O, Pramstaller PP, Psaty BM, Qi L, Quertermous T, Raitakari OT, Rankinen T, Rauramaa R, Ridker PM, Rioux JD, Rivadeneira F, Rotter JI, Rudan I, den Ruijter HM, Saltevo J, Sattar N, Schunkert H, Schwarz PE, Shuldiner AR, Sinisalo J, Snieder H, Sørensen TI, Spector TD, Staessen JA, Stefania B, Thorsteinsdottir U, Stumvoll M, Tardif JC, Tremoli E, Tuomilehto J, Uitterlinden AG, Uusitupa M, Verbeek AL, Vermeulen SH, Viikari JS, Vitart V, Völzke H, Vollenweider P, Waeber G, Walker M, Wallaschofski H, Wareham NJ, Watkins H, Zeggini E, Chakravarti A, Clegg DJ, Cupples LA, Gordon-Larsen P, Jaquish CE, Rao DC, Abecasis GR, Assimes TL, Barroso I, Berndt SI, Boehnke M, Deloukas P, Fox CS, Groop LC, Hunter DJ, Ingelsson E, Kaplan RC, McCarthy MI, Mohlke KL, O'Connell JR, Schlessinger D, Strachan DP, Stefansson K, van Duijn CM, Hirschhorn JN, Lindgren CM, Heid IM, North KE, Borecki IB, Kutalik Z, and Loos RJ

Abstract

[This corrects the article DOI: 10.1371/journal.pgen.1005378.].

Published
2016
Full Text
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14. The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.

Author

Winkler TW, Justice AE, Graff M, Barata L, Feitosa MF, Chu S, Czajkowski J, Esko T, Fall T, Kilpeläinen TO, Lu Y, Mägi R, Mihailov E, Pers TH, Rüeger S, Teumer A, Ehret GB, Ferreira T, Heard-Costa NL, Karjalainen J, Lagou V, Mahajan A, Neinast MD, Prokopenko I, Simino J, Teslovich TM, Jansen R, Westra HJ, White CC, Absher D, Ahluwalia TS, Ahmad S, Albrecht E, Alves AC, Bragg-Gresham JL, de Craen AJ, Bis JC, Bonnefond A, Boucher G, Cadby G, Cheng YC, Chiang CW, Delgado G, Demirkan A, Dueker N, Eklund N, Eiriksdottir G, Eriksson J, Feenstra B, Fischer K, Frau F, Galesloot TE, Geller F, Goel A, Gorski M, Grammer TB, Gustafsson S, Haitjema S, Hottenga JJ, Huffman JE, Jackson AU, Jacobs KB, Johansson Å, Kaakinen M, Kleber ME, Lahti J, Mateo Leach I, Lehne B, Liu Y, Lo KS, Lorentzon M, Luan J, Madden PA, Mangino M, McKnight B, Medina-Gomez C, Monda KL, Montasser ME, Müller G, Müller-Nurasyid M, Nolte IM, Panoutsopoulou K, Pascoe L, Paternoster L, Rayner NW, Renström F, Rizzi F, Rose LM, Ryan KA, Salo P, Sanna S, Scharnagl H, Shi J, Smith AV, Southam L, Stančáková A, Steinthorsdottir V, Strawbridge RJ, Sung YJ, Tachmazidou I, Tanaka T, Thorleifsson G, Trompet S, Pervjakova N, Tyrer JP, Vandenput L, van der Laan SW, van der Velde N, van Setten J, van Vliet-Ostaptchouk JV, Verweij N, Vlachopoulou E, Waite LL, Wang SR, Wang Z, Wild SH, Willenborg C, Wilson JF, Wong A, Yang J, Yengo L, Yerges-Armstrong LM, Yu L, Zhang W, Zhao JH, Andersson EA, Bakker SJ, Baldassarre D, Banasik K, Barcella M, Barlassina C, Bellis C, Benaglio P, Blangero J, Blüher M, Bonnet F, Bonnycastle LL, Boyd HA, Bruinenberg M, Buchman AS, Campbell H, Chen YD, Chines PS, Claudi-Boehm S, Cole J, Collins FS, de Geus EJ, de Groot LC, Dimitriou M, Duan J, Enroth S, Eury E, Farmaki AE, Forouhi NG, Friedrich N, Gejman PV, Gigante B, Glorioso N, Go AS, Gottesman O, Gräßler J, Grallert H, Grarup N, Gu YM, Broer L, Ham AC, Hansen T, Harris TB, Hartman CA, Hassinen M, Hastie N, Hattersley AT, Heath AC, Henders AK, Hernandez D, Hillege H, Holmen O, Hovingh KG, Hui J, Husemoen LL, Hutri-Kähönen N, Hysi PG, Illig T, De Jager PL, Jalilzadeh S, Jørgensen T, Jukema JW, Juonala M, Kanoni S, Karaleftheri M, Khaw KT, Kinnunen L, Kittner SJ, Koenig W, Kolcic I, Kovacs P, Krarup NT, Kratzer W, Krüger J, Kuh D, Kumari M, Kyriakou T, Langenberg C, Lannfelt L, Lanzani C, Lotay V, Launer LJ, Leander K, Lindström J, Linneberg A, Liu YP, Lobbens S, Luben R, Lyssenko V, Männistö S, Magnusson PK, McArdle WL, Menni C, Merger S, Milani L, Montgomery GW, Morris AP, Narisu N, Nelis M, Ong KK, Palotie A, Pérusse L, Pichler I, Pilia MG, Pouta A, Rheinberger M, Ribel-Madsen R, Richards M, Rice KM, Rice TK, Rivolta C, Salomaa V, Sanders AR, Sarzynski MA, Scholtens S, Scott RA, Scott WR, Sebert S, Sengupta S, Sennblad B, Seufferlein T, Silveira A, Slagboom PE, Smit JH, Sparsø TH, Stirrups K, Stolk RP, Stringham HM, Swertz MA, Swift AJ, Syvänen AC, Tan ST, Thorand B, Tönjes A, Tremblay A, Tsafantakis E, van der Most PJ, Völker U, Vohl MC, Vonk JM, Waldenberger M, Walker RW, Wennauer R, Widén E, Willemsen G, Wilsgaard T, Wright AF, Zillikens MC, van Dijk SC, van Schoor NM, Asselbergs FW, de Bakker PI, Beckmann JS, Beilby J, Bennett DA, Bergman RN, Bergmann S, Böger CA, Boehm BO, Boerwinkle E, Boomsma DI, Bornstein SR, Bottinger EP, Bouchard C, Chambers JC, Chanock SJ, Chasman DI, Cucca F, Cusi D, Dedoussis G, Erdmann J, Eriksson JG, Evans DA, de Faire U, Farrall M, Ferrucci L, Ford I, Franke L, Franks PW, Froguel P, Gansevoort RT, Gieger C, Grönberg H, Gudnason V, Gyllensten U, Hall P, Hamsten A, van der Harst P, Hayward C, Heliövaara M, Hengstenberg C, Hicks AA, Hingorani A, Hofman A, Hu F, Huikuri HV, Hveem K, James AL, Jordan JM, Jula A, Kähönen M, Kajantie E, Kathiresan S, Kiemeney LA, Kivimaki M, Knekt PB, Koistinen HA, Kooner JS, Koskinen S, Kuusisto J, Maerz W, Martin NG, Laakso M, Lakka TA, Lehtimäki T, Lettre G, Levinson DF, Lind L, Lokki ML, Mäntyselkä P, Melbye M, Metspalu A, Mitchell BD, Moll FL, Murray JC, Musk AW, Nieminen MS, Njølstad I, Ohlsson C, Oldehinkel AJ, Oostra BA, Palmer LJ, Pankow JS, Pasterkamp G, Pedersen NL, Pedersen O, Penninx BW, Perola M, Peters A, Polašek O, Pramstaller PP, Psaty BM, Qi L, Quertermous T, Raitakari OT, Rankinen T, Rauramaa R, Ridker PM, Rioux JD, Rivadeneira F, Rotter JI, Rudan I, den Ruijter HM, Saltevo J, Sattar N, Schunkert H, Schwarz PE, Shuldiner AR, Sinisalo J, Snieder H, Sørensen TI, Spector TD, Staessen JA, Stefania B, Thorsteinsdottir U, Stumvoll M, Tardif JC, Tremoli E, Tuomilehto J, Uitterlinden AG, Uusitupa M, Verbeek AL, Vermeulen SH, Viikari JS, Vitart V, Völzke H, Vollenweider P, Waeber G, Walker M, Wallaschofski H, Wareham NJ, Watkins H, Zeggini E, Chakravarti A, Clegg DJ, Cupples LA, Gordon-Larsen P, Jaquish CE, Rao DC, Abecasis GR, Assimes TL, Barroso I, Berndt SI, Boehnke M, Deloukas P, Fox CS, Groop LC, Hunter DJ, Ingelsson E, Kaplan RC, McCarthy MI, Mohlke KL, O'Connell JR, Schlessinger D, Strachan DP, Stefansson K, van Duijn CM, Hirschhorn JN, Lindgren CM, Heid IM, North KE, Borecki IB, Kutalik Z, and Loos RJ

Subjects
Adult, Age Factors, Aged, Chromosome Mapping, Female, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Sex Characteristics, Waist-Hip Ratio, White People, Body Mass Index, Body Size genetics, Genetic Predisposition to Disease, Genome-Wide Association Study
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<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.

Published
2015
Full Text
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