PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (300)
 

Clipboard (0)
None

Select a Filter Below

Journals
more »
Year of Publication
more »
1.  Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels 
Kilpeläinen, Tuomas O. | Carli, Jayne F. Martin | Skowronski, Alicja A. | Sun, Qi | Kriebel, Jennifer | Feitosa, Mary F | Hedman, Åsa K. | Drong, Alexander W. | Hayes, James E. | Zhao, Jinghua | Pers, Tune H. | Schick, Ursula | Grarup, Niels | Kutalik, Zoltán | Trompet, Stella | Mangino, Massimo | Kristiansson, Kati | Beekman, Marian | Lyytikäinen, Leo-Pekka | Eriksson, Joel | Henneman, Peter | Lahti, Jari | Tanaka, Toshiko | Luan, Jian'an | Greco M, Fabiola Del | Pasko, Dorota | Renström, Frida | Willems, Sara M. | Mahajan, Anubha | Rose, Lynda M. | Guo, Xiuqing | Liu, Yongmei | Kleber, Marcus E. | Pérusse, Louis | Gaunt, Tom | Ahluwalia, Tarunveer S. | Ju Sung, Yun | Ramos, Yolande F. | Amin, Najaf | Amuzu, Antoinette | Barroso, Inês | Bellis, Claire | Blangero, John | Buckley, Brendan M. | Böhringer, Stefan | I Chen, Yii-Der | de Craen, Anton J. N. | Crosslin, David R. | Dale, Caroline E. | Dastani, Zari | Day, Felix R. | Deelen, Joris | Delgado, Graciela E. | Demirkan, Ayse | Finucane, Francis M. | Ford, Ian | Garcia, Melissa E. | Gieger, Christian | Gustafsson, Stefan | Hallmans, Göran | Hankinson, Susan E. | Havulinna, Aki S | Herder, Christian | Hernandez, Dena | Hicks, Andrew A. | Hunter, David J. | Illig, Thomas | Ingelsson, Erik | Ioan-Facsinay, Andreea | Jansson, John-Olov | Jenny, Nancy S. | Jørgensen, Marit E. | Jørgensen, Torben | Karlsson, Magnus | Koenig, Wolfgang | Kraft, Peter | Kwekkeboom, Joanneke | Laatikainen, Tiina | Ladwig, Karl-Heinz | LeDuc, Charles A. | Lowe, Gordon | Lu, Yingchang | Marques-Vidal, Pedro | Meisinger, Christa | Menni, Cristina | Morris, Andrew P. | Myers, Richard H. | Männistö, Satu | Nalls, Mike A. | Paternoster, Lavinia | Peters, Annette | Pradhan, Aruna D. | Rankinen, Tuomo | Rasmussen-Torvik, Laura J. | Rathmann, Wolfgang | Rice, Treva K. | Brent Richards, J | Ridker, Paul M. | Sattar, Naveed | Savage, David B. | Söderberg, Stefan | Timpson, Nicholas J. | Vandenput, Liesbeth | van Heemst, Diana | Uh, Hae-Won | Vohl, Marie-Claude | Walker, Mark | Wichmann, Heinz-Erich | Widén, Elisabeth | Wood, Andrew R. | Yao, Jie | Zeller, Tanja | Zhang, Yiying | Meulenbelt, Ingrid | Kloppenburg, Margreet | Astrup, Arne | Sørensen, Thorkild I. A. | Sarzynski, Mark A. | Rao, D. C. | Jousilahti, Pekka | Vartiainen, Erkki | Hofman, Albert | Rivadeneira, Fernando | Uitterlinden, André G. | Kajantie, Eero | Osmond, Clive | Palotie, Aarno | Eriksson, Johan G. | Heliövaara, Markku | Knekt, Paul B. | Koskinen, Seppo | Jula, Antti | Perola, Markus | Huupponen, Risto K. | Viikari, Jorma S. | Kähönen, Mika | Lehtimäki, Terho | Raitakari, Olli T. | Mellström, Dan | Lorentzon, Mattias | Casas, Juan P. | Bandinelli, Stefanie | März, Winfried | Isaacs, Aaron | van Dijk, Ko W. | van Duijn, Cornelia M. | Harris, Tamara B. | Bouchard, Claude | Allison, Matthew A. | Chasman, Daniel I. | Ohlsson, Claes | Lind, Lars | Scott, Robert A. | Langenberg, Claudia | Wareham, Nicholas J. | Ferrucci, Luigi | Frayling, Timothy M. | Pramstaller, Peter P. | Borecki, Ingrid B. | Waterworth, Dawn M. | Bergmann, Sven | Waeber, Gérard | Vollenweider, Peter | Vestergaard, Henrik | Hansen, Torben | Pedersen, Oluf | Hu, Frank B. | Eline Slagboom, P | Grallert, Harald | Spector, Tim D. | Jukema, J.W. | Klein, Robert J. | Schadt, Erik E | Franks, Paul W. | Lindgren, Cecilia M. | Leibel, Rudolph L. | Loos, Ruth J. F.
Nature Communications  2016;7:10494.
Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10−6 in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10−8) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.
This meta-analysis of genome-wide association studies identifies four genetic loci associated with circulating leptin levels independent of adiposity. Examination in mouse adipose tissue explants provides functional support for the leptin-associated loci.
doi:10.1038/ncomms10494
PMCID: PMC4740377  PMID: 26833098
2.  Directional dominance on stature and cognition in diverse human populations 
Joshi, Peter K. | Esko, Tonu | Mattsson, Hannele | Eklund, Niina | Gandin, Ilaria | Nutile, Teresa | Jackson, Anne U. | Schurmann, Claudia | Smith, Albert V. | Zhang, Weihua | Okada, Yukinori | Stančáková, Alena | Faul, Jessica D. | Zhao, Wei | Bartz, Traci M. | Concas, Maria Pina | Franceschini, Nora | Enroth, Stefan | Vitart, Veronique | Trompet, Stella | Guo, Xiuqing | Chasman, Daniel I. | O’Connel, Jeffery R. | Corre, Tanguy | Nongmaithem, Suraj S. | Chen, Yuning | Mangino, Massimo | Ruggiero, Daniela | Traglia, Michela | Farmaki, Aliki-Eleni | Kacprowski, Tim | Bjonnes, Andrew | van der Spek, Ashley | Wu, Ying | Giri, Anil K. | Yanek, Lisa R. | Wang, Lihua | Hofer, Edith | Rietveld, Cornelius A. | McLeod, Olga | Cornelis, Marilyn C. | Pattaro, Cristian | Verweij, Niek | Baumbach, Clemens | Abdellaoui, Abdel | Warren, Helen R. | Vuckovic, Dragana | Mei, Hao | Bouchard, Claude | Perry, John R.B. | Cappellani, Stefania | Mirza, Saira S. | Benton, Miles C. | Broeckel, Ulrich | Medland, Sarah E. | Lind, Penelope A. | Malerba, Giovanni | Drong, Alexander | Yengo, Loic | Bielak, Lawrence F. | Zhi, Degui | van der Most, Peter J. | Shriner, Daniel | Mägi, Reedik | Hemani, Gibran | Karaderi, Tugce | Wang, Zhaoming | Liu, Tian | Demuth, Ilja | Zhao, Jing Hua | Meng, Weihua | Lataniotis, Lazaros | van der Laan, Sander W. | Bradfield, Jonathan P. | Wood, Andrew R. | Bonnefond, Amelie | Ahluwalia, Tarunveer S. | Hall, Leanne M. | Salvi, Erika | Yazar, Seyhan | Carstensen, Lisbeth | de Haan, Hugoline G. | Abney, Mark | Afzal, Uzma | Allison, Matthew A. | Amin, Najaf | Asselbergs, Folkert W. | Bakker, Stephan J.L. | Barr, R. Graham | Baumeister, Sebastian E. | Benjamin, Daniel J. | Bergmann, Sven | Boerwinkle, Eric | Bottinger, Erwin P. | Campbell, Archie | Chakravarti, Aravinda | Chan, Yingleong | Chanock, Stephen J. | Chen, Constance | Chen, Y.-D. Ida | Collins, Francis S. | Connell, John | Correa, Adolfo | Cupples, L. Adrienne | Smith, George Davey | Davies, Gail | Dörr, Marcus | Ehret, Georg | Ellis, Stephen B. | Feenstra, Bjarke | Feitosa, Mary F. | Ford, Ian | Fox, Caroline S. | Frayling, Timothy M. | Friedrich, Nele | Geller, Frank | Scotland, Generation | Gillham-Nasenya, Irina | Gottesman, Omri | Graff, Misa | Grodstein, Francine | Gu, Charles | Haley, Chris | Hammond, Christopher J. | Harris, Sarah E. | Harris, Tamara B. | Hastie, Nicholas D. | Heard-Costa, Nancy L. | Heikkilä, Kauko | Hocking, Lynne J. | Homuth, Georg | Hottenga, Jouke-Jan | Huang, Jinyan | Huffman, Jennifer E. | Hysi, Pirro G. | Ikram, M. Arfan | Ingelsson, Erik | Joensuu, Anni | Johansson, Åsa | Jousilahti, Pekka | Jukema, J. Wouter | Kähönen, Mika | Kamatani, Yoichiro | Kanoni, Stavroula | Kerr, Shona M. | Khan, Nazir M. | Koellinger, Philipp | Koistinen, Heikki A. | Kooner, Manraj K. | Kubo, Michiaki | Kuusisto, Johanna | Lahti, Jari | Launer, Lenore J. | Lea, Rodney A. | Lehne, Benjamin | Lehtimäki, Terho | Liewald, David C.M. | Lind, Lars | Loh, Marie | Lokki, Marja-Liisa | London, Stephanie J. | Loomis, Stephanie J. | Loukola, Anu | Lu, Yingchang | Lumley, Thomas | Lundqvist, Annamari | Männistö, Satu | Marques-Vidal, Pedro | Masciullo, Corrado | Matchan, Angela | Mathias, Rasika A. | Matsuda, Koichi | Meigs, James B. | Meisinger, Christa | Meitinger, Thomas | Menni, Cristina | Mentch, Frank D. | Mihailov, Evelin | Milani, Lili | Montasser, May E. | Montgomery, Grant W. | Morrison, Alanna | Myers, Richard H. | Nadukuru, Rajiv | Navarro, Pau | Nelis, Mari | Nieminen, Markku S. | Nolte, Ilja M. | O’Connor, George T. | Ogunniyi, Adesola | Padmanabhan, Sandosh | Palmas, Walter R. | Pankow, James S. | Patarcic, Inga | Pavani, Francesca | Peyser, Patricia A. | Pietilainen, Kirsi | Poulter, Neil | Prokopenko, Inga | Ralhan, Sarju | Redmond, Paul | Rich, Stephen S. | Rissanen, Harri | Robino, Antonietta | Rose, Lynda M. | Rose, Richard | Sala, Cinzia | Salako, Babatunde | Salomaa, Veikko | Sarin, Antti-Pekka | Saxena, Richa | Schmidt, Helena | Scott, Laura J. | Scott, William R. | Sennblad, Bengt | Seshadri, Sudha | Sever, Peter | Shrestha, Smeeta | Smith, Blair H. | Smith, Jennifer A. | Soranzo, Nicole | Sotoodehnia, Nona | Southam, Lorraine | Stanton, Alice V. | Stathopoulou, Maria G. | Strauch, Konstantin | Strawbridge, Rona J. | Suderman, Matthew J. | Tandon, Nikhil | Tang, Sian-Tsun | Taylor, Kent D. | Tayo, Bamidele O. | Töglhofer, Anna Maria | Tomaszewski, Maciej | Tšernikova, Natalia | Tuomilehto, Jaakko | Uitterlinden, Andre G. | Vaidya, Dhananjay | van Hylckama Vlieg, Astrid | van Setten, Jessica | Vasankari, Tuula | Vedantam, Sailaja | Vlachopoulou, Efthymia | Vozzi, Diego | Vuoksimaa, Eero | Waldenberger, Melanie | Ware, Erin B. | Wentworth-Shields, William | Whitfield, John B. | Wild, Sarah | Willemsen, Gonneke | Yajnik, Chittaranjan S. | Yao, Jie | Zaza, Gianluigi | Zhu, Xiaofeng | Project, The BioBank Japan | Salem, Rany M. | Melbye, Mads | Bisgaard, Hans | Samani, Nilesh J. | Cusi, Daniele | Mackey, David A. | Cooper, Richard S. | Froguel, Philippe | Pasterkamp, Gerard | Grant, Struan F.A. | Hakonarson, Hakon | Ferrucci, Luigi | Scott, Robert A. | Morris, Andrew D. | Palmer, Colin N.A. | Dedoussis, George | Deloukas, Panos | Bertram, Lars | Lindenberger, Ulman | Berndt, Sonja I. | Lindgren, Cecilia M. | Timpson, Nicholas J. | Tönjes, Anke | Munroe, Patricia B. | Sørensen, Thorkild I.A. | Rotimi, Charles N. | Arnett, Donna K. | Oldehinkel, Albertine J. | Kardia, Sharon L.R. | Balkau, Beverley | Gambaro, Giovanni | Morris, Andrew P. | Eriksson, Johan G. | Wright, Margie J. | Martin, Nicholas G. | Hunt, Steven C. | Starr, John M. | Deary, Ian J. | Griffiths, Lyn R. | Tiemeier, Henning | Pirastu, Nicola | Kaprio, Jaakko | Wareham, Nicholas J. | Pérusse, Louis | Wilson, James G. | Girotto, Giorgia | Caulfield, Mark J. | Raitakari, Olli | Boomsma, Dorret I. | Gieger, Christian | van der Harst, Pim | Hicks, Andrew A. | Kraft, Peter | Sinisalo, Juha | Knekt, Paul | Johannesson, Magnus | Magnusson, Patrik K.E. | Hamsten, Anders | Schmidt, Reinhold | Borecki, Ingrid B. | Vartiainen, Erkki | Becker, Diane M. | Bharadwaj, Dwaipayan | Mohlke, Karen L. | Boehnke, Michael | van Duijn, Cornelia M. | Sanghera, Dharambir K. | Teumer, Alexander | Zeggini, Eleftheria | Metspalu, Andres | Gasparini, Paolo | Ulivi, Sheila | Ober, Carole | Toniolo, Daniela | Rudan, Igor | Porteous, David J. | Ciullo, Marina | Spector, Tim D. | Hayward, Caroline | Dupuis, Josée | Loos, Ruth J.F. | Wright, Alan F. | Chandak, Giriraj R. | Vollenweider, Peter | Shuldiner, Alan | Ridker, Paul M. | Rotter, Jerome I. | Sattar, Naveed | Gyllensten, Ulf | North, Kari E. | Pirastu, Mario | Psaty, Bruce M. | Weir, David R. | Laakso, Markku | Gudnason, Vilmundur | Takahashi, Atsushi | Chambers, John C. | Kooner, Jaspal S. | Strachan, David P. | Campbell, Harry | Hirschhorn, Joel N. | Perola, Markus | Polašek, Ozren | Wilson, James F.
Nature  2015;523(7561):459-462.
Homozygosity has long been associated with rare, often devastating, Mendelian disorders1 and Darwin was one of the first to recognise that inbreeding reduces evolutionary fitness2. However, the effect of the more distant parental relatedness common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity, ROH), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power3,4. Here we use ROH to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts and find statistically significant associations between summed runs of homozygosity (SROH) and four complex traits: height, forced expiratory lung volume in 1 second (FEV1), general cognitive ability (g) and educational attainment (nominal p<1 × 10−300, 2.1 × 10−6, 2.5 × 10−10, 1.8 × 10−10). In each case increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing convincing evidence for the first time that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples5,6, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein (LDL) cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection7, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
doi:10.1038/nature14618
PMCID: PMC4516141  PMID: 26131930
3.  Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes 
Zeggini, Eleftheria | Scott, Laura J. | Saxena, Richa | Voight, Benjamin F. | Marchini, Jonathan L | Hu, Tainle | de Bakker, Paul IW | Abecasis, Gonçalo R | Almgren, Peter | Andersen, Gitte | Ardlie, Kristin | Boström, Kristina Bengtsson | Bergman, Richard N | Bonnycastle, Lori L | Borch-Johnsen, Knut | Burtt, Noël P | Chen, Hong | Chines, Peter S | Daly, Mark J | Deodhar, Parimal | Ding, Charles | Doney, Alex S F | Duren, William L | Elliott, Katherine S | Erdos, Michael R | Frayling, Timothy M | Freathy, Rachel M | Gianniny, Lauren | Grallert, Harald | Grarup, Niels | Groves, Christopher J | Guiducci, Candace | Hansen, Torben | Herder, Christian | Hitman, Graham A | Hughes, Thomas E | Isomaa, Bo | Jackson, Anne U | Jørgensen, Torben | Kong, Augustine | Kubalanza, Kari | Kuruvilla, Finny G | Kuusisto, Johanna | Langenberg, Claudia | Lango, Hana | Lauritzen, Torsten | Li, Yun | Lindgren, Cecilia M | Lyssenko, Valeriya | Marvelle, Amanda F | Meisinger, Christa | Midthjell, Kristian | Mohlke, Karen L | Morken, Mario A | Morris, Andrew D | Narisu, Narisu | Nilsson, Peter | Owen, Katharine R | Palmer, Colin NA | Payne, Felicity | Perry, John RB | Pettersen, Elin | Platou, Carl | Prokopenko, Inga | Qi, Lu | Qin, Li | Rayner, Nigel W | Rees, Matthew | Roix, Jeffrey J | Sandbæk, Anelli | Shields, Beverley | Sjögren, Marketa | Steinthorsdottir, Valgerdur | Stringham, Heather M | Swift, Amy J | Thorleifsson, Gudmar | Thorsteinsdottir, Unnur | Timpson, Nicholas J | Tuomi, Tiinamaija | Tuomilehto, Jaakko | Walker, Mark | Watanabe, Richard M | Weedon, Michael N | Willer, Cristen J | Illig, Thomas | Hveem, Kristian | Hu, Frank B | Laakso, Markku | Stefansson, Kari | Pedersen, Oluf | Wareham, Nicholas J | Barroso, Inês | Hattersley, Andrew T | Collins, Francis S | Groop, Leif | McCarthy, Mark I | Boehnke, Michael | Altshuler, David
Nature genetics  2008;40(5):638-645.
Genome-wide association (GWA) studies have identified multiple new genomic loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D)1-11. Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to discover loci at which common alleles have modest effects, we performed meta-analysis of three T2D GWA scans encompassing 10,128 individuals of European-descent and ~2.2 million SNPs (directly genotyped and imputed). Replication testing was performed in an independent sample with an effective sample size of up to 53,975. At least six new loci with robust evidence for association were detected, including the JAZF1 (p=5.0×10−14), CDC123/CAMK1D (p=1.2×10−10), TSPAN8/LGR5 (p=1.1×10−9), THADA (p=1.1×10−9), ADAMTS9 (p=1.2×10−8), and NOTCH2 (p=4.1×10−8) gene regions. The large number of loci with relatively small effects indicates the value of large discovery and follow-up samples in identifying additional clues about the inherited basis of T2D.
doi:10.1038/ng.120
PMCID: PMC2672416  PMID: 18372903
4.  New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism 
Horikoshi, Momoko | Yaghootkar, Hanieh | Mook-Kanamori, Dennis O. | Sovio, Ulla | Taal, H. Rob | Hennig, Branwen J. | Bradfield, Jonathan P. | St. Pourcain, Beate | Evans, David M. | Charoen, Pimphen | Kaakinen, Marika | Cousminer, Diana L. | Lehtimäki, Terho | Kreiner-Møller, Eskil | Warrington, Nicole M. | Bustamante, Mariona | Feenstra, Bjarke | Berry, Diane J. | Thiering, Elisabeth | Pfab, Thiemo | Barton, Sheila J. | Shields, Beverley M. | Kerkhof, Marjan | van Leeuwen, Elisabeth M. | Fulford, Anthony J. | Kutalik, Zoltán | Zhao, Jing Hua | den Hoed, Marcel | Mahajan, Anubha | Lindi, Virpi | Goh, Liang-Kee | Hottenga, Jouke-Jan | Wu, Ying | Raitakari, Olli T. | Harder, Marie N. | Meirhaeghe, Aline | Ntalla, Ioanna | Salem, Rany M. | Jameson, Karen A. | Zhou, Kaixin | Monies, Dorota M. | Lagou, Vasiliki | Kirin, Mirna | Heikkinen, Jani | Adair, Linda S. | Alkuraya, Fowzan S. | Al-Odaib, Ali | Amouyel, Philippe | Andersson, Ehm Astrid | Bennett, Amanda J. | Blakemore, Alexandra I.F. | Buxton, Jessica L. | Dallongeville, Jean | Das, Shikta | de Geus, Eco J. C. | Estivill, Xavier | Flexeder, Claudia | Froguel, Philippe | Geller, Frank | Godfrey, Keith M. | Gottrand, Frédéric | Groves, Christopher J. | Hansen, Torben | Hirschhorn, Joel N. | Hofman, Albert | Hollegaard, Mads V. | Hougaard, David M. | Hyppönen, Elina | Inskip, Hazel M. | Isaacs, Aaron | Jørgensen, Torben | Kanaka-Gantenbein, Christina | Kemp, John P. | Kiess, Wieland | Kilpeläinen, Tuomas O. | Klopp, Norman | Knight, Bridget A. | Kuzawa, Christopher W. | McMahon, George | Newnham, John P. | Niinikoski, Harri | Oostra, Ben A. | Pedersen, Louise | Postma, Dirkje S. | Ring, Susan M. | Rivadeneira, Fernando | Robertson, Neil R. | Sebert, Sylvain | Simell, Olli | Slowinski, Torsten | Tiesler, Carla M.T. | Tönjes, Anke | Vaag, Allan | Viikari, Jorma S. | Vink, Jacqueline M. | Vissing, Nadja Hawwa | Wareham, Nicholas J. | Willemsen, Gonneke | Witte, Daniel R. | Zhang, Haitao | Zhao, Jianhua | Wilson, James F. | Stumvoll, Michael | Prentice, Andrew M. | Meyer, Brian F. | Pearson, Ewan R. | Boreham, Colin A.G. | Cooper, Cyrus | Gillman, Matthew W. | Dedoussis, George V. | Moreno, Luis A | Pedersen, Oluf | Saarinen, Maiju | Mohlke, Karen L. | Boomsma, Dorret I. | Saw, Seang-Mei | Lakka, Timo A. | Körner, Antje | Loos, Ruth J.F. | Ong, Ken K. | Vollenweider, Peter | van Duijn, Cornelia M. | Koppelman, Gerard H. | Hattersley, Andrew T. | Holloway, John W. | Hocher, Berthold | Heinrich, Joachim | Power, Chris | Melbye, Mads | Guxens, Mònica | Pennell, Craig E. | Bønnelykke, Klaus | Bisgaard, Hans | Eriksson, Johan G. | Widén, Elisabeth | Hakonarson, Hakon | Uitterlinden, André G. | Pouta, Anneli | Lawlor, Debbie A. | Smith, George Davey | Frayling, Timothy M. | McCarthy, Mark I. | Grant, Struan F.A. | Jaddoe, Vincent W.V. | Jarvelin, Marjo-Riitta | Timpson, Nicholas J. | Prokopenko, Inga | Freathy, Rachel M.
Nature genetics  2012;45(1):76-82.
Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood1. Previous genome-wide association studies identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes, and a second variant, near CCNL1, with no obvious link to adult traits2. In an expanded genome-wide association meta-analysis and follow-up study (up to 69,308 individuals of European descent from 43 studies), we have now extended the number of genome-wide significant loci to seven, accounting for a similar proportion of variance to maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes; ADRB1 with adult blood pressure; and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.
doi:10.1038/ng.2477
PMCID: PMC3605762  PMID: 23202124
5.  Parent-of-origin specific allelic associations among 106 genomic loci for age at menarche 
Perry, John RB | Day, Felix | Elks, Cathy E | Sulem, Patrick | Thompson, Deborah J | Ferreira, Teresa | He, Chunyan | Chasman, Daniel I | Esko, Tõnu | Thorleifsson, Gudmar | Albrecht, Eva | Ang, Wei Q | Corre, Tanguy | Cousminer, Diana L | Feenstra, Bjarke | Franceschini, Nora | Ganna, Andrea | Johnson, Andrew D | Kjellqvist, Sanela | Lunetta, Kathryn L | McMahon, George | Nolte, Ilja M | Paternoster, Lavinia | Porcu, Eleonora | Smith, Albert V | Stolk, Lisette | Teumer, Alexander | Tšernikova, Natalia | Tikkanen, Emmi | Ulivi, Sheila | Wagner, Erin K | Amin, Najaf | Bierut, Laura J | Byrne, Enda M | Hottenga, Jouke-Jan | Koller, Daniel L | Mangino, Massimo | Pers, Tune H | Yerges-Armstrong, Laura M | Zhao, Jing Hua | Andrulis, Irene L | Anton-Culver, Hoda | Atsma, Femke | Bandinelli, Stefania | Beckmann, Matthias W | Benitez, Javier | Blomqvist, Carl | Bojesen, Stig E | Bolla, Manjeet K | Bonanni, Bernardo | Brauch, Hiltrud | Brenner, Hermann | Buring, Julie E | Chang-Claude, Jenny | Chanock, Stephen | Chen, Jinhui | Chenevix-Trench, Georgia | Collée, J. Margriet | Couch, Fergus J | Couper, David | Coveillo, Andrea D | Cox, Angela | Czene, Kamila | D’adamo, Adamo Pio | Smith, George Davey | De Vivo, Immaculata | Demerath, Ellen W | Dennis, Joe | Devilee, Peter | Dieffenbach, Aida K | Dunning, Alison M | Eiriksdottir, Gudny | Eriksson, Johan G | Fasching, Peter A | Ferrucci, Luigi | Flesch-Janys, Dieter | Flyger, Henrik | Foroud, Tatiana | Franke, Lude | Garcia, Melissa E | García-Closas, Montserrat | Geller, Frank | de Geus, Eco EJ | Giles, Graham G | Gudbjartsson, Daniel F | Gudnason, Vilmundur | Guénel, Pascal | Guo, Suiqun | Hall, Per | Hamann, Ute | Haring, Robin | Hartman, Catharina A | Heath, Andrew C | Hofman, Albert | Hooning, Maartje J | Hopper, John L | Hu, Frank B | Hunter, David J | Karasik, David | Kiel, Douglas P | Knight, Julia A | Kosma, Veli-Matti | Kutalik, Zoltan | Lai, Sandra | Lambrechts, Diether | Lindblom, Annika | Mägi, Reedik | Magnusson, Patrik K | Mannermaa, Arto | Martin, Nicholas G | Masson, Gisli | McArdle, Patrick F | McArdle, Wendy L | Melbye, Mads | Michailidou, Kyriaki | Mihailov, Evelin | Milani, Lili | Milne, Roger L | Nevanlinna, Heli | Neven, Patrick | Nohr, Ellen A | Oldehinkel, Albertine J | Oostra, Ben A | Palotie, Aarno | Peacock, Munro | Pedersen, Nancy L | Peterlongo, Paolo | Peto, Julian | Pharoah, Paul DP | Postma, Dirkje S | Pouta, Anneli | Pylkäs, Katri | Radice, Paolo | Ring, Susan | Rivadeneira, Fernando | Robino, Antonietta | Rose, Lynda M | Rudolph, Anja | Salomaa, Veikko | Sanna, Serena | Schlessinger, David | Schmidt, Marjanka K | Southey, Mellissa C | Sovio, Ulla | Stampfer, Meir J | Stöckl, Doris | Storniolo, Anna M | Timpson, Nicholas J | Tyrer, Jonathan | Visser, Jenny A | Vollenweider, Peter | Völzke, Henry | Waeber, Gerard | Waldenberger, Melanie | Wallaschofski, Henri | Wang, Qin | Willemsen, Gonneke | Winqvist, Robert | Wolffenbuttel, Bruce HR | Wright, Margaret J | Boomsma, Dorret I | Econs, Michael J | Khaw, Kay-Tee | Loos, Ruth JF | McCarthy, Mark I | Montgomery, Grant W | Rice, John P | Streeten, Elizabeth A | Thorsteinsdottir, Unnur | van Duijn, Cornelia M | Alizadeh, Behrooz Z | Bergmann, Sven | Boerwinkle, Eric | Boyd, Heather A | Crisponi, Laura | Gasparini, Paolo | Gieger, Christian | Harris, Tamara B | Ingelsson, Erik | Järvelin, Marjo-Riitta | Kraft, Peter | Lawlor, Debbie | Metspalu, Andres | Pennell, Craig E | Ridker, Paul M | Snieder, Harold | Sørensen, Thorkild IA | Spector, Tim D | Strachan, David P | Uitterlinden, André G | Wareham, Nicholas J | Widen, Elisabeth | Zygmunt, Marek | Murray, Anna | Easton, Douglas F | Stefansson, Kari | Murabito, Joanne M | Ong, Ken K
Nature  2014;514(7520):92-97.
Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality1. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation2,3, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P<5×10−8) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1/WDR25, MKRN3/MAGEL2 and KCNK9) demonstrating parent-of-origin specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signaling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.
doi:10.1038/nature13545
PMCID: PMC4185210  PMID: 25231870
6.  Identification of heart rate–associated loci and their effects on cardiac conduction and rhythm disorders 
den Hoed, Marcel | Eijgelsheim, Mark | Esko, Tõnu | Brundel, Bianca J J M | Peal, David S | Evans, David M | Nolte, Ilja M | Segrè, Ayellet V | Holm, Hilma | Handsaker, Robert E | Westra, Harm-Jan | Johnson, Toby | Isaacs, Aaron | Yang, Jian | Lundby, Alicia | Zhao, Jing Hua | Kim, Young Jin | Go, Min Jin | Almgren, Peter | Bochud, Murielle | Boucher, Gabrielle | Cornelis, Marilyn C | Gudbjartsson, Daniel | Hadley, David | Van Der Harst, Pim | Hayward, Caroline | Heijer, Martin Den | Igl, Wilmar | Jackson, Anne U | Kutalik, Zoltán | Luan, Jian’an | Kemp, John P | Kristiansson, Kati | Ladenvall, Claes | Lorentzon, Mattias | Montasser, May E | Njajou, Omer T | O’Reilly, Paul F | Padmanabhan, Sandosh | Pourcain, Beate St. | Rankinen, Tuomo | Salo, Perttu | Tanaka, Toshiko | Timpson, Nicholas J | Vitart, Veronique | Waite, Lindsay | Wheeler, William | Zhang, Weihua | Draisma, Harmen H M | Feitosa, Mary F | Kerr, Kathleen F | Lind, Penelope A | Mihailov, Evelin | Onland-Moret, N Charlotte | Song, Ci | Weedon, Michael N | Xie, Weijia | Yengo, Loic | Absher, Devin | Albert, Christine M | Alonso, Alvaro | Arking, Dan E | de Bakker, Paul I W | Balkau, Beverley | Barlassina, Cristina | Benaglio, Paola | Bis, Joshua C | Bouatia-Naji, Nabila | Brage, Søren | Chanock, Stephen J | Chines, Peter S | Chung, Mina | Darbar, Dawood | Dina, Christian | Dörr, Marcus | Elliott, Paul | Felix, Stephan B | Fischer, Krista | Fuchsberger, Christian | de Geus, Eco J C | Goyette, Philippe | Gudnason, Vilmundur | Harris, Tamara B | Hartikainen, Anna-liisa | Havulinna, Aki S | Heckbert, Susan R | Hicks, Andrew A | Hofman, Albert | Holewijn, Suzanne | Hoogstra-Berends, Femke | Hottenga, Jouke-Jan | Jensen, Majken K | Johansson, Åsa | Junttila, Juhani | Kääb, Stefan | Kanon, Bart | Ketkar, Shamika | Khaw, Kay-Tee | Knowles, Joshua W | Kooner, Angrad S | Kors, Jan A | Kumari, Meena | Milani, Lili | Laiho, Päivi | Lakatta, Edward G | Langenberg, Claudia | Leusink, Maarten | Liu, Yongmei | Luben, Robert N | Lunetta, Kathryn L | Lynch, Stacey N | Markus, Marcello R P | Marques-Vidal, Pedro | Leach, Irene Mateo | McArdle, Wendy L | McCarroll, Steven A | Medland, Sarah E | Miller, Kathryn A | Montgomery, Grant W | Morrison, Alanna C | Müller-Nurasyid, Martina | Navarro, Pau | Nelis, Mari | O’Connell, Jeffrey R | O’Donnell, Christopher J | Ong, Ken K | Newman, Anne B | Peters, Annette | Polasek, Ozren | Pouta, Anneli | Pramstaller, Peter P | Psaty, Bruce M | Rao, Dabeeru C | Ring, Susan M | Rossin, Elizabeth J | Rudan, Diana | Sanna, Serena | Scott, Robert A | Sehmi, Jaban S | Sharp, Stephen | Shin, Jordan T | Singleton, Andrew B | Smith, Albert V | Soranzo, Nicole | Spector, Tim D | Stewart, Chip | Stringham, Heather M | Tarasov, Kirill V | Uitterlinden, André G | Vandenput, Liesbeth | Hwang, Shih-Jen | Whitfield, John B | Wijmenga, Cisca | Wild, Sarah H | Willemsen, Gonneke | Wilson, James F | Witteman, Jacqueline C M | Wong, Andrew | Wong, Quenna | Jamshidi, Yalda | Zitting, Paavo | Boer, Jolanda M A | Boomsma, Dorret I | Borecki, Ingrid B | Van Duijn, Cornelia M | Ekelund, Ulf | Forouhi, Nita G | Froguel, Philippe | Hingorani, Aroon | Ingelsson, Erik | Kivimaki, Mika | Kronmal, Richard A | Kuh, Diana | Lind, Lars | Martin, Nicholas G | Oostra, Ben A | Pedersen, Nancy L | Quertermous, Thomas | Rotter, Jerome I | van der Schouw, Yvonne T | Verschuren, W M Monique | Walker, Mark | Albanes, Demetrius | Arnar, David O | Assimes, Themistocles L | Bandinelli, Stefania | Boehnke, Michael | de Boer, Rudolf A | Bouchard, Claude | Caulfield, W L Mark | Chambers, John C | Curhan, Gary | Cusi, Daniele | Eriksson, Johan | Ferrucci, Luigi | van Gilst, Wiek H | Glorioso, Nicola | de Graaf, Jacqueline | Groop, Leif | Gyllensten, Ulf | Hsueh, Wen-Chi | Hu, Frank B | Huikuri, Heikki V | Hunter, David J | Iribarren, Carlos | Isomaa, Bo | Jarvelin, Marjo-Riitta | Jula, Antti | Kähönen, Mika | Kiemeney, Lambertus A | van der Klauw, Melanie M | Kooner, Jaspal S | Kraft, Peter | Iacoviello, Licia | Lehtimäki, Terho | Lokki, Marja-Liisa L | Mitchell, Braxton D | Navis, Gerjan | Nieminen, Markku S | Ohlsson, Claes | Poulter, Neil R | Qi, Lu | Raitakari, Olli T | Rimm, Eric B | Rioux, John D | Rizzi, Federica | Rudan, Igor | Salomaa, Veikko | Sever, Peter S | Shields, Denis C | Shuldiner, Alan R | Sinisalo, Juha | Stanton, Alice V | Stolk, Ronald P | Strachan, David P | Tardif, Jean-Claude | Thorsteinsdottir, Unnur | Tuomilehto, Jaako | van Veldhuisen, Dirk J | Virtamo, Jarmo | Viikari, Jorma | Vollenweider, Peter | Waeber, Gérard | Widen, Elisabeth | Cho, Yoon Shin | Olsen, Jesper V | Visscher, Peter M | Willer, Cristen | Franke, Lude | Erdmann, Jeanette | Thompson, John R | Pfeufer, Arne | Sotoodehnia, Nona | Newton-Cheh, Christopher | Ellinor, Patrick T | Stricker, Bruno H Ch | Metspalu, Andres | Perola, Markus | Beckmann, Jacques S | Smith, George Davey | Stefansson, Kari | Wareham, Nicholas J | Munroe, Patricia B | Sibon, Ody C M | Milan, David J | Snieder, Harold | Samani, Nilesh J | Loos, Ruth J F
Nature genetics  2013;45(6):621-631.
Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate–increasing and heart rate–decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.
doi:10.1038/ng.2610
PMCID: PMC3696959  PMID: 23583979
7.  Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways 
Scott, Robert A | Lagou, Vasiliki | Welch, Ryan P | Wheeler, Eleanor | Montasser, May E | Luan, Jian’an | Mägi, Reedik | Strawbridge, Rona J | Rehnberg, Emil | Gustafsson, Stefan | Kanoni, Stavroula | Rasmussen-Torvik, Laura J | Yengo, Loïc | Lecoeur, Cecile | Shungin, Dmitry | Sanna, Serena | Sidore, Carlo | Johnson, Paul C D | Jukema, J Wouter | Johnson, Toby | Mahajan, Anubha | Verweij, Niek | Thorleifsson, Gudmar | Hottenga, Jouke-Jan | Shah, Sonia | Smith, Albert V | Sennblad, Bengt | Gieger, Christian | Salo, Perttu | Perola, Markus | Timpson, Nicholas J | Evans, David M | Pourcain, Beate St | Wu, Ying | Andrews, Jeanette S | Hui, Jennie | Bielak, Lawrence F | Zhao, Wei | Horikoshi, Momoko | Navarro, Pau | Isaacs, Aaron | O’Connell, Jeffrey R | Stirrups, Kathleen | Vitart, Veronique | Hayward, Caroline | Esko, Tönu | Mihailov, Evelin | Fraser, Ross M | Fall, Tove | Voight, Benjamin F | Raychaudhuri, Soumya | Chen, Han | Lindgren, Cecilia M | Morris, Andrew P | Rayner, Nigel W | Robertson, Neil | Rybin, Denis | Liu, Ching-Ti | Beckmann, Jacques S | Willems, Sara M | Chines, Peter S | Jackson, Anne U | Kang, Hyun Min | Stringham, Heather M | Song, Kijoung | Tanaka, Toshiko | Peden, John F | Goel, Anuj | Hicks, Andrew A | An, Ping | Müller-Nurasyid, Martina | Franco-Cereceda, Anders | Folkersen, Lasse | Marullo, Letizia | Jansen, Hanneke | Oldehinkel, Albertine J | Bruinenberg, Marcel | Pankow, James S | North, Kari E | Forouhi, Nita G | Loos, Ruth J F | Edkins, Sarah | Varga, Tibor V | Hallmans, Göran | Oksa, Heikki | Antonella, Mulas | Nagaraja, Ramaiah | Trompet, Stella | Ford, Ian | Bakker, Stephan J L | Kong, Augustine | Kumari, Meena | Gigante, Bruna | Herder, Christian | Munroe, Patricia B | Caulfield, Mark | Antti, Jula | Mangino, Massimo | Small, Kerrin | Miljkovic, Iva | Liu, Yongmei | Atalay, Mustafa | Kiess, Wieland | James, Alan L | Rivadeneira, Fernando | Uitterlinden, Andre G | Palmer, Colin N A | Doney, Alex S F | Willemsen, Gonneke | Smit, Johannes H | Campbell, Susan | Polasek, Ozren | Bonnycastle, Lori L | Hercberg, Serge | Dimitriou, Maria | Bolton, Jennifer L | Fowkes, Gerard R | Kovacs, Peter | Lindström, Jaana | Zemunik, Tatijana | Bandinelli, Stefania | Wild, Sarah H | Basart, Hanneke V | Rathmann, Wolfgang | Grallert, Harald | Maerz, Winfried | Kleber, Marcus E | Boehm, Bernhard O | Peters, Annette | Pramstaller, Peter P | Province, Michael A | Borecki, Ingrid B | Hastie, Nicholas D | Rudan, Igor | Campbell, Harry | Watkins, Hugh | Farrall, Martin | Stumvoll, Michael | Ferrucci, Luigi | Waterworth, Dawn M | Bergman, Richard N | Collins, Francis S | Tuomilehto, Jaakko | Watanabe, Richard M | de Geus, Eco J C | Penninx, Brenda W | Hofman, Albert | Oostra, Ben A | Psaty, Bruce M | Vollenweider, Peter | Wilson, James F | Wright, Alan F | Hovingh, G Kees | Metspalu, Andres | Uusitupa, Matti | Magnusson, Patrik K E | Kyvik, Kirsten O | Kaprio, Jaakko | Price, Jackie F | Dedoussis, George V | Deloukas, Panos | Meneton, Pierre | Lind, Lars | Boehnke, Michael | Shuldiner, Alan R | van Duijn, Cornelia M | Morris, Andrew D | Toenjes, Anke | Peyser, Patricia A | Beilby, John P | Körner, Antje | Kuusisto, Johanna | Laakso, Markku | Bornstein, Stefan R | Schwarz, Peter E H | Lakka, Timo A | Rauramaa, Rainer | Adair, Linda S | Smith, George Davey | Spector, Tim D | Illig, Thomas | de Faire, Ulf | Hamsten, Anders | Gudnason, Vilmundur | Kivimaki, Mika | Hingorani, Aroon | Keinanen-Kiukaanniemi, Sirkka M | Saaristo, Timo E | Boomsma, Dorret I | Stefansson, Kari | van der Harst, Pim | Dupuis, Josée | Pedersen, Nancy L | Sattar, Naveed | Harris, Tamara B | Cucca, Francesco | Ripatti, Samuli | Salomaa, Veikko | Mohlke, Karen L | Balkau, Beverley | Froguel, Philippe | Pouta, Anneli | Jarvelin, Marjo-Riitta | Wareham, Nicholas J | Bouatia-Naji, Nabila | McCarthy, Mark I | Franks, Paul W | Meigs, James B | Teslovich, Tanya M | Florez, Jose C | Langenberg, Claudia | Ingelsson, Erik | Prokopenko, Inga | Barroso, Inês
Nature genetics  2012;44(9):991-1005.
Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have raised the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional follow-up of these newly discovered loci will further improve our understanding of glycemic control.
doi:10.1038/ng.2385
PMCID: PMC3433394  PMID: 22885924
8.  Association of Genetic Loci With Glucose Levels in Childhood and Adolescence 
Diabetes  2011;60(6):1805-1812.
OBJECTIVE
To investigate whether associations of common genetic variants recently identified for fasting glucose or insulin levels in nondiabetic adults are detectable in healthy children and adolescents.
RESEARCH DESIGN AND METHODS
A total of 16 single nucleotide polymorphisms (SNPs) associated with fasting glucose were genotyped in six studies of children and adolescents of European origin, including over 6,000 boys and girls aged 9–16 years. We performed meta-analyses to test associations of individual SNPs and a weighted risk score of the 16 loci with fasting glucose.
RESULTS
Nine loci were associated with glucose levels in healthy children and adolescents, with four of these associations reported in previous studies and five reported here for the first time (GLIS3, PROX1, SLC2A2, ADCY5, and CRY2). Effect sizes were similar to those in adults, suggesting age-independent effects of these fasting glucose loci. Children and adolescents carrying glucose-raising alleles of G6PC2, MTNR1B, GCK, and GLIS3 also showed reduced β-cell function, as indicated by homeostasis model assessment of β-cell function. Analysis using a weighted risk score showed an increase [β (95% CI)] in fasting glucose level of 0.026 mmol/L (0.021–0.031) for each unit increase in the score.
CONCLUSIONS
Novel fasting glucose loci identified in genome-wide association studies of adults are associated with altered fasting glucose levels in healthy children and adolescents with effect sizes comparable to adults. In nondiabetic adults, fasting glucose changes little over time, and our results suggest that age-independent effects of fasting glucose loci contribute to long-term interindividual differences in glucose levels from childhood onwards.
doi:10.2337/db10-1575
PMCID: PMC3114379  PMID: 21515849
9.  Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies 
Elks, Cathy E. | Perry, John R.B. | Sulem, Patrick | Chasman, Daniel I. | Franceschini, Nora | He, Chunyan | Lunetta, Kathryn L. | Visser, Jenny A. | Byrne, Enda M. | Cousminer, Diana L. | Gudbjartsson, Daniel F. | Esko, Tõnu | Feenstra, Bjarke | Hottenga, Jouke-Jan | Koller, Daniel L. | Kutalik, Zoltán | Lin, Peng | Mangino, Massimo | Marongiu, Mara | McArdle, Patrick F. | Smith, Albert V. | Stolk, Lisette | van Wingerden, Sophie W. | Zhao, Jing Hua | Albrecht, Eva | Corre, Tanguy | Ingelsson, Erik | Hayward, Caroline | Magnusson, Patrik K.E. | Smith, Erin N. | Ulivi, Shelia | Warrington, Nicole M. | Zgaga, Lina | Alavere, Helen | Amin, Najaf | Aspelund, Thor | Bandinelli, Stefania | Barroso, Ines | Berenson, Gerald S. | Bergmann, Sven | Blackburn, Hannah | Boerwinkle, Eric | Buring, Julie E. | Busonero, Fabio | Campbell, Harry | Chanock, Stephen J. | Chen, Wei | Cornelis, Marilyn C. | Couper, David | Coviello, Andrea D. | d’Adamo, Pio | de Faire, Ulf | de Geus, Eco J.C. | Deloukas, Panos | Döring, Angela | Smith, George Davey | Easton, Douglas F. | Eiriksdottir, Gudny | Emilsson, Valur | Eriksson, Johan | Ferrucci, Luigi | Folsom, Aaron R. | Foroud, Tatiana | Garcia, Melissa | Gasparini, Paolo | Geller, Frank | Gieger, Christian | Gudnason, Vilmundur | Hall, Per | Hankinson, Susan E. | Ferreli, Liana | Heath, Andrew C. | Hernandez, Dena G. | Hofman, Albert | Hu, Frank B. | Illig, Thomas | Järvelin, Marjo-Riitta | Johnson, Andrew D. | Karasik, David | Khaw, Kay-Tee | Kiel, Douglas P. | Kilpeläinen, Tuomas O. | Kolcic, Ivana | Kraft, Peter | Launer, Lenore J. | Laven, Joop S.E. | Li, Shengxu | Liu, Jianjun | Levy, Daniel | Martin, Nicholas G. | McArdle, Wendy L. | Melbye, Mads | Mooser, Vincent | Murray, Jeffrey C. | Murray, Sarah S. | Nalls, Michael A. | Navarro, Pau | Nelis, Mari | Ness, Andrew R. | Northstone, Kate | Oostra, Ben A. | Peacock, Munro | Palmer, Lyle J. | Palotie, Aarno | Paré, Guillaume | Parker, Alex N. | Pedersen, Nancy L. | Peltonen, Leena | Pennell, Craig E. | Pharoah, Paul | Polasek, Ozren | Plump, Andrew S. | Pouta, Anneli | Porcu, Eleonora | Rafnar, Thorunn | Rice, John P. | Ring, Susan M. | Rivadeneira, Fernando | Rudan, Igor | Sala, Cinzia | Salomaa, Veikko | Sanna, Serena | Schlessinger, David | Schork, Nicholas J. | Scuteri, Angelo | Segrè, Ayellet V. | Shuldiner, Alan R. | Soranzo, Nicole | Sovio, Ulla | Srinivasan, Sathanur R. | Strachan, David P. | Tammesoo, Mar-Liis | Tikkanen, Emmi | Toniolo, Daniela | Tsui, Kim | Tryggvadottir, Laufey | Tyrer, Jonathon | Uda, Manuela | van Dam, Rob M. | van Meurs, Joyve B.J. | Vollenweider, Peter | Waeber, Gerard | Wareham, Nicholas J. | Waterworth, Dawn M. | Weedon, Michael N. | Wichmann, H. Erich | Willemsen, Gonneke | Wilson, James F. | Wright, Alan F. | Young, Lauren | Zhai, Guangju | Zhuang, Wei Vivian | Bierut, Laura J. | Boomsma, Dorret I. | Boyd, Heather A. | Crisponi, Laura | Demerath, Ellen W. | van Duijn, Cornelia M. | Econs, Michael J. | Harris, Tamara B. | Hunter, David J. | Loos, Ruth J.F. | Metspalu, Andres | Montgomery, Grant W. | Ridker, Paul M. | Spector, Tim D. | Streeten, Elizabeth A. | Stefansson, Kari | Thorsteinsdottir, Unnur | Uitterlinden, André G. | Widen, Elisabeth | Murabito, Joanne M. | Ong, Ken K. | Murray, Anna
Nature genetics  2010;42(12):1077-1085.
To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P=5.4×10−60) and 9q31.2 (P=2.2×10−33), we identified 30 novel menarche loci (all P<5×10−8) and found suggestive evidence for a further 10 loci (P<1.9×10−6). New loci included four previously associated with BMI (in/near FTO, SEC16B, TRA2B and TMEM18), three in/near other genes implicated in energy homeostasis (BSX, CRTC1, and MCHR2), and three in/near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and MAGENTA pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.
doi:10.1038/ng.714
PMCID: PMC3140055  PMID: 21102462
10.  Physical Activity Attenuates the Influence of FTO Variants on Obesity Risk: A Meta-Analysis of 218,166 Adults and 19,268 Children 
Kilpeläinen, Tuomas O. | Qi, Lu | Brage, Soren | Sharp, Stephen J. | Sonestedt, Emily | Demerath, Ellen | Ahmad, Tariq | Mora, Samia | Kaakinen, Marika | Sandholt, Camilla Helene | Holzapfel, Christina | Autenrieth, Christine S. | Hyppönen, Elina | Cauchi, Stéphane | He, Meian | Kutalik, Zoltan | Kumari, Meena | Stančáková, Alena | Meidtner, Karina | Balkau, Beverley | Tan, Jonathan T. | Mangino, Massimo | Timpson, Nicholas J. | Song, Yiqing | Zillikens, M. Carola | Jablonski, Kathleen A. | Garcia, Melissa E. | Johansson, Stefan | Bragg-Gresham, Jennifer L. | Wu, Ying | van Vliet-Ostaptchouk, Jana V. | Onland-Moret, N. Charlotte | Zimmermann, Esther | Rivera, Natalia V. | Tanaka, Toshiko | Stringham, Heather M. | Silbernagel, Günther | Kanoni, Stavroula | Feitosa, Mary F. | Snitker, Soren | Ruiz, Jonatan R. | Metter, Jeffery | Larrad, Maria Teresa Martinez | Atalay, Mustafa | Hakanen, Maarit | Amin, Najaf | Cavalcanti-Proença, Christine | Grøntved, Anders | Hallmans, Göran | Jansson, John-Olov | Kuusisto, Johanna | Kähönen, Mika | Lutsey, Pamela L. | Nolan, John J. | Palla, Luigi | Pedersen, Oluf | Pérusse, Louis | Renström, Frida | Scott, Robert A. | Shungin, Dmitry | Sovio, Ulla | Tammelin, Tuija H. | Rönnemaa, Tapani | Lakka, Timo A. | Uusitupa, Matti | Rios, Manuel Serrano | Ferrucci, Luigi | Bouchard, Claude | Meirhaeghe, Aline | Fu, Mao | Walker, Mark | Borecki, Ingrid B. | Dedoussis, George V. | Fritsche, Andreas | Ohlsson, Claes | Boehnke, Michael | Bandinelli, Stefania | van Duijn, Cornelia M. | Ebrahim, Shah | Lawlor, Debbie A. | Gudnason, Vilmundur | Harris, Tamara B. | Sørensen, Thorkild I. A. | Mohlke, Karen L. | Hofman, Albert | Uitterlinden, André G. | Tuomilehto, Jaakko | Lehtimäki, Terho | Raitakari, Olli | Isomaa, Bo | Njølstad, Pål R. | Florez, Jose C. | Liu, Simin | Ness, Andy | Spector, Timothy D. | Tai, E. Shyong | Froguel, Philippe | Boeing, Heiner | Laakso, Markku | Marmot, Michael | Bergmann, Sven | Power, Chris | Khaw, Kay-Tee | Chasman, Daniel | Ridker, Paul | Hansen, Torben | Monda, Keri L. | Illig, Thomas | Järvelin, Marjo-Riitta | Wareham, Nicholas J. | Hu, Frank B. | Groop, Leif C. | Orho-Melander, Marju | Ekelund, Ulf | Franks, Paul W. | Loos, Ruth J. F.
PLoS Medicine  2011;8(11):e1001116.
Ruth Loos and colleagues report findings from a meta-analysis of multiple studies examining the extent to which physical activity attenuates effects of a specific gene variant, FTO, on obesity in adults and children. They report a fairly substantial attenuation by physical activity on the effects of this genetic variant on the risk of obesity in adults.
Background
The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n = 218,166) and nine studies of children and adolescents (n = 19,268).
Methods and Findings
All studies identified to have data on the FTO rs9939609 variant (or any proxy [r2>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTO×PA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A−) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20–1.26), but PA attenuated this effect (pinteraction  = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio  = 1.22/allele, 95% CI 1.19–1.25) than in the inactive group (odds ratio  = 1.30/allele, 95% CI 1.24–1.36). No such interaction was found in children and adolescents.
Conclusions
The association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity.
Please see later in the article for the Editors' Summary
Editors’ Summary
Background
Two in three Americans are overweight, of whom half are obese, and the trend towards increasing obesity is now seen across developed and developing countries. There has long been interest in understanding the impact of genes and environment when it comes to apportioning responsibility for obesity. Carrying a change in the FTO gene is common (found in three-quarters of Europeans and North Americans) and is associated with a 20%–30% increased risk of obesity. Some overweight or obese individuals may feel that the dice are loaded and there is little point in fighting the fat; it has been reported that those made aware of their genetic susceptibility to obesity may still choose a poor diet. A similar fatalism may occur when overweight and obese people consider physical activity. But disentangling the influence of physical activity on those genetically susceptible to obesity from other factors that might impact weight is not straightforward, as it requires large sample sizes, could be subject to publication bias, and may rely on less than ideal self-reporting methods.
Why Was This Study Done?
The public health ramifications of understanding the interaction between genetic susceptibility to obesity and physical activity are considerable. Tackling the rising prevalence of obesity will inevitably include interventions principally aimed at changing dietary intake and/or increasing physical activity, but the evidence for these with regards to those genetically susceptible has been lacking to date. The authors of this paper set out to explore the interaction between the commonest genetic susceptibility trait and physical activity using a rigorous meta-analysis of a large number of studies.
What Did the Researchers Do and Find?
The authors were concerned that a meta-analysis of published studies would be limited both by the data available to them and by possible bias. Instead of this more widely used approach, they took the literature search as their starting point, identified other studies through their collaborators’ network, and then undertook a meta-analysis of all available studies using a new and standardized analysis plan. This entailed an extremely large number of authors mining their data afresh to extract the relevant data points to enable such a meta-analysis. Physical activity was identified in the original studies in many different ways, including by self-report or by using an external measure of activity or heart rate. In order to perform the meta-analysis, participants were labeled as physically active or inactive in each study. For studies that had used a continuous scale, the authors decided that the bottom 20% of the participants were inactive (10% for children and adolescents). Using data from over 218,000 adults, the authors found that carrying a copy of the susceptibility gene increased the odds of obesity by 1.23-fold. But the size of this influence was 27% less in the genetically susceptible adults who were physically active (1.22-fold) compared to those who were physically inactive (1.30-fold). In a smaller study of about 19,000 children, no such effect of physical activity was seen.
What Do these Findings Mean?
This study demonstrates that people who carry the susceptibility gene for obesity can benefit from physical activity. This should inform health care professionals and the wider public that the view of genetically determined obesity not being amenable to exercise is incorrect and should be challenged. Dissemination, implementation, and ensuring uptake of effective physical activity programs remains a challenge and deserves further consideration. That the researchers treated “physically active” as a yes/no category, and how they categorized individuals, could be criticized, but this was done for pragmatic reasons, as a variety of means of assessing physical activity were used across the studies. It is unlikely that the findings would have changed if the authors had used a different method of defining physically active. Most of the studies included in the meta-analysis looked at one time point only; information about the influence of physical activity on weight changes over time in genetically susceptible individuals is only beginning to emerge.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001116.
This study is further discussed in a PLoS Medicine Perspective by Lennert Veerman
The US Centers for Disease Control and Prevention provides obesity-related statistics, details of prevention programs, and an overview on public health strategy in the United States
A more worldwide view is given by the World Health Organization
The UK National Health Service website gives information on physical activity guidelines for different age groups, while similar information can also be found from US sources
doi:10.1371/journal.pmed.1001116
PMCID: PMC3206047  PMID: 22069379
11.  Association analyses of 249,796 individuals reveal eighteen new loci associated with body mass index 
Speliotes, Elizabeth K. | Willer, Cristen J. | Berndt, Sonja I. | Monda, Keri L. | Thorleifsson, Gudmar | Jackson, Anne U. | Allen, Hana Lango | Lindgren, Cecilia M. | Luan, Jian’an | Mägi, Reedik | Randall, Joshua C. | Vedantam, Sailaja | Winkler, Thomas W. | Qi, Lu | Workalemahu, Tsegaselassie | Heid, Iris M. | Steinthorsdottir, Valgerdur | Stringham, Heather M. | Weedon, Michael N. | Wheeler, Eleanor | Wood, Andrew R. | Ferreira, Teresa | Weyant, Robert J. | Segré, Ayellet V. | Estrada, Karol | Liang, Liming | Nemesh, James | Park, Ju-Hyun | Gustafsson, Stefan | Kilpeläinen, Tuomas O. | Yang, Jian | Bouatia-Naji, Nabila | Esko, Tõnu | Feitosa, Mary F. | Kutalik, Zoltán | Mangino, Massimo | Raychaudhuri, Soumya | Scherag, Andre | Smith, Albert Vernon | Welch, Ryan | Zhao, Jing Hua | Aben, Katja K. | Absher, Devin M. | Amin, Najaf | Dixon, Anna L. | Fisher, Eva | Glazer, Nicole L. | Goddard, Michael E. | Heard-Costa, Nancy L. | Hoesel, Volker | Hottenga, Jouke-Jan | Johansson, Åsa | Johnson, Toby | Ketkar, Shamika | Lamina, Claudia | Li, Shengxu | Moffatt, Miriam F. | Myers, Richard H. | Narisu, Narisu | Perry, John R.B. | Peters, Marjolein J. | Preuss, Michael | Ripatti, Samuli | Rivadeneira, Fernando | Sandholt, Camilla | Scott, Laura J. | Timpson, Nicholas J. | Tyrer, Jonathan P. | van Wingerden, Sophie | Watanabe, Richard M. | White, Charles C. | Wiklund, Fredrik | Barlassina, Christina | Chasman, Daniel I. | Cooper, Matthew N. | Jansson, John-Olov | Lawrence, Robert W. | Pellikka, Niina | Prokopenko, Inga | Shi, Jianxin | Thiering, Elisabeth | Alavere, Helene | Alibrandi, Maria T. S. | Almgren, Peter | Arnold, Alice M. | Aspelund, Thor | Atwood, Larry D. | Balkau, Beverley | Balmforth, Anthony J. | Bennett, Amanda J. | Ben-Shlomo, Yoav | Bergman, Richard N. | Bergmann, Sven | Biebermann, Heike | Blakemore, Alexandra I.F. | Boes, Tanja | Bonnycastle, Lori L. | Bornstein, Stefan R. | Brown, Morris J. | Buchanan, Thomas A. | Busonero, Fabio | Campbell, Harry | Cappuccio, Francesco P. | Cavalcanti-Proença, Christine | Chen, Yii-Der Ida | Chen, Chih-Mei | Chines, Peter S. | Clarke, Robert | Coin, Lachlan | Connell, John | Day, Ian N.M. | den Heijer, Martin | Duan, Jubao | Ebrahim, Shah | Elliott, Paul | Elosua, Roberto | Eiriksdottir, Gudny | Erdos, Michael R. | Eriksson, Johan G. | Facheris, Maurizio F. | Felix, Stephan B. | Fischer-Posovszky, Pamela | Folsom, Aaron R. | Friedrich, Nele | Freimer, Nelson B. | Fu, Mao | Gaget, Stefan | Gejman, Pablo V. | Geus, Eco J.C. | Gieger, Christian | Gjesing, Anette P. | Goel, Anuj | Goyette, Philippe | Grallert, Harald | Gräßler, Jürgen | Greenawalt, Danielle M. | Groves, Christopher J. | Gudnason, Vilmundur | Guiducci, Candace | Hartikainen, Anna-Liisa | Hassanali, Neelam | Hall, Alistair S. | Havulinna, Aki S. | Hayward, Caroline | Heath, Andrew C. | Hengstenberg, Christian | Hicks, Andrew A. | Hinney, Anke | Hofman, Albert | Homuth, Georg | Hui, Jennie | Igl, Wilmar | Iribarren, Carlos | Isomaa, Bo | Jacobs, Kevin B. | Jarick, Ivonne | Jewell, Elizabeth | John, Ulrich | Jørgensen, Torben | Jousilahti, Pekka | Jula, Antti | Kaakinen, Marika | Kajantie, Eero | Kaplan, Lee M. | Kathiresan, Sekar | Kettunen, Johannes | Kinnunen, Leena | Knowles, Joshua W. | Kolcic, Ivana | König, Inke R. | Koskinen, Seppo | Kovacs, Peter | Kuusisto, Johanna | Kraft, Peter | Kvaløy, Kirsti | Laitinen, Jaana | Lantieri, Olivier | Lanzani, Chiara | Launer, Lenore J. | Lecoeur, Cecile | Lehtimäki, Terho | Lettre, Guillaume | Liu, Jianjun | Lokki, Marja-Liisa | Lorentzon, Mattias | Luben, Robert N. | Ludwig, Barbara | Manunta, Paolo | Marek, Diana | Marre, Michel | Martin, Nicholas G. | McArdle, Wendy L. | McCarthy, Anne | McKnight, Barbara | Meitinger, Thomas | Melander, Olle | Meyre, David | Midthjell, Kristian | Montgomery, Grant W. | Morken, Mario A. | Morris, Andrew P. | Mulic, Rosanda | Ngwa, Julius S. | Nelis, Mari | Neville, Matt J. | Nyholt, Dale R. | O’Donnell, Christopher J. | O’Rahilly, Stephen | Ong, Ken K. | Oostra, Ben | Paré, Guillaume | Parker, Alex N. | Perola, Markus | Pichler, Irene | Pietiläinen, Kirsi H. | Platou, Carl G.P. | Polasek, Ozren | Pouta, Anneli | Rafelt, Suzanne | Raitakari, Olli | Rayner, Nigel W. | Ridderstråle, Martin | Rief, Winfried | Ruokonen, Aimo | Robertson, Neil R. | Rzehak, Peter | Salomaa, Veikko | Sanders, Alan R. | Sandhu, Manjinder S. | Sanna, Serena | Saramies, Jouko | Savolainen, Markku J. | Scherag, Susann | Schipf, Sabine | Schreiber, Stefan | Schunkert, Heribert | Silander, Kaisa | Sinisalo, Juha | Siscovick, David S. | Smit, Jan H. | Soranzo, Nicole | Sovio, Ulla | Stephens, Jonathan | Surakka, Ida | Swift, Amy J. | Tammesoo, Mari-Liis | Tardif, Jean-Claude | Teder-Laving, Maris | Teslovich, Tanya M. | Thompson, John R. | Thomson, Brian | Tönjes, Anke | Tuomi, Tiinamaija | van Meurs, Joyce B.J. | van Ommen, Gert-Jan | Vatin, Vincent | Viikari, Jorma | Visvikis-Siest, Sophie | Vitart, Veronique | Vogel, Carla I. G. | Voight, Benjamin F. | Waite, Lindsay L. | Wallaschofski, Henri | Walters, G. Bragi | Widen, Elisabeth | Wiegand, Susanna | Wild, Sarah H. | Willemsen, Gonneke | Witte, Daniel R. | Witteman, Jacqueline C. | Xu, Jianfeng | Zhang, Qunyuan | Zgaga, Lina | Ziegler, Andreas | Zitting, Paavo | Beilby, John P. | Farooqi, I. Sadaf | Hebebrand, Johannes | Huikuri, Heikki V. | James, Alan L. | Kähönen, Mika | Levinson, Douglas F. | Macciardi, Fabio | Nieminen, Markku S. | Ohlsson, Claes | Palmer, Lyle J. | Ridker, Paul M. | Stumvoll, Michael | Beckmann, Jacques S. | Boeing, Heiner | Boerwinkle, Eric | Boomsma, Dorret I. | Caulfield, Mark J. | Chanock, Stephen J. | Collins, Francis S. | Cupples, L. Adrienne | Smith, George Davey | Erdmann, Jeanette | Froguel, Philippe | Grönberg, Henrik | Gyllensten, Ulf | Hall, Per | Hansen, Torben | Harris, Tamara B. | Hattersley, Andrew T. | Hayes, Richard B. | Heinrich, Joachim | Hu, Frank B. | Hveem, Kristian | Illig, Thomas | Jarvelin, Marjo-Riitta | Kaprio, Jaakko | Karpe, Fredrik | Khaw, Kay-Tee | Kiemeney, Lambertus A. | Krude, Heiko | Laakso, Markku | Lawlor, Debbie A. | Metspalu, Andres | Munroe, Patricia B. | Ouwehand, Willem H. | Pedersen, Oluf | Penninx, Brenda W. | Peters, Annette | Pramstaller, Peter P. | Quertermous, Thomas | Reinehr, Thomas | Rissanen, Aila | Rudan, Igor | Samani, Nilesh J. | Schwarz, Peter E.H. | Shuldiner, Alan R. | Spector, Timothy D. | Tuomilehto, Jaakko | Uda, Manuela | Uitterlinden, André | Valle, Timo T. | Wabitsch, Martin | Waeber, Gérard | Wareham, Nicholas J. | Watkins, Hugh | Wilson, James F. | Wright, Alan F. | Zillikens, M. Carola | Chatterjee, Nilanjan | McCarroll, Steven A. | Purcell, Shaun | Schadt, Eric E. | Visscher, Peter M. | Assimes, Themistocles L. | Borecki, Ingrid B. | Deloukas, Panos | Fox, Caroline S. | Groop, Leif C. | Haritunians, Talin | Hunter, David J. | Kaplan, Robert C. | Mohlke, Karen L. | O’Connell, Jeffrey R. | Peltonen, Leena | Schlessinger, David | Strachan, David P. | van Duijn, Cornelia M. | Wichmann, H.-Erich | Frayling, Timothy M. | Thorsteinsdottir, Unnur | Abecasis, Gonçalo R. | Barroso, Inês | Boehnke, Michael | Stefansson, Kari | North, Kari E. | McCarthy, Mark I. | Hirschhorn, Joel N. | Ingelsson, Erik | Loos, Ruth J.F.
Nature genetics  2010;42(11):937-948.
Obesity is globally prevalent and highly heritable, but the underlying genetic factors remain largely elusive. To identify genetic loci for obesity-susceptibility, we examined associations between body mass index (BMI) and ~2.8 million SNPs in up to 123,865 individuals, with targeted follow-up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity-susceptibility loci and identified 18 new loci associated with BMI (P<5×10−8), one of which includes a copy number variant near GPRC5B. Some loci (MC4R, POMC, SH2B1, BDNF) map near key hypothalamic regulators of energy balance, and one is near GIPR, an incretin receptor. Furthermore, genes in other newly-associated loci may provide novel insights into human body weight regulation.
doi:10.1038/ng.686
PMCID: PMC3014648  PMID: 20935630
12.  New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk 
Dupuis, Josée | Langenberg, Claudia | Prokopenko, Inga | Saxena, Richa | Soranzo, Nicole | Jackson, Anne U | Wheeler, Eleanor | Glazer, Nicole L | Bouatia-Naji, Nabila | Gloyn, Anna L | Lindgren, Cecilia M | Mägi, Reedik | Morris, Andrew P | Randall, Joshua | Johnson, Toby | Elliott, Paul | Rybin, Denis | Thorleifsson, Gudmar | Steinthorsdottir, Valgerdur | Henneman, Peter | Grallert, Harald | Dehghan, Abbas | Hottenga, Jouke Jan | Franklin, Christopher S | Navarro, Pau | Song, Kijoung | Goel, Anuj | Perry, John R B | Egan, Josephine M | Lajunen, Taina | Grarup, Niels | Sparsø, Thomas | Doney, Alex | Voight, Benjamin F | Stringham, Heather M | Li, Man | Kanoni, Stavroula | Shrader, Peter | Cavalcanti-Proença, Christine | Kumari, Meena | Qi, Lu | Timpson, Nicholas J | Gieger, Christian | Zabena, Carina | Rocheleau, Ghislain | Ingelsson, Erik | An, Ping | O’Connell, Jeffrey | Luan, Jian'an | Elliott, Amanda | McCarroll, Steven A | Payne, Felicity | Roccasecca, Rosa Maria | Pattou, François | Sethupathy, Praveen | Ardlie, Kristin | Ariyurek, Yavuz | Balkau, Beverley | Barter, Philip | Beilby, John P | Ben-Shlomo, Yoav | Benediktsson, Rafn | Bennett, Amanda J | Bergmann, Sven | Bochud, Murielle | Boerwinkle, Eric | Bonnefond, Amélie | Bonnycastle, Lori L | Borch-Johnsen, Knut | Böttcher, Yvonne | Brunner, Eric | Bumpstead, Suzannah J | Charpentier, Guillaume | Chen, Yii-Der Ida | Chines, Peter | Clarke, Robert | Coin, Lachlan J M | Cooper, Matthew N | Cornelis, Marilyn | Crawford, Gabe | Crisponi, Laura | Day, Ian N M | de Geus, Eco | Delplanque, Jerome | Dina, Christian | Erdos, Michael R | Fedson, Annette C | Fischer-Rosinsky, Antje | Forouhi, Nita G | Fox, Caroline S | Frants, Rune | Franzosi, Maria Grazia | Galan, Pilar | Goodarzi, Mark O | Graessler, Jürgen | Groves, Christopher J | Grundy, Scott | Gwilliam, Rhian | Gyllensten, Ulf | Hadjadj, Samy | Hallmans, Göran | Hammond, Naomi | Han, Xijing | Hartikainen, Anna-Liisa | Hassanali, Neelam | Hayward, Caroline | Heath, Simon C | Hercberg, Serge | Herder, Christian | Hicks, Andrew A | Hillman, David R | Hingorani, Aroon D | Hofman, Albert | Hui, Jennie | Hung, Joe | Isomaa, Bo | Johnson, Paul R V | Jørgensen, Torben | Jula, Antti | Kaakinen, Marika | Kaprio, Jaakko | Kesaniemi, Y Antero | Kivimaki, Mika | Knight, Beatrice | Koskinen, Seppo | Kovacs, Peter | Kyvik, Kirsten Ohm | Lathrop, G Mark | Lawlor, Debbie A | Le Bacquer, Olivier | Lecoeur, Cécile | Li, Yun | Lyssenko, Valeriya | Mahley, Robert | Mangino, Massimo | Manning, Alisa K | Martínez-Larrad, María Teresa | McAteer, Jarred B | McCulloch, Laura J | McPherson, Ruth | Meisinger, Christa | Melzer, David | Meyre, David | Mitchell, Braxton D | Morken, Mario A | Mukherjee, Sutapa | Naitza, Silvia | Narisu, Narisu | Neville, Matthew J | Oostra, Ben A | Orrù, Marco | Pakyz, Ruth | Palmer, Colin N A | Paolisso, Giuseppe | Pattaro, Cristian | Pearson, Daniel | Peden, John F | Pedersen, Nancy L. | Perola, Markus | Pfeiffer, Andreas F H | Pichler, Irene | Polasek, Ozren | Posthuma, Danielle | Potter, Simon C | Pouta, Anneli | Province, Michael A | Psaty, Bruce M | Rathmann, Wolfgang | Rayner, Nigel W | Rice, Kenneth | Ripatti, Samuli | Rivadeneira, Fernando | Roden, Michael | Rolandsson, Olov | Sandbaek, Annelli | Sandhu, Manjinder | Sanna, Serena | Sayer, Avan Aihie | Scheet, Paul | Scott, Laura J | Seedorf, Udo | Sharp, Stephen J | Shields, Beverley | Sigurðsson, Gunnar | Sijbrands, Erik J G | Silveira, Angela | Simpson, Laila | Singleton, Andrew | Smith, Nicholas L | Sovio, Ulla | Swift, Amy | Syddall, Holly | Syvänen, Ann-Christine | Tanaka, Toshiko | Thorand, Barbara | Tichet, Jean | Tönjes, Anke | Tuomi, Tiinamaija | Uitterlinden, André G | van Dijk, Ko Willems | van Hoek, Mandy | Varma, Dhiraj | Visvikis-Siest, Sophie | Vitart, Veronique | Vogelzangs, Nicole | Waeber, Gérard | Wagner, Peter J | Walley, Andrew | Walters, G Bragi | Ward, Kim L | Watkins, Hugh | Weedon, Michael N | Wild, Sarah H | Willemsen, Gonneke | Witteman, Jaqueline C M | Yarnell, John W G | Zeggini, Eleftheria | Zelenika, Diana | Zethelius, Björn | Zhai, Guangju | Zhao, Jing Hua | Zillikens, M Carola | Borecki, Ingrid B | Loos, Ruth J F | Meneton, Pierre | Magnusson, Patrik K E | Nathan, David M | Williams, Gordon H | Hattersley, Andrew T | Silander, Kaisa | Salomaa, Veikko | Smith, George Davey | Bornstein, Stefan R | Schwarz, Peter | Spranger, Joachim | Karpe, Fredrik | Shuldiner, Alan R | Cooper, Cyrus | Dedoussis, George V | Serrano-Ríos, Manuel | Morris, Andrew D | Lind, Lars | Palmer, Lyle J | Hu, Frank B. | Franks, Paul W | Ebrahim, Shah | Marmot, Michael | Kao, W H Linda | Pankow, James S | Sampson, Michael J | Kuusisto, Johanna | Laakso, Markku | Hansen, Torben | Pedersen, Oluf | Pramstaller, Peter Paul | Wichmann, H Erich | Illig, Thomas | Rudan, Igor | Wright, Alan F | Stumvoll, Michael | Campbell, Harry | Wilson, James F | Hamsten, Anders | Bergman, Richard N | Buchanan, Thomas A | Collins, Francis S | Mohlke, Karen L | Tuomilehto, Jaakko | Valle, Timo T | Altshuler, David | Rotter, Jerome I | Siscovick, David S | Penninx, Brenda W J H | Boomsma, Dorret | Deloukas, Panos | Spector, Timothy D | Frayling, Timothy M | Ferrucci, Luigi | Kong, Augustine | Thorsteinsdottir, Unnur | Stefansson, Kari | van Duijn, Cornelia M | Aulchenko, Yurii S | Cao, Antonio | Scuteri, Angelo | Schlessinger, David | Uda, Manuela | Ruokonen, Aimo | Jarvelin, Marjo-Riitta | Waterworth, Dawn M | Vollenweider, Peter | Peltonen, Leena | Mooser, Vincent | Abecasis, Goncalo R | Wareham, Nicholas J | Sladek, Robert | Froguel, Philippe | Watanabe, Richard M | Meigs, James B | Groop, Leif | Boehnke, Michael | McCarthy, Mark I | Florez, Jose C | Barroso, Inês
Nature genetics  2010;42(2):105-116.
Circulating glucose levels are tightly regulated. To identify novel glycemic loci, we performed meta-analyses of 21 genome-wide associations studies informative for fasting glucose (FG), fasting insulin (FI) and indices of β-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 non-diabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with FG/HOMA-B and two associated with FI/HOMA-IR. These include nine new FG loci (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and FAM148B) and one influencing FI/HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB/TMEM195 with type 2 diabetes (T2D). Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify T2D risk loci, as well as loci that elevate FG modestly, but do not cause overt diabetes.
doi:10.1038/ng.520
PMCID: PMC3018764  PMID: 20081858
13.  Genetic Markers of Adult Obesity Risk Are Associated with Greater Early Infancy Weight Gain and Growth 
PLoS Medicine  2010;7(5):e1000284.
Ken Ong and colleagues genotyped children from the ALSPAC birth cohort and showed an association between greater early infancy gains in weight and length and genetic markers for adult obesity risk.
Background
Genome-wide studies have identified several common genetic variants that are robustly associated with adult obesity risk. Exploration of these genotype associations in children may provide insights into the timing of weight changes leading to adult obesity.
Methods and Findings
Children from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort were genotyped for ten genetic variants previously associated with adult BMI. Eight variants that showed individual associations with childhood BMI (in/near: FTO, MC4R, TMEM18, GNPDA2, KCTD15, NEGR1, BDNF, and ETV5) were used to derive an “obesity-risk-allele score” comprising the total number of risk alleles (range: 2–15 alleles) in each child with complete genotype data (n = 7,146). Repeated measurements of weight, length/height, and body mass index from birth to age 11 years were expressed as standard deviation scores (SDS). Early infancy was defined as birth to age 6 weeks, and early infancy failure to thrive was defined as weight gain between below the 5th centile, adjusted for birth weight. The obesity-risk-allele score showed little association with birth weight (regression coefficient: 0.01 SDS per allele; 95% CI 0.00–0.02), but had an apparently much larger positive effect on early infancy weight gain (0.119 SDS/allele/year; 0.023–0.216) than on subsequent childhood weight gain (0.004 SDS/allele/year; 0.004–0.005). The obesity-risk-allele score was also positively associated with early infancy length gain (0.158 SDS/allele/year; 0.032–0.284) and with reduced risk of early infancy failure to thrive (odds ratio  = 0.92 per allele; 0.86–0.98; p = 0.009).
Conclusions
The use of robust genetic markers identified greater early infancy gains in weight and length as being on the pathway to adult obesity risk in a contemporary birth cohort.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The proportion of overweight and obese children is increasing across the globe. In the US, the Surgeon General estimates that, compared with 1980, twice as many children and three times the number of adolescents are now overweight. Worldwide, 22 million children under five years old are considered by the World Health Organization to be overweight.
Being overweight or obese in childhood is associated with poor physical and mental health. In addition, childhood obesity is considered a major risk factor for adult obesity, which is itself a major risk factor for cancer, heart disease, diabetes, osteoarthritis, and other chronic conditions.
The most commonly used measure of whether an adult is a healthy weight is body mass index (BMI), defined as weight in kilograms/(height in metres)2. However, adult categories of obese (>30) and overweight (>25) BMI are not directly applicable to children, whose BMI naturally varies as they grow. BMI can be used to screen children for being overweight and or obese but a diagnosis requires further information.
Why Was This Study Done?
As the numbers of obese and overweight children increase, a corresponding rise in future numbers of overweight and obese adults is also expected. This in turn is expected to lead to an increasing incidence of poor health. As a result, there is great interest among health professionals in possible pathways between childhood and adult obesity. It has been proposed that certain periods in childhood may be critical for the development of obesity.
In the last few years, ten genetic variants have been found to be more common in overweight or obese adults. Eight of these have also been linked to childhood BMI and/or obesity. The authors wanted to identify the timing of childhood weight changes that may be associated with adult obesity. Knowledge of obesity risk genetic variants gave them an opportunity to do so now, without following a set of children to adulthood.
What Did the Researchers Do and Find?
The authors analysed data gathered from a subset of 7,146 singleton white European children enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC) study, which is investigating associations between genetics, lifestyle, and health outcomes for a group of children in Bristol whose due date of birth fell between April 1991 and December 1992. They used knowledge of the children's genetic makeup to find associations between an obesity risk allele score—a measure of how many of the obesity risk genetic variants a child possessed—and the children's weight, height, BMI, levels of body fat (at nine years old), and rate of weight gain, up to age 11 years.
They found that, at birth, children with a higher obesity risk allele score were not any heavier, but in the immediate postnatal period they were less likely to be in the bottom 5% of the population for weight gain (adjusted for birthweight), often termed “failure to thrive.” At six weeks of age, children with a higher obesity risk allele score tended to be longer and heavier, even allowing for weight at birth.
After six weeks of age, the obesity risk allele score was not associated with any further increase in length/height, but it was associated with a more rapid weight gain between birth and age 11 years. BMI is derived from height and weight measurements, and the association between the obesity risk allele score and BMI was weak between birth and age three-and-a-half years, but after that age the association with BMI increased rapidly. By age nine, children with a higher obesity risk allele score tended to be heavier and taller, with more fat on their bodies.
What Do These Findings Mean?
The combined obesity allele risk score is associated with higher rates of weight gain and adult obesity, and so the authors conclude that weight gain and growth even in the first few weeks after birth may be the beginning of a pathway of greater adult obesity risk.
A study that tracks a population over time can find associations but it cannot show cause and effect. In addition, only a relatively small proportion (1.7%) of the variation in BMI at nine years of age is explained by the obesity risk allele score.
The authors' method of finding associations between childhood events and adult outcomes via genetic markers of risk of disease as an adult has a significant advantage: the authors did not have to follow the children themselves to adulthood, so their findings are more likely to be relevant to current populations. Despite this, this research does not yield advice for parents how to reduce their children's obesity risk. It does suggest that “failure to thrive” in the first six weeks of life is not simply due to a lack of provision of food by the baby's caregiver but that genetic factors also contribute to early weight gain and growth.
The study looked at the combined obesity risk allele score and the authors did not attempt to identify which individual alleles have greater or weaker associations with weight gain and overweight or obesity. This would require further research based on far larger numbers of babies and children. The findings may also not be relevant to children in other types of setting because of the effects of different nutrition and lifestyles.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000284.
Further information is available on the ALSPAC study
The UK National Health Service and other partners provide guidance on establishing a healthy lifestyle for children and families in their Change4Life programme
The International Obesity Taskforce is a global network of expertise and the advocacy arm of the International Association for the Study of Obesity. It works with the World Health Organization, other NGOs, and stakeholders and provides information on overweight and obesity
The Centers for Disease Control and Prevention (CDC) in the US provide guidance and tips on maintaining a healthy weight, including BMI calculators in both metric and Imperial measurements for both adults and children. They also provide BMI growth charts for boys and girls showing how healthy ranges vary for each sex at with age
The Royal College of Paediatrics and Child Health provides growth charts for weight and length/height from birth to age 4 years that are based on WHO 2006 growth standards and have been adapted for use in the UK
The CDC Web site provides information on overweight and obesity in adults and children, including definitions, causes, and data
The CDC also provide information on the role of genes in causing obesity.
The World Health Organization publishes a fact sheet on obesity, overweight and weight management, including links to childhood overweight and obesity
Wikipedia includes an article on childhood obesity (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1000284
PMCID: PMC2876048  PMID: 20520848
14.  Correction: Genome-Wide Association Scan Meta-Analysis Identifies Three Loci Influencing Adiposity and Fat Distribution 
Lindgren, Cecilia M. | Heid, Iris M. | Randall, Joshua C. | Lamina, Claudia | Steinthorsdottir, Valgerdur | Qi, Lu | Speliotes, Elizabeth K. | Thorleifsson, Gudmar | Willer, Cristen J. | Herrera, Blanca M. | Jackson, Anne U. | Lim, Noha | Scheet, Paul | Soranzo, Nicole | Amin, Najaf | Aulchenko, Yurii S. | Chambers, John C. | Drong, Alexander | Luan, Jian'an | Lyon, Helen N. | Rivadeneira, Fernando | Sanna, Serena | Timpson, Nicholas J. | Zillikens, M. Carola | Zhao, Jing Hua | Almgren, Peter | Bandinelli, Stefania | Bennett, Amanda J. | Bergman, Richard N. | Bonnycastle, Lori L. | Bumpstead, Suzannah J. | Chanock, Stephen J. | Cherkas, Lynn | Chines, Peter | Coin, Lachlan | Cooper, Cyrus | Crawford, Gabriel | Doering, Angela | Dominiczak, Anna | Doney, Alex S. F. | Ebrahim, Shah | Elliott, Paul | Erdos, Michael R. | Estrada, Karol | Ferrucci, Luigi | Fischer, Guido | Forouhi, Nita G. | Gieger, Christian | Grallert, Harald | Groves, Christopher J. | Grundy, Scott | Guiducci, Candace | Hadley, David | Hamsten, Anders | Havulinna, Aki S. | Hofman, Albert | Holle, Rolf | Holloway, John W. | Illig, Thomas | Isomaa, Bo | Jacobs, Leonie C. | Jameson, Karen | Jousilahti, Pekka | Karpe, Fredrik | Kuusisto, Johanna | Laitinen, Jaana | Lathrop, G. Mark | Lawlor, Debbie A. | Mangino, Massimo | McArdle, Wendy L. | Meitinger, Thomas | Morken, Mario A. | Morris, Andrew P. | Munroe, Patricia | Narisu, Narisu | Nordström, Anna | Nordström, Peter | Oostra, Ben A. | Palmer, Colin N. A. | Payne, Felicity | Peden, John F. | Prokopenko, Inga | Renström, Frida | Ruokonen, Aimo | Salomaa, Veikko | Sandhu, Manjinder S. | Scott, Laura J. | Scuteri, Angelo | Silander, Kaisa | Song, Kijoung | Yuan, Xin | Stringham, Heather M. | Swift, Amy J. | Tuomi, Tiinamaija | Uda, Manuela | Vollenweider, Peter | Waeber, Gerard | Wallace, Chris | Walters, G. Bragi | Weedon, Michael N. | Witteman, Jacqueline C. M. | Zhang, Cuilin | Zhang, Weihua | Caulfield, Mark J. | Collins, Francis S. | Davey Smith, George | Day, Ian N. M. | Franks, Paul W. | Hattersley, Andrew T. | Hu, Frank B. | Jarvelin, Marjo-Riitta | Kong, Augustine | Kooner, Jaspal S. | Laakso, Markku | Lakatta, Edward | Mooser, Vincent | Morris, Andrew D. | Peltonen, Leena | Samani, Nilesh J. | Spector, Timothy D. | Strachan, David P. | Tanaka, Toshiko | Tuomilehto, Jaakko | Uitterlinden, André G. | van Duijn, Cornelia M. | Wareham, Nicholas J. | Watkins for the PROCARDIS consortia, Hugh | Waterworth, Dawn M. | Boehnke, Michael | Deloukas, Panos | Groop, Leif | Hunter, David J. | Thorsteinsdottir, Unnur | Schlessinger, David | Wichmann, H.-Erich | Frayling, Timothy M. | Abecasis, Gonçalo R. | Hirschhorn, Joel N. | Loos, Ruth J. F. | Stefansson, Kari | Mohlke, Karen L. | Barroso, Inês | McCarthy for the GIANT consortium, Mark I.
PLoS Genetics  2009;5(7):10.1371/annotation/b6e8f9f6-2496-4a40-b0e3-e1d1390c1928.
doi:10.1371/annotation/b6e8f9f6-2496-4a40-b0e3-e1d1390c1928
PMCID: PMC2722420
15.  Six new loci associated with body mass index highlight a neuronal influence on body weight regulation 
Willer, Cristen J | Speliotes, Elizabeth K | Loos, Ruth J F | Li, Shengxu | Lindgren, Cecilia M | Heid, Iris M | Berndt, Sonja I | Elliott, Amanda L | Jackson, Anne U | Lamina, Claudia | Lettre, Guillaume | Lim, Noha | Lyon, Helen N | McCarroll, Steven A | Papadakis, Konstantinos | Qi, Lu | Randall, Joshua C | Roccasecca, Rosa Maria | Sanna, Serena | Scheet, Paul | Weedon, Michael N | Wheeler, Eleanor | Zhao, Jing Hua | Jacobs, Leonie C | Prokopenko, Inga | Soranzo, Nicole | Tanaka, Toshiko | Timpson, Nicholas J | Almgren, Peter | Bennett, Amanda | Bergman, Richard N | Bingham, Sheila A | Bonnycastle, Lori L | Brown, Morris | Burtt, Noël P | Chines, Peter | Coin, Lachlan | Collins, Francis S | Connell, John M | Cooper, Cyrus | Smith, George Davey | Dennison, Elaine M | Deodhar, Parimal | Elliott, Paul | Erdos, Michael R | Estrada, Karol | Evans, David M | Gianniny, Lauren | Gieger, Christian | Gillson, Christopher J | Guiducci, Candace | Hackett, Rachel | Hadley, David | Hall, Alistair S | Havulinna, Aki S | Hebebrand, Johannes | Hofman, Albert | Isomaa, Bo | Jacobs, Kevin B | Johnson, Toby | Jousilahti, Pekka | Jovanovic, Zorica | Khaw, Kay-Tee | Kraft, Peter | Kuokkanen, Mikko | Kuusisto, Johanna | Laitinen, Jaana | Lakatta, Edward G | Luan, Jian'an | Luben, Robert N | Mangino, Massimo | McArdle, Wendy L | Meitinger, Thomas | Mulas, Antonella | Munroe, Patricia B | Narisu, Narisu | Ness, Andrew R | Northstone, Kate | O'Rahilly, Stephen | Purmann, Carolin | Rees, Matthew G | Ridderstråle, Martin | Ring, Susan M | Rivadeneira, Fernando | Ruokonen, Aimo | Sandhu, Manjinder S | Saramies, Jouko | Scott, Laura J | Scuteri, Angelo | Silander, Kaisa | Sims, Matthew A | Song, Kijoung | Stephens, Jonathan | Stevens, Suzanne | Stringham, Heather M | Tung, Y C Loraine | Valle, Timo T | Van Duijn, Cornelia M | Vimaleswaran, Karani S | Vollenweider, Peter | Waeber, Gerard | Wallace, Chris | Watanabe, Richard M | Waterworth, Dawn M | Watkins, Nicholas | Witteman, Jacqueline C M | Zeggini, Eleftheria | Zhai, Guangju | Zillikens, M Carola | Altshuler, David | Caulfield, Mark J | Chanock, Stephen J | Farooqi, I Sadaf | Ferrucci, Luigi | Guralnik, Jack M | Hattersley, Andrew T | Hu, Frank B | Jarvelin, Marjo-Riitta | Laakso, Markku | Mooser, Vincent | Ong, Ken K | Ouwehand, Willem H | Salomaa, Veikko | Samani, Nilesh J | Spector, Timothy D | Tuomi, Tiinamaija | Tuomilehto, Jaakko | Uda, Manuela | Uitterlinden, André G | Wareham, Nicholas J | Deloukas, Panagiotis | Frayling, Timothy M | Groop, Leif C | Hayes, Richard B | Hunter, David J | Mohlke, Karen L | Peltonen, Leena | Schlessinger, David | Strachan, David P | Wichmann, H-Erich | McCarthy, Mark I | Boehnke, Michael | Barroso, Inês | Abecasis, Gonçalo R | Hirschhorn, Joel N
Nature genetics  2008;41(1):25-34.
Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 × 10−8): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.
doi:10.1038/ng.287
PMCID: PMC2695662  PMID: 19079261
16.  Genome-Wide Association Scan Meta-Analysis Identifies Three Loci Influencing Adiposity and Fat Distribution 
Lindgren, Cecilia M. | Heid, Iris M. | Randall, Joshua C. | Lamina, Claudia | Steinthorsdottir, Valgerdur | Qi, Lu | Speliotes, Elizabeth K. | Thorleifsson, Gudmar | Willer, Cristen J. | Herrera, Blanca M. | Jackson, Anne U. | Lim, Noha | Scheet, Paul | Soranzo, Nicole | Amin, Najaf | Aulchenko, Yurii S. | Chambers, John C. | Drong, Alexander | Luan, Jian'an | Lyon, Helen N. | Rivadeneira, Fernando | Sanna, Serena | Timpson, Nicholas J. | Zillikens, M. Carola | Zhao, Jing Hua | Almgren, Peter | Bandinelli, Stefania | Bennett, Amanda J. | Bergman, Richard N. | Bonnycastle, Lori L. | Bumpstead, Suzannah J. | Chanock, Stephen J. | Cherkas, Lynn | Chines, Peter | Coin, Lachlan | Cooper, Cyrus | Crawford, Gabriel | Doering, Angela | Dominiczak, Anna | Doney, Alex S. F. | Ebrahim, Shah | Elliott, Paul | Erdos, Michael R. | Estrada, Karol | Ferrucci, Luigi | Fischer, Guido | Forouhi, Nita G. | Gieger, Christian | Grallert, Harald | Groves, Christopher J. | Grundy, Scott | Guiducci, Candace | Hadley, David | Hamsten, Anders | Havulinna, Aki S. | Hofman, Albert | Holle, Rolf | Holloway, John W. | Illig, Thomas | Isomaa, Bo | Jacobs, Leonie C. | Jameson, Karen | Jousilahti, Pekka | Karpe, Fredrik | Kuusisto, Johanna | Laitinen, Jaana | Lathrop, G. Mark | Lawlor, Debbie A. | Mangino, Massimo | McArdle, Wendy L. | Meitinger, Thomas | Morken, Mario A. | Morris, Andrew P. | Munroe, Patricia | Narisu, Narisu | Nordström, Anna | Nordström, Peter | Oostra, Ben A. | Palmer, Colin N. A. | Payne, Felicity | Peden, John F. | Prokopenko, Inga | Renström, Frida | Ruokonen, Aimo | Salomaa, Veikko | Sandhu, Manjinder S. | Scott, Laura J. | Scuteri, Angelo | Silander, Kaisa | Song, Kijoung | Yuan, Xin | Stringham, Heather M. | Swift, Amy J. | Tuomi, Tiinamaija | Uda, Manuela | Vollenweider, Peter | Waeber, Gerard | Wallace, Chris | Walters, G. Bragi | Weedon, Michael N. | Witteman, Jacqueline C. M. | Zhang, Cuilin | Zhang, Weihua | Caulfield, Mark J. | Collins, Francis S. | Davey Smith, George | Day, Ian N. M. | Franks, Paul W. | Hattersley, Andrew T. | Hu, Frank B. | Jarvelin, Marjo-Riitta | Kong, Augustine | Kooner, Jaspal S. | Laakso, Markku | Lakatta, Edward | Mooser, Vincent | Morris, Andrew D. | Peltonen, Leena | Samani, Nilesh J. | Spector, Timothy D. | Strachan, David P. | Tanaka, Toshiko | Tuomilehto, Jaakko | Uitterlinden, André G. | van Duijn, Cornelia M. | Wareham, Nicholas J. | Watkins for the PROCARDIS consortia, Hugh | Waterworth, Dawn M. | Boehnke, Michael | Deloukas, Panos | Groop, Leif | Hunter, David J. | Thorsteinsdottir, Unnur | Schlessinger, David | Wichmann, H.-Erich | Frayling, Timothy M. | Abecasis, Gonçalo R. | Hirschhorn, Joel N. | Loos, Ruth J. F. | Stefansson, Kari | Mohlke, Karen L. | Barroso, Inês | McCarthy for the GIANT consortium, Mark I.
PLoS Genetics  2009;5(6):e1000508.
To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist–hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9×10−11) and MSRA (WC, P = 8.9×10−9). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6×10−8). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity.
Author Summary
Here, we describe a meta-analysis of genome-wide association data from 38,580 individuals, followed by large-scale replication (in up to 70,689 individuals) designed to uncover variants influencing anthropometric measures of central obesity and fat distribution, namely waist circumference (WC) and waist–hip ratio (WHR). This work complements parallel efforts that have been successful in defining variants impacting overall adiposity and focuses on the visceral fat accumulation which has particularly strong relationships to metabolic and cardiovascular disease. Our analyses have identified two loci (TFAP2B and MSRA) associated with WC, and a further locus, near LYPLAL1, which shows gender-specific relationships with WHR (all to levels of genome-wide significance). These loci vary in the strength of their associations with overall adiposity, and LYPLAL1 in particular appears to have a specific effect on patterns of fat distribution. All in all, these three loci provide novel insights into human physiology and the development of obesity.
doi:10.1371/journal.pgen.1000508
PMCID: PMC2695778  PMID: 19557161
17.  Common variants near MC4R are associated with fat mass, weight and risk of obesity 
Loos, Ruth J F | Lindgren, Cecilia M | Li, Shengxu | Wheeler, Eleanor | Zhao, Jing Hua | Prokopenko, Inga | Inouye, Michael | Freathy, Rachel M | Attwood, Antony P | Beckmann, Jacques S | Berndt, Sonja I | Bergmann, Sven | Bennett, Amanda J | Bingham, Sheila A | Bochud, Murielle | Brown, Morris | Cauchi, Stéphane | Connell, John M | Cooper, Cyrus | Smith, George Davey | Day, Ian | Dina, Christian | De, Subhajyoti | Dermitzakis, Emmanouil T | Doney, Alex S F | Elliott, Katherine S | Elliott, Paul | Evans, David M | Farooqi, I Sadaf | Froguel, Philippe | Ghori, Jilur | Groves, Christopher J | Gwilliam, Rhian | Hadley, David | Hall, Alistair S | Hattersley, Andrew T | Hebebrand, Johannes | Heid, Iris M | Herrera, Blanca | Hinney, Anke | Hunt, Sarah E | Jarvelin, Marjo-Riitta | Johnson, Toby | Jolley, Jennifer D M | Karpe, Fredrik | Keniry, Andrew | Khaw, Kay-Tee | Luben, Robert N | Mangino, Massimo | Marchini, Jonathan | McArdle, Wendy L | McGinnis, Ralph | Meyre, David | Munroe, Patricia B | Morris, Andrew D | Ness, Andrew R | Neville, Matthew J | Nica, Alexandra C | Ong, Ken K | O'Rahilly, Stephen | Owen, Katharine R | Palmer, Colin N A | Papadakis, Konstantinos | Potter, Simon | Pouta, Anneli | Qi, Lu | Randall, Joshua C | Rayner, Nigel W | Ring, Susan M | Sandhu, Manjinder S | Scherag, André | Sims, Matthew A | Song, Kijoung | Soranzo, Nicole | Speliotes, Elizabeth K | Syddall, Holly E | Teichmann, Sarah A | Timpson, Nicholas J | Tobias, Jonathan H | Uda, Manuela | Vogel, Carla I Ganz | Wallace, Chris | Waterworth, Dawn M | Weedon, Michael N | Willer, Cristen J | Wraight, Vicki L | Yuan, Xin | Zeggini, Eleftheria | Hirschhorn, Joel N | Strachan, David P | Ouwehand, Willem H | Caulfield, Mark J | Samani, Nilesh J | Frayling, Timothy M | Vollenweider, Peter | Waeber, Gerard | Mooser, Vincent | Deloukas, Panos | McCarthy, Mark I | Wareham, Nicholas J | Barroso, Inês | Jacobs, Kevin B | Chanock, Stephen J | Hayes, Richard B | Lamina, Claudia | Gieger, Christian | Illig, Thomas | Meitinger, Thomas | Wichmann, H-Erich | Kraft, Peter | Hankinson, Susan E | Hunter, David J | Hu, Frank B | Lyon, Helen N | Voight, Benjamin F | Ridderstrale, Martin | Groop, Leif | Scheet, Paul | Sanna, Serena | Abecasis, Goncalo R | Albai, Giuseppe | Nagaraja, Ramaiah | Schlessinger, David | Jackson, Anne U | Tuomilehto, Jaakko | Collins, Francis S | Boehnke, Michael | Mohlke, Karen L
Nature genetics  2008;40(6):768-775.
To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 × 10−6) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 × 10−15) and 5,988 children aged 7–11 (0.13 Z-score units; P = 1.5 × 10−8). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 × 10−11). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 × 10−4). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits.
doi:10.1038/ng.140
PMCID: PMC2669167  PMID: 18454148
18.  A Common Variant in the FTO Gene Is Associated with Body Mass Index and Predisposes to Childhood and Adult Obesity 
Science (New York, N.Y.)  2007;316(5826):889-894.
Obesity is a serious international health problem that increases the risk of several common diseases. The genetic factors predisposing to obesity are poorly understood. A genome-wide search for type 2 diabetes–susceptibility genes identified a common variant in the FTO (fat mass and obesity associated) gene that predisposes to diabetes through an effect on body mass index (BMI). An additive association of the variant with BMI was replicated in 13 cohorts with 38,759 participants. The 16% of adults who are homozygous for the risk allele weighed about 3 kilograms more and had 1.67-fold increased odds of obesity when compared with those not inheriting a risk allele. This association was observed from age 7 years upward and reflects a specific increase in fat mass.
doi:10.1126/science.1141634
PMCID: PMC2646098  PMID: 17434869
19.  Lipoprotein (a) and risk of coronary, cerebrovascular and peripheral artery disease; the EPIC-Norfolk prospective population study 
Objective
While the association between circulating levels of lipoprotein(a) (Lp(a)) and risk of coronary artery disease (CAD) and stroke is well established, its role in risk of peripheral artery disease (PAD) remains unclear. Here, we examine the association between Lp(a) levels and PAD in a large prospective cohort. To contextualise these findings, we also examined the association between Lp(a) levels and risk of stroke and CAD and studied the role of LDL as an effect modifier of Lp(a) associated cardiovascular risk.
Methods and Results
Lp(a) levels were measured in apparently healthy participants in the EPIC-Norfolk cohort. Cox regression was used to quantify the association between Lp(a) levels and risk of PAD, stroke and CAD outcomes. During 212,981 person-years at risk, a total of 2365 CAD, 284 ischemic stroke and 596 PAD events occurred in 18,720 participants. Lp(a) was associated with PAD and CAD outcomes but not with ischemic stroke (HR per 2.7 fold increase in Lp(a) of 1.37, 95% CI 1.25-1.50, 1.13, 95% CI 1.04-1.22 and 0.91, 95%CI 0.79-1.03 respectively). LDL-C levels did not modify these associations.
Conclusion
Lp(a) levels were associated with future PAD and CAD events. The association between Lp(a) and cardiovascular disease was not modified by LDL-C levels.
doi:10.1161/ATVBAHA.112.255521
PMCID: PMC4210842  PMID: 23065826
20.  Association of Plasma Phospholipid n-3 and n-6 Polyunsaturated Fatty Acids with Type 2 Diabetes: The EPIC-InterAct Case-Cohort Study 
PLoS Medicine  2016;13(7):e1002094.
Background
Whether and how n-3 and n-6 polyunsaturated fatty acids (PUFAs) are related to type 2 diabetes (T2D) is debated. Objectively measured plasma PUFAs can help to clarify these associations.
Methods and Findings
Plasma phospholipid PUFAs were measured by gas chromatography among 12,132 incident T2D cases and 15,919 subcohort participants in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct study across eight European countries. Country-specific hazard ratios (HRs) were estimated using Prentice-weighted Cox regression and pooled by random-effects meta-analysis. We also systematically reviewed published prospective studies on circulating PUFAs and T2D risk and pooled the quantitative evidence for comparison with results from EPIC-InterAct. In EPIC-InterAct, among long-chain n-3 PUFAs, α-linolenic acid (ALA) was inversely associated with T2D (HR per standard deviation [SD] 0.93; 95% CI 0.88–0.98), but eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were not significantly associated. Among n-6 PUFAs, linoleic acid (LA) (0.80; 95% CI 0.77–0.83) and eicosadienoic acid (EDA) (0.89; 95% CI 0.85–0.94) were inversely related, and arachidonic acid (AA) was not significantly associated, while significant positive associations were observed with γ-linolenic acid (GLA), dihomo-GLA, docosatetraenoic acid (DTA), and docosapentaenoic acid (n6-DPA), with HRs between 1.13 to 1.46 per SD. These findings from EPIC-InterAct were broadly similar to comparative findings from summary estimates from up to nine studies including between 71 to 2,499 T2D cases. Limitations included potential residual confounding and the inability to distinguish between dietary and metabolic influences on plasma phospholipid PUFAs.
Conclusions
These large-scale findings suggest an important inverse association of circulating plant-origin n-3 PUFA (ALA) but no convincing association of marine-derived n3 PUFAs (EPA and DHA) with T2D. Moreover, they highlight that the most abundant n6-PUFA (LA) is inversely associated with T2D. The detection of associations with previously less well-investigated PUFAs points to the importance of considering individual fatty acids rather than focusing on fatty acid class.
Using a large European cohort, Nita Forouhi and colleagues investigate the association between the concentration of polyunsaturated fatty acids measured in plasma and risk of developing type 2 diabetes.
Author Summary
Why Was This Study Done?
Most dietary guidelines recommend the consumption of polyunsaturated fatty acids for cardiovascular health, but it is unclear whether or how n-3 and n-6 types of polyunsaturated fatty acids are related to type 2 diabetes.
Health concerns have been raised previously about a diet high in linoleic acid (n-6 fatty acid), but its association with type 2 diabetes is unclear.
Major limitations in previous studies have included the error-prone subjective assessment of the habitual consumption of polyunsaturated fatty acids when dietary intakes were evaluated and a small number of type 2 diabetes cases (n = 71 to 673) when objective biomarkers of polyunsaturated fatty acids were measured.
What Did the Researchers Do and Find?
We measured circulating individual polyunsaturated fatty acids in the blood samples of individuals within a large study from across eight countries of Europe among a reference sample of 15,919 individuals as well as 12,132 individuals who subsequently developed diabetes. Individuals were followed up for an average of approximately 10 y.
We investigated the association between individual polyunsaturated fatty acids and the risk of future type 2 diabetes using statistical analyses that accounted for factors that could be potential alternative explanations for any observed associations.
We found that higher levels of blood alpha-linolenic acid, a plant-origin n-3 fatty acid, and n-6 linoleic acid, the most abundant type of polyunsaturated fatty acid, were associated with a lower risk of future type 2 diabetes. In contrast, higher levels of four other minor individual n-6 fatty acids were associated with higher type 2 diabetes risk, while the blood marine-origin n-3 fatty acids were not associated with future diabetes.
What Do These Findings Mean?
Our findings show that it is important to consider individual circulating polyunsaturated fatty acids for association with type 2 diabetes risk, rather than placing emphasis on the class of circulating polyunsaturated fatty acids.
We found that blood n-6 linoleic acid, the most abundant polyunsaturated fatty acid, is inversely associated with type 2 diabetes.
We found no evidence that blood total n-6 polyunsaturated fatty acids may elevate the risk of type 2 diabetes, but several individual minor blood n-6 polyunsaturated fatty acids were associated with increased type 2 diabetes risk, highlighting the importance of polyunsaturated fatty acid metabolism in the development of type 2 diabetes.
doi:10.1371/journal.pmed.1002094
PMCID: PMC4951144  PMID: 27434045
21.  A Systematic Review of Biomarkers and Risk of Incident Type 2 Diabetes: An Overview of Epidemiological, Prediction and Aetiological Research Literature 
PLoS ONE  2016;11(10):e0163721.
Background
Blood-based or urinary biomarkers may play a role in quantifying the future risk of type 2 diabetes (T2D) and in understanding possible aetiological pathways to disease. However, no systematic review has been conducted that has identified and provided an overview of available biomarkers for incident T2D. We aimed to systematically review the associations of biomarkers with risk of developing T2D and to highlight evidence gaps in the existing literature regarding the predictive and aetiological value of these biomarkers and to direct future research in this field.
Methods and Findings
We systematically searched PubMed MEDLINE (January 2000 until March 2015) and Embase (until January 2016) databases for observational studies of biomarkers and incident T2D according to the 2009 PRISMA guidelines. We also searched availability of meta-analyses, Mendelian randomisation and prediction research for the identified biomarkers. We reviewed 3910 titles (705 abstracts) and 164 full papers and included 139 papers from 69 cohort studies that described the prospective relationships between 167 blood-based or urinary biomarkers and incident T2D. Only 35 biomarkers were reported in large scale studies with more than 1000 T2D cases, and thus the evidence for association was inconclusive for the majority of biomarkers. Fourteen biomarkers have been investigated using Mendelian randomisation approaches. Only for one biomarker was there strong observational evidence of association and evidence from genetic association studies that was compatible with an underlying causal association. In additional search for T2D prediction, we found only half of biomarkers were examined with formal evidence of predictive value for a minority of these biomarkers. Most biomarkers did not enhance the strength of prediction, but the strongest evidence for prediction was for biomarkers that quantify measures of glycaemia.
Conclusions
This study presents an extensive review of the current state of the literature to inform the strategy for future interrogation of existing and newly described biomarkers for T2D. Many biomarkers have been reported to be associated with the risk of developing T2D. The evidence of their value in adding to understanding of causal pathways to disease is very limited so far. The utility of most biomarkers remains largely unknown in clinical prediction. Future research should focus on providing good genetic instruments across consortia for possible biomarkers in Mendelian randomisation, prioritising biomarkers for measurement in large-scale cohort studies and examining predictive utility of biomarkers for a given context.
doi:10.1371/journal.pone.0163721
PMCID: PMC5082867  PMID: 27788146
22.  Genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease 
Scott, Robert A. | Freitag, Daniel F. | Li, Li | Chu, Audrey Y. | Surendran, Praveen | Young, Robin | Grarup, Niels | Stancáková, Alena | Chen, Yuning | V.Varga, Tibor | Yaghootkar, Hanieh | Luan, Jian'an | Zhao, Jing Hua | Willems, Sara M. | Wessel, Jennifer | Wang, Shuai | Maruthur, Nisa | Michailidou, Kyriaki | Pirie, Ailith | van der Lee, Sven J. | Gillson, Christopher | Olama, Ali Amin Al | Amouyel, Philippe | Arriola, Larraitz | Arveiler, Dominique | Aviles-Olmos, Iciar | Balkau, Beverley | Barricarte, Aurelio | Barroso, Inês | Garcia, Sara Benlloch | Bis, Joshua C. | Blankenberg, Stefan | Boehnke, Michael | Boeing, Heiner | Boerwinkle, Eric | Borecki, Ingrid B. | Bork-Jensen, Jette | Bowden, Sarah | Caldas, Carlos | Caslake, Muriel | Cupples, L. Adrienne | Cruchaga, Carlos | Czajkowski, Jacek | den Hoed, Marcel | Dunn, Janet A. | Earl, Helena M. | Ehret, Georg B. | Ferrannini, Ele | Ferrieres, Jean | Foltynie, Thomas | Ford, Ian | Forouhi, Nita G. | Gianfagna, Francesco | Gonzalez, Carlos | Grioni, Sara | Hiller, Louise | Jansson, Jan-Håkan | Jørgensen, Marit E. | Jukema, J. Wouter | Kaaks, Rudolf | Kee, Frank | Kerrison, Nicola D. | Key, Timothy J. | Kontto, Jukka | Kote-Jarai, Zsofia | Kraja, Aldi T. | Kuulasmaa, Kari | Kuusisto, Johanna | Linneberg, Allan | Liu, Chunyu | Marenne, Gaëlle | Mohlke, Karen L. | Morris, Andrew P. | Muir, Kenneth | Müller-Nurasyid, Martina | Munroe, Patricia B. | Navarro, Carmen | Nielsen, Sune F. | Nilsson, Peter M. | Nordestgaard, Børge G. | Packard, Chris J. | Palli, Domenico | Panico, Salvatore | Peloso, Gina M. | Perola, Markus | Peters, Annette | Poole, Christopher J. | Quirós, J. Ramón | Rolandsson, Olov | Sacerdote, Carlotta | Salomaa, Veikko | Sánchez, María-José | Sattar, Naveed | Sharp, Stephen J. | Sims, Rebecca | Slimani, Nadia | Smith, Jennifer A. | Thompson, Deborah J. | Trompet, Stella | Tumino, Rosario | van der A, Daphne L. | van der Schouw, Yvonne T. | Virtamo, Jarmo | Walker, Mark | Walter, Klaudia | Abraham, Jean E. | Amundadottir, Laufey T. | Aponte, Jennifer L. | Butterworth, Adam S. | Dupuis, Josée | Easton, Douglas F. | Eeles, Rosalind A. | Erdmann, Jeanette | Franks, Paul W. | Frayling, Timothy M. | Hansen, Torben | Howson, Joanna M. M. | Jørgensen, Torben | Kooner, Jaspal | Laakso, Markku | Langenberg, Claudia | McCarthy, Mark I. | Pankow, James S. | Pedersen, Oluf | Riboli, Elio | Rotter, Jerome I. | Saleheen, Danish | Samani, Nilesh J. | Schunkert, Heribert | Vollenweider, Peter | O'Rahilly, Stephen | Deloukas, Panos | Danesh, John | Goodarzi, Mark O. | Kathiresan, Sekar | Meigs, James B. | Ehm, Margaret G. | Wareham, Nicholas J. | Waterworth, Dawn M.
Science translational medicine  2016;8(341):341ra76.
Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to inform development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in 6 genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing, and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr;rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and lower T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomised controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.
doi:10.1126/scitranslmed.aad3744
PMCID: PMC5219001  PMID: 27252175
23.  Corrigendum: Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis 
Nature communications  2015;6:6542.
doi:10.1038/ncomms7542
PMCID: PMC5183534  PMID: 25817829
24.  DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases 
Ligthart, Symen | Marzi, Carola | Aslibekyan, Stella | Mendelson, Michael M. | Conneely, Karen N. | Tanaka, Toshiko | Colicino, Elena | Waite, Lindsay L. | Joehanes, Roby | Guan, Weihua | Brody, Jennifer A. | Elks, Cathy | Marioni, Riccardo | Jhun, Min A. | Agha, Golareh | Bressler, Jan | Ward-Caviness, Cavin K. | Chen, Brian H. | Huan, Tianxiao | Bakulski, Kelly | Salfati, Elias L. | Fiorito, Giovanni | Wahl, Simone | Schramm, Katharina | Sha, Jin | Hernandez, Dena G. | Just, Allan C. | Smith, Jennifer A. | Sotoodehnia, Nona | Pilling, Luke C. | Pankow, James S. | Tsao, Phil S. | Liu, Chunyu | Zhao, Wei | Guarrera, Simonetta | Michopoulos, Vasiliki J. | Smith, Alicia K. | Peters, Marjolein J. | Melzer, David | Vokonas, Pantel | Fornage, Myriam | Prokisch, Holger | Bis, Joshua C. | Chu, Audrey Y. | Herder, Christian | Grallert, Harald | Yao, Chen | Shah, Sonia | McRae, Allan F. | Lin, Honghuang | Horvath, Steve | Fallin, Daniele | Hofman, Albert | Wareham, Nicholas J. | Wiggins, Kerri L. | Feinberg, Andrew P. | Starr, John M. | Visscher, Peter M. | Murabito, Joanne M. | Kardia, Sharon L. R. | Absher, Devin M. | Binder, Elisabeth B. | Singleton, Andrew B. | Bandinelli, Stefania | Peters, Annette | Waldenberger, Melanie | Matullo, Giuseppe | Schwartz, Joel D. | Demerath, Ellen W. | Uitterlinden, André G. | van Meurs, Joyce B. J. | Franco, Oscar H. | Chen, Yii-Der Ida | Levy, Daniel | Turner, Stephen T. | Deary, Ian J. | Ressler, Kerry J. | Dupuis, Josée | Ferrucci, Luigi | Ong, Ken K. | Assimes, Themistocles L. | Boerwinkle, Eric | Koenig, Wolfgang | Arnett, Donna K. | Baccarelli, Andrea A. | Benjamin, Emelia J. | Dehghan, Abbas
Genome Biology  2016;17:255.
Background
Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation.
Results
We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 × 10–7) in the discovery panel of European ancestry and replicated (P < 2.29 × 10–4) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 × 10–5), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 × 10–3), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58 × 10–5). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants.
Conclusion
We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-016-1119-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s13059-016-1119-5
PMCID: PMC5151130  PMID: 27955697
Inflammation; DNA methylation; Epigenome-wide association study; C-reactive protein; Body mass index; Diabetes; Coronary heart disease
25.  Estimation of Physical Activity Energy Expenditure during Free-Living from Wrist Accelerometry in UK Adults 
PLoS ONE  2016;11(12):e0167472.
Background
Wrist-worn accelerometers are emerging as the most common instrument for measuring physical activity in large-scale epidemiological studies, though little is known about the relationship between wrist acceleration and physical activity energy expenditure (PAEE).
Methods
1695 UK adults wore two devices simultaneously for six days; a combined sensor and a wrist accelerometer. The combined sensor measured heart rate and trunk acceleration, which was combined with a treadmill test to yield a signal of individually-calibrated PAEE. Multi-level regression models were used to characterise the relationship between the two time-series, and their estimations were evaluated in an independent holdout sample. Finally, the relationship between PAEE and BMI was described separately for each source of PAEE estimate (wrist acceleration models and combined-sensing).
Results
Wrist acceleration explained 44–47% between-individual variance in PAEE, with RMSE between 34–39 J•min-1•kg-1. Estimations agreed well with PAEE in cross-validation (mean bias [95% limits of agreement]: 0.07 [-70.6:70.7]) but overestimated in women by 3% and underestimated in men by 4%. Estimation error was inversely related to age (-2.3 J•min-1•kg-1 per 10y) and BMI (-0.3 J•min-1•kg-1 per kg/m2). Associations with BMI were similar for all PAEE estimates (approximately -0.08 kg/m2 per J•min-1•kg-1).
Conclusions
A strong relationship exists between wrist acceleration and PAEE in free-living adults, such that irrespective of the objective method of PAEE assessment, a strong inverse association between PAEE and BMI was observed.
doi:10.1371/journal.pone.0167472
PMCID: PMC5147924  PMID: 27936024

Results 1-25 (300)