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1. 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
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2. The role of polygenic susceptibility to obesity among carriers of pathogenic mutations in MC4R in the UK Biobank population.

Author

Chami, Nathalie, Preuss, Michael, Walker, Ryan W., Moscati, Arden, and Loos, Ruth J. F.

Subjects
REGULATION of body weight, BODY composition, MELANOCORTIN receptors, OBESITY, NON-communicable diseases, BODY mass index, RESEARCH, GENETIC mutation, BODY weight, TISSUE banks, RESEARCH methodology, CELL receptors, EVALUATION research, MEDICAL cooperation, GENETIC carriers, COMPARATIVE studies, DISEASE susceptibility, RESEARCH funding, PHENOTYPES
Abstract

Background: Melanocortin 4 receptor (MC4R) deficiency, caused by mutations in MC4R, is the most common cause of monogenic forms of obesity. However, these mutations have often been identified in small-scale, case-focused studies. Here, we assess the penetrance of previously reported MC4R mutations at a population level. Furthermore, we examine why some carriers of pathogenic mutations remain of normal weight, to gain insight into the mechanisms that control body weight.Methods and Findings: We identified 59 known obesity-increasing mutations in MC4R from the Human Gene Mutation Database (HGMD) and Clinvar. We assessed their penetrance and effect on obesity (body mass index [BMI] ≥ 30 kg/m2) in >450,000 individuals (age 40-69 years) of the UK Biobank, a population-based cohort study. Of these 59 mutations, only 11 had moderate-to-high penetrance and increased the odds of obesity by more than 2-fold. We subsequently focused on these 11 mutations and examined differences between carriers of normal weight and carriers with obesity. Twenty-eight of the 182 carriers of these 11 mutations were of normal weight. Body composition of carriers of normal weight was similar to noncarriers of normal weight, whereas among individuals with obesity, carriers had a somewhat higher BMI than noncarriers (1.44 ± 0.07 standard deviation scores [SDSs] ± standard error [SE] versus 1.29 ± 0.001, P = 0.03), because of greater lean mass (1.44 ± 0.09 versus 1.15 ± 0.002, P = 0.002). Carriers of normal weight more often reported that, already at age 10 years, their body size was below average or average (72%) compared with carriers with obesity (48%) (P = 0.01). To assess the polygenic contribution to body weight in carriers of normal weight and carriers with obesity, we calculated a genome-wide polygenic risk score for BMI (PRSBMI). The PRSBMI of carriers of normal weight (PRSBMI = -0.64 ± 0.18) was significantly lower than of carriers with obesity (0.40 ± 0.11; P = 1.7 × 10-6), and tended to be lower than that of noncarriers of normal weight (-0.29 ± 0.003; P = 0.05). Among carriers, those with a low PRSBMI (bottom quartile) have an approximately 5-kg/m2 lower BMI (approximately 14 kg of body weight for a 1.7-m-tall person) than those with a high PRS (top quartile). Because the UK Biobank population is healthier than the general population in the United Kingdom, penetrance may have been somewhat underestimated.Conclusions: We showed that large-scale data are needed to validate the impact of mutations observed in small-scale and case-focused studies. Furthermore, we observed that despite the key role of MC4R in obesity, the effects of pathogenic MC4R mutations may be countered, at least in part, by a low polygenic risk potentially representing other innate mechanisms implicated in body weight regulation. [ABSTRACT FROM AUTHOR]

Published
2020
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3. Genetic and Clinical Markers of Elevated Liver Fat Content in Overweight and Obese Hispanic Children

Author

Walker, Ryan W., Sinatra, Frank, Hartiala, Jaana, Weigensberg, Marc, Spruijt-Metz, Donna, Alderete, Tanya L., Goran, Michael I., and Allayee, Hooman

Subjects
Blood Glucose, Male, obesity, Adolescent, Genotype, Hispanic, genetic risk, Polymorphism, Single Nucleotide, Article, Body Mass Index, Non-alcoholic Fatty Liver Disease, Risk Factors, NAFLD, Humans, Aspartate Aminotransferases, Child, Alleles, Triglycerides, Apolipoprotein C-III, Anthropometry, Membrane Proteins, Alanine Transaminase, Hispanic or Latino, Lipase, liver fat, Overweight, Fatty Liver, Cross-Sectional Studies, Body Composition, Female
Abstract

Objective Genetic variation in six genes has been associated with elevated liver fat and nonalcoholic fatty liver disease in adults. We sought to determine the influence of these genes on liver fat and whether a genetic risk score (GRS) would improve upon the ability of common clinical risk factors to predict elevated liver fat content (ELF) in Hispanic children. Design and Methods 223 obese Hispanic children were genotyped for six SNPs. MRI was used to measure liver fat. A GRS was tested for association with ELF using multivariate linear regression. Predictors were assessed via ROC curves and pair-wise analysis was used to determine significance alone and combined with clinical markers. Results Only variants in PNPLA3 and APOC3 genes were associated with liver fat (p

Published
2013

4. 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 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 ALM, 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 EH, Shuldiner, Alan R, Sinisalo, Juha, Snieder, Harold, Sørensen, Thorkild IA, 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 LM, 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, arcOGEN Consortium, CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, MAGIC Consortium, Chakravarti, Aravinda, Clegg, Deborah J, Cupples, L Adrienne, Gordon-Larsen, Penny, Jaquish, Cashell E, Rao, DC, 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, Loos, Ruth JF, 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
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5. Macrophage accumulation and fibrosis in adipose tissue is linked to liver damage and metabolic risk in obese children

Author

Walker, Ryan W, Allayee, Hooman, Inserra, Alessandro, Fruhwirth, Rodolfo, Alisi, Anna, Devito, Rita, Carey, Magalie E, Sinatra, Frank, Goran, Michael I, and Nobili, Valerio

Subjects
Blood Glucose, Liver Cirrhosis, Male, Adolescent, Intra-Abdominal Fat, Article, Body Mass Index, Risk Factors, Humans, Insulin, Aspartate Aminotransferases, Obesity, Prospective Studies, Child, Adiposity, Interleukin-6, Tumor Necrosis Factor-alpha, Macrophages, Body Weight, Alanine Transaminase, Fasting, Body Height, Subcutaneous Fat, Abdominal, C-Reactive Protein, Diabetes Mellitus, Type 2, Liver, Female, Adiponectin, Biomarkers
Abstract

Obesity in childhood is associated with an inflammatory state in adipose tissue and liver, which elevates risk for diabetes and liver disease. No prior study has examined associations between pathologies occurring in adipose tissue and liver to identify elements of tissue damage associated with type 2 diabetes risk. This study sought to determine whether inflammation and fibrosis in abdominal subcutaneous adipose tissue (SAT) in obese/overweight children (BMI-z 2.3 ± 0.76) was related to the extent of observed liver disease or type 2 diabetes risk.Biopsy samples of abdominal (SAT) and liver were simultaneously collected from 33 Italian children (mean BMI 28.1 ± 5.1 kg/m(2) and mean age 11.6 ± 2.2 years) with confirmed NAFLD. Histology and immunohistochemistry were conducted on biopsies to assess inflammation and fibrosis in adipose tissue and fibrosis and inflammation in liver.Presence vs. absence of crown-like structures (CLS) in SAT was significantly related to liver fibrosis scores (1.7 ± 0.7 vs. 1.2 ± 0.7, P = 0.04) independent of BMI. SAT fibrosis was significantly correlated with a lower disposition index (r = -0.48, P = 0.006). No other adipose measures were associated with liver disease parameters.Markers of subcutaneous white adipose tissue inflammation are associated with greater extent of liver fibrosis independent of obesity and SAT fibrosis may contribute to diabetes risk through reduced insulin secretion.

Published
2014

6. The Association of Human Apolipoprotein C-III Sialylation Proteoforms with Plasma Triglycerides.

Author

Yassine, Hussein N., Trenchevska, Olgica, Ramrakhiani, Ambika, Parekh, Aarushi, Koska, Juraj, Walker, Ryan W., Billheimer, Dean, Reaven, Peter D., Yen, Frances T., Nelson, Randall W., Goran, Michael I., and Nedelkov, Dobrin

Subjects
APOLIPOPROTEIN C, TRIGLYCERIDES, BLOOD plasma, BODY mass index, IMMUNOASSAY
Abstract

Introduction: Apolipoprotein C-III (apoC-III) regulates triglyceride (TG) metabolism. In plasma, apoC-III exists in non-sialylated (apoC-III0a without glycosylation and apoC-III0b with glycosylation), monosialylated (apoC-III1) or disialylated (apoC-III2) proteoforms. Our aim was to clarify the relationship between apoC-III sialylation proteoforms with fasting plasma TG concentrations. Methods: In 204 non-diabetic adolescent participants, the relative abundance of apoC-III plasma proteoforms was measured using mass spectrometric immunoassay. Results: Compared with the healthy weight subgroup (n = 16), the ratios of apoC-III0a, apoC-III0b, and apoC-III1 to apoC-III2 were significantly greater in overweight (n = 33) and obese participants (n = 155). These ratios were positively correlated with BMI z-scores and negatively correlated with measures of insulin sensitivity (Si). The relationship of apoC-III1 / apoC-III2 with Si persisted after adjusting for BMI (p = 0.02). Fasting TG was correlated with the ratio of apoC-III0a / apoC-III2 (r = 0.47, p<0.001), apoC-III0b / apoC-III2 (r = 0.41, p<0.001), apoC-III1 / apoC-III2 (r = 0.43, p<0.001). By examining apoC-III concentrations, the association of apoC-III proteoforms with TG was driven by apoC-III0a (r = 0.57, p<0.001), apoC-III0b (r = 0.56. p<0.001) and apoC-III1 (r = 0.67, p<0.001), but not apoC-III2 (r = 0.006, p = 0.9) concentrations, indicating that apoC-III relationship with plasma TG differed in apoC-III2 compared with the other proteoforms. Conclusion: We conclude that apoC-III0a, apoC-III0b, and apoC-III1, but not apoC- III2 appear to be under metabolic control and associate with fasting plasma TG. Measurement of apoC-III proteoforms can offer insights into the biology of TG metabolism in obesity. [ABSTRACT FROM AUTHOR]

Published
2015
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7. 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 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 ALM, 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 EH, Shuldiner, Alan R, Sinisalo, Juha, Snieder, Harold, Sørensen, Thorkild IA, 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 LM, 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, CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, MAGIC Consortium, Chakravarti, Aravinda, Clegg, Deborah J, Cupples, L Adrienne, Gordon-Larsen, Penny, Jaquish, Cashell E, Rao, DC, 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 JF

Subjects
Adult, Male, Sex Characteristics, Waist-Hip Ratio, Age Factors, Chromosome Mapping, Middle Aged, Polymorphism, Single Nucleotide, White People, 3. Good health, Body Mass Index, Body Size, Humans, Female, Genetic Predisposition to Disease, Aged, 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

8. A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Author

Niina Eklund, Robert C. Kaplan, Niek Verweij, Marcus Richards, Nancy L. Heard-Costa, Angelo Tremblay, Lu Qi, Andres Metspalu, Mark A. Sarzynski, Charleston W. K. Chiang, Tõnu Esko, Jaana Lindström, Pirro G. Hysi, Torben Hansen, James F. Wilson, Serena Sanna, Marie-Claude Vohl, Lynda M. Rose, Daniele Cusi, Megan T. Smith, Anne U. Jackson, Jing Hua Zhao, Anubha Mahajan, Nele Friedrich, Marcel Bruinenberg, Lori L. Bonnycastle, Ilja M. Nolte, Timothy M. Frayling, Weihua Zhang, Lavinia Paternoster, Jenny van Dongen, Torben Jørgensen, Aarno Palotie, Jana V. van Vliet-Ostaptchouk, Martin Farrall, Konstantin Strauch, Jan Smit, Zoltán Kutalik, Anne E. Justice, Elisabeth Widen, Tuomo Rankinen, Timo A. Lakka, Maria Dimitriou, Louis Pérusse, Peter J. van der Most, Yun Ju Sung, George Dedoussis, Caroline Hayward, Tom Wilsgaard, Peter P. Pramstaller, Maria Karaleftheri, Seppo Koskinen, Clive Osmond, Panos Deloukas, David J. Hunter, Kathleen Stirrups, Nicola Glorioso, Andrew T. Hattersley, Hugh Watkins, Sven Bergmann, Eric Boerwinkle, Catharina A. Hartman, Anke Tönjes, Daniel I. Chasman, May E. Montasser, Alan James, Ben A. Oostra, Nigel W. Rayner, Massimo Mangino, Ron T. Gansevoort, Cristina Barlassina, Johanna Kuusisto, Andrew A. Hicks, Roberto Lorbeer, Tomi Laitinen, Narisu Narisu, Stefan R. Bornstein, Gemma Cadby, Johan G. Eriksson, Gudmar Thorleifsson, Erika Salvi, Jari Lahti, Cornelia M. van Duijn, Janina M. Jeff, Heather M. Stringham, Bruce M. Psaty, Thomas W. Winkler, Paul M. Ridker, Unnur Thorsteinsdottir, Lyle J. Palmer, Alexander Teumer, Jürgen Gräßler, Allan Linneberg, Francesca D'Avila, Markku Heliövaara, Harald Grallert, Ivana Kolcic, Kari E. North, Eleftheria Zeggini, James S. Pankow, Alena Standáková, Marjo-Riitta Järvelin, Ozren Polasek, Krista Fischer, Valeriya Lyssenko, Thorkild I. A. Sørensen, André G. Uitterlinden, Stavroula Kanoni, Caroline S. Fox, Sophie R. Wang, Treva Rice, Maria Grazia Pilia, Olli T. Raitakari, Claudia Langenberg, Thomas Sparsø, Emmanouil Tsafantakis, Irene Pichler, Kathy Ryan, Eero Jokinen, Mika Kähönen, Leif Groop, Irene Mateo Leach, Gabriele Müller, Annette Peters, Peter Vollenweider, Oddgeir L. Holmen, David Schlessinger, Paul Knekt, M. Carola Zillikens, Evelin Mihailov, Erkki Vartiainen, Nicholas J. Wareham, Francis S. Collins, Sirkka Keinänen-Kiukaanniemi, Mark I. McCarthy, Joel N. Hirschhorn, Frank B. Hu, Janina S. Ried, Valgerdur Steinthorsdottir, Shapour Jalilzadeh, Peter Kovacs, Anuj Goel, Pim van der Harst, Peter Schwarz, Mathias Gorski, Jorma Viikari, Uwe Völker, Cecilia M. Lindgren, Theodosios Kyriakou, Morris A. Swertz, Inga Prokopenko, Ken K. Ong, Leena Kinnunen, Markus Perola, Kristian Hveem, Matthias Blüher, Rebecca Mills, Albertine J. Oldehinkel, Anders Hamsten, Mattias Lorentzon, Joel Eriksson, Karen L. Mohlke, Rasmus Ribel-Madsen, Pekka Jousilahti, Paolo Manunta, Eva Albrecht, Jeffrey R. O'Connell, Wendy L. McArdle, Amy J. Swift, Dorret I. Boomsma, Harry Campbell, Fracensco Cucca, Aaron Isaacs, Andrew Wong, Georg Homuth, Laura M. Yerges-Armstrong, Carolina Medina-Gomez, Kay-Tee Khaw, Claes Ohlsson, Claude Bouchard, John Blangero, Aliki-Eleni Farmaki, Lorraine Southam, Anette P. Gjesing, Traci M. Bartz, Dabeeru C. Rao, Andrew P. Morris, David P. Strachan, Nita G. Forouhi, Eco J. C. de Geus, Jaakko Tuomilehto, Antti Jula, Ryan W. Walker, Mary F. Feitosa, Reedik Mägi, Aki S. Havulinna, Inger Njølstad, Alan R. Shudiner, Jennifer E. Huffman, Peter Lichtner, Richard N. Bergman, Mariaelisa Graff, Diana Kuh, Tim D. Spector, Robert Luben, Veikko Salomaa, Christian Gieger, Jaspal S. Kooner, Teresa Ferreira, Jennifer L. Bragg-Gresham, Sylvain Sebert, Terho Lehtimäki, Heikki A. Koistinen, Alexandra M. Lewin, Alexessander Couto Alves, Peter S. Chines, Lise Lotte N. Husemoen, Salome Scholtens, Yii-Der Ida Chen, Kati Kristiansson, Barbara McKnight, Sara M. Willems, Rainer Rauramaa, Satu Männistö, Stephan J. L. Bakker, Angela Döring, Audrey Y. Chu, Niels Grarup, Matti Uusitupa, Hannu Puolijoki, L. Adrienne Cupples, Veronique Vitart, Marie Neergaard Harder, Jouke-Jan Hottenga, Kari Stefansson, Alan F. Wright, Igor Rudan, Keri L. Monda, Jian'an Luan, Robert A. Scott, Albert Hofman, Tarunveer S. Ahluwalia, Liesbeth Vandenput, Maija Hassinen, Sarah H. Wild, Iris M. Heid, Brenda W.J.H. Penninx, John C. Chambers, Claire Bellis, Nicholas D. Hastie, Ruth J. F. Loos, Martina Müller-Nurasyid, Johanne Marie Justesen, Gérard Waeber, Jennie Hui, Gonçalo R. Abecasis, Ishminder K. Kooner, Harold Snieder, Judith M. Vonk, Ioanna Tachmazidou, Ronald P. Stolk, Michael Stumvoll, Till Ittermann, Oluf Pedersen, Ingrid B. Borecki, Gonneke Willemsen, Jagvir Grewal, Markku Laakso, Arthur W. Musk, Eero Kajantie, Hans L. Hillege, Michael Boehnke, Cristina Venturini, Lili Milani, John Beilby, Fernando Rivadeneira, Biochemie, RS: FHML MaCSBio, RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, Goel, Anuj [0000-0003-2307-4021], Jackson, Anne U [0000-0002-9672-2547], Kristiansson, Kati [0000-0003-4688-107X], Medina-Gomez, Carolina [0000-0001-7999-5538], Nolte, Ilja M [0000-0001-5047-4077], Prokopenko, Inga [0000-0003-1624-7457], Teumer, Alexander [0000-0002-8309-094X], Wong, Andrew [0000-0003-2079-4779], Beilby, John [0000-0002-4915-2254], Bergmann, Sven [0000-0002-6785-9034], Strachan, David P [0000-0001-7854-1366], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Groningen Energy & Sustainability Programme, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), Center for Liver, Digestive and Metabolic Diseases (CLDM), Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Children's Hospital, Lastentautien yksikkö, Clinicum, Institute for Molecular Medicine Finland, Behavioural Sciences, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Department of Medicine, Endokrinologian yksikkö, Aarno Palotie / Principal Investigator, Elisabeth Ingrid Maria Widen / Principal Investigator, University of Helsinki, Leif Groop Research Group, Quantitative Genetics, HUS Children and Adolescents, Developmental Psychology Research Group, Complex Disease Genetics, Genomics of Neurological and Neuropsychiatric Disorders, Genomic Discoveries and Clinical Translation, School of Medicine / Clinical Medicine, School of Medicine / Biomedicine,School of Medicine / Clinical Nutrition, Ried, Janina S., Jeff, Janina M., Chu, Audrey Y., Bragg Gresham, Jennifer L., Van Dongen, Jenny, Huffman, Jennifer E., Ahluwalia, Tarunveer S., Cadby, Gemma, Eklund, Niina, Eriksson, Joel, Esko, Toñu, Feitosa, Mary F., Goel, Anuj, Gorski, Mathia, Hayward, Caroline, Heard Costa, Nancy L., Jackson, Anne U., Jokinen, Eero, Kanoni, Stavroula, Kristiansson, Kati, Kutalik, Zoltán, Lahti, Jari, Luan, Jian'An, Mägi, Reedik, Mahajan, Anubha, Mangino, Massimo, Medina Gomez, Carolina, Monda, Keri L., Nolte, Ilja M., Pérusse, Loui, Prokopenko, Inga, Qi, Lu, Rose, Lynda M., Salvi, Erika, Smith, Megan T., Snieder, Harold, Standáková, Alena, Ju Sung, Yun, Tachmazidou, Ioanna, Teumer, Alexander, Thorleifsson, Gudmar, Van Der Harst, Pim, Walker, Ryan W., Wang, Sophie R., Wild, Sarah H., Willems, Sara M., Wong, Andrew, Zhang, Weihua, Albrecht, Eva, Couto Alves, Alexessander, Bakker, Stephan J. L., Barlassina, Cristina, Bartz, Traci M., Beilby, John, Bellis, Claire, Bergman, Richard N., Bergmann, Sven, Blangero, John, Blüher, Matthia, Boerwinkle, Eric, Bonnycastle, Lori L., Bornstein, Stefan R., Bruinenberg, Marcel, Campbell, Harry, Chen, Yii Der Ida, Chiang, Charleston W. K., Chines, Peter S., Collins, Francis S, Cucca, Fracensco, Cupples, L. Adrienne, D'Avila, Francesca, De Geus, Eco J. C., Dedoussis, George, Dimitriou, Maria, Döring, Angela, Eriksson, Johan G., Farmaki, Aliki Eleni, Farrall, Martin, Ferreira, Teresa, Fischer, Krista, Forouhi, Nita G., Friedrich, Nele, Gjesing, Anette Prior, Glorioso, Nicola, Graff, Mariaelisa, Grallert, Harald, Grarup, Niel, Gräßler, Jürgen, Grewal, Jagvir, Hamsten, Ander, Harder, Marie Neergaard, Hartman, Catharina A., Hassinen, Maija, Hastie, Nichola, Hattersley, Andrew Tym, Havulinna, Aki S., Heliövaara, Markku, Hillege, Han, Hofman, Albert, Holmen, Oddgeir, Homuth, Georg, Hottenga, Jouke Jan, Hui, Jennie, Husemoen, Lise Lotte, Hysi, Pirro G., Isaacs, Aaron, Ittermann, Till, Jalilzadeh, Shapour, James, Alan L., Jørgensen, Torben, Jousilahti, Pekka, Jula, Antti, Marie Justesen, Johanne, Justice, Anne E., Kähönen, Mika, Karaleftheri, Maria, Tee Khaw, Kay, Keinanen Kiukaanniemi, Sirkka M., Kinnunen, Leena, Knekt, Paul B., Koistinen, Heikki A., Kolcic, Ivana, Kooner, Ishminder K., Koskinen, Seppo, Kovacs, Peter, Kyriakou, Theodosio, Laitinen, Tomi, Langenberg, Claudia, Lewin, Alexandra M., Lichtner, Peter, Lindgren, Cecilia M., Lindström, Jaana, Linneberg, Allan, Lorbeer, Roberto, Lorentzon, Mattia, Luben, Robert, Lyssenko, Valeriya, Männistö, Satu, Manunta, Paolo, Leach, Irene Mateo, Mcardle, Wendy L., Mcknight, Barbara, Mohlke, Karen L., Mihailov, Evelin, Milani, Lili, Mills, Rebecca, Montasser, May E., Morris, Andrew P., Müller, Gabriele, Musk, Arthur W., Narisu, Narisu, Ong, Ken K., Oostra, Ben A., Osmond, Clive, Palotie, Aarno, Pankow, James S., Paternoster, Lavinia, Penninx, Brenda W., Pichler, Irene, Pilia, Maria G., Polašek, Ozren, Pramstaller, Peter P., Raitakari, Olli T, Rankinen, Tuomo, Rao, D. C., Rayner, Nigel W., Ribel Madsen, Rasmu, Rice, Treva K., Richards, Marcu, Ridker, Paul M., Rivadeneira, Fernando, Ryan, Kathy A., Sanna, Serena, Sarzynski, Mark A., Scholtens, Salome, Scott, Robert A., Sebert, Sylvain, Southam, Lorraine, Sparsø, Thomas Hempel, Steinthorsdottir, Valgerdur, Stirrups, Kathleen, Stolk, Ronald P., Strauch, Konstantin, Stringham, Heather M., Swertz, Morris A., Swift, Amy J., Tönjes, Anke, Tsafantakis, Emmanouil, Van Der Most, Peter J., Van Vliet Ostaptchouk, Jana V., Vandenput, Liesbeth, Vartiainen, Erkki, Venturini, Cristina, Verweij, Niek, Viikari, Jorma S., Vitart, Veronique, Vohl, Marie Claude, Vonk, Judith M., Waeber, Gérard, Widén, Elisabeth, Willemsen, Gonneke, Wilsgaard, Tom, Winkler, Thomas W., Wright, Alan F., Yerges Armstrong, Laura M., Zhao, Jing Hua, Carola Zillikens, M., Boomsma, Dorret I., Bouchard, Claude, Chambers, John C., Chasman, Daniel I., Cusi, Daniele, Gansevoort, Ron T., Gieger, Christian, Hansen, Torben, Hicks, Andrew A., Hu, Frank, Hveem, Kristian, Jarvelin, Marjo Riitta, Kajantie, Eero, Kooner, Jaspal S., Kuh, Diana, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A., Lehtimäki, Terho, Metspalu, Andre, Njølstad, Inger, Ohlsson, Clae, Oldehinkel, Albertine J., Palmer, Lyle J., Pedersen, Oluf, Perola, Marku, Peters, Annette, Psaty, Bruce M., Puolijoki, Hannu, Rauramaa, Rainer, Rudan, Igor, Salomaa, Veikko, Schwarz, Peter E. H., Shudiner, Alan R., Smit, Jan H., Sørensen, Thorkild I. A., Spector, Timothy D., Stefansson, Kari, Stumvoll, Michael, Tremblay, Angelo, Tuomilehto, Jaakko, Uitterlinden, André G., Uusitupa, Matti, Völker, Uwe, Vollenweider, Peter, Wareham, Nicholas J., Watkins, Hugh, Wilson, James F., Zeggini, Eleftheria, Abecasis, Goncalo R., Boehnke, Michael, Borecki, Ingrid B., Deloukas, Pano, Van Duijn, Cornelia M., Fox, Caroline, Groop, Leif C., Heid, Iris M., Hunter, David J., Kaplan, Robert C., Mccarthy, Mark I., North, Kari E., O'Connell, Jeffrey R., Schlessinger, David, Thorsteinsdottir, Unnur, Strachan, David P., Frayling, Timothy, Hirschhorn, Joel N., Müller Nurasyid, Martina, Loos, Ruth J. F., Internal medicine, Psychiatry, EMGO - Mental health, Public Health, Epidemiology, Surgery, Internal Medicine, Erasmus MC other, and Child and Adolescent Psychiatry / Psychology

Subjects
0301 basic medicine, Netherlands Twin Register (NTR), Statistical methods, General Physics and Astronomy, Genome-wide association study, Genome-wide association studies, Mice, HEIGHT, Body Size, Mass index, 2. Zero hunger, Genetics, Principal Component Analysis, Multidisciplinary, VDP::Medisinske Fag: 700::Helsefag: 800::Samfunnsmedisin, sosialmedisin: 801, Anthropometry, Chemistry (all), Phenotype, Common, gene, body, shape, Multidisciplinary Sciences, Principal component analysis, Trait, Science & Technology - Other Topics, DIET-INDUCED OBESITY, Waist, Genotype, 515 Psychology, Science, EARLY-ONSET, Snp, BIOLOGY, HIP RATIO, Genome-wide association studies Statistical methods, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Physics and Astronomy (all), MASS INDEX, DISEASE ASSOCIATIONS, RESOURCE, MD Multidisciplinary, Humans, GENOME-WIDE ASSOCIATION, Biochemistry, Genetics and Molecular Biology (all), Science & Technology, Models, Genetic, ta1184, FAT DISTRIBUTION, General Chemistry, ta3121, 030104 developmental biology, 3121 General medicine, internal medicine and other clinical medicine, 3111 Biomedicine, VDP::Medical disciplines: 700::Health sciences: 800::Community medicine, Social medicine: 801, Body mass index, Genome-Wide Association Study
Abstract

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways., published version, peerReviewed

Published
2016
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