%0 Journal Article %J Nat Genet %D 2010 %T Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. %A Speliotes, Elizabeth K %A Willer, Cristen J %A Berndt, Sonja I %A Monda, Keri L %A Thorleifsson, Gudmar %A Jackson, Anne U %A Lango Allen, Hana %A Lindgren, Cecilia M %A Luan, Jian'an %A Mägi, Reedik %A Randall, Joshua C %A Vedantam, Sailaja %A Winkler, Thomas W %A Qi, Lu %A Workalemahu, Tsegaselassie %A Heid, Iris M %A Steinthorsdottir, Valgerdur %A Stringham, Heather M %A Weedon, Michael N %A Wheeler, Eleanor %A Wood, Andrew R %A Ferreira, Teresa %A Weyant, Robert J %A Segrè, Ayellet V %A Estrada, Karol %A Liang, Liming %A Nemesh, James %A Park, Ju-Hyun %A Gustafsson, Stefan %A Kilpeläinen, Tuomas O %A Yang, Jian %A Bouatia-Naji, Nabila %A Esko, Tõnu %A Feitosa, Mary F %A Kutalik, Zoltán %A Mangino, Massimo %A Raychaudhuri, Soumya %A Scherag, Andre %A Smith, Albert Vernon %A Welch, Ryan %A Zhao, Jing Hua %A Aben, Katja K %A Absher, Devin M %A Amin, Najaf %A Dixon, Anna L %A Fisher, Eva %A Glazer, Nicole L %A Goddard, Michael E %A Heard-Costa, Nancy L %A Hoesel, Volker %A Hottenga, Jouke-Jan %A Johansson, Asa %A Johnson, Toby %A Ketkar, Shamika %A Lamina, Claudia %A Li, Shengxu %A Moffatt, Miriam F %A Myers, Richard H %A Narisu, Narisu %A Perry, John R B %A Peters, Marjolein J %A Preuss, Michael %A Ripatti, Samuli %A Rivadeneira, Fernando %A Sandholt, Camilla %A Scott, Laura J %A Timpson, Nicholas J %A Tyrer, Jonathan P %A van Wingerden, Sophie %A Watanabe, Richard M %A White, Charles C %A Wiklund, Fredrik %A Barlassina, Christina %A Chasman, Daniel I %A Cooper, Matthew N %A Jansson, John-Olov %A Lawrence, Robert W %A Pellikka, Niina %A Prokopenko, Inga %A Shi, Jianxin %A Thiering, Elisabeth %A Alavere, Helene %A Alibrandi, Maria T S %A Almgren, Peter %A Arnold, Alice M %A Aspelund, Thor %A Atwood, Larry D %A Balkau, Beverley %A Balmforth, Anthony J %A Bennett, Amanda J %A Ben-Shlomo, Yoav %A Bergman, Richard N %A Bergmann, Sven %A Biebermann, Heike %A Blakemore, Alexandra I F %A Boes, Tanja %A Bonnycastle, Lori L %A Bornstein, Stefan R %A Brown, Morris J %A Buchanan, Thomas A %A Busonero, Fabio %A Campbell, Harry %A Cappuccio, Francesco P %A Cavalcanti-Proença, Christine %A Chen, Yii-Der Ida %A Chen, Chih-Mei %A Chines, Peter S %A Clarke, Robert %A Coin, Lachlan %A Connell, John %A Day, Ian N M %A den Heijer, Martin %A Duan, Jubao %A Ebrahim, Shah %A Elliott, Paul %A Elosua, Roberto %A Eiriksdottir, Gudny %A Erdos, Michael R %A Eriksson, Johan G %A Facheris, Maurizio F %A Felix, Stephan B %A Fischer-Posovszky, Pamela %A Folsom, Aaron R %A Friedrich, Nele %A Freimer, Nelson B %A Fu, Mao %A Gaget, Stefan %A Gejman, Pablo V %A Geus, Eco J C %A Gieger, Christian %A Gjesing, Anette P %A Goel, Anuj %A Goyette, Philippe %A Grallert, Harald %A Grässler, Jürgen %A Greenawalt, Danielle M %A Groves, Christopher J %A Gudnason, Vilmundur %A Guiducci, Candace %A Hartikainen, Anna-Liisa %A Hassanali, Neelam %A Hall, Alistair S %A Havulinna, Aki S %A Hayward, Caroline %A Heath, Andrew C %A Hengstenberg, Christian %A Hicks, Andrew A %A Hinney, Anke %A Hofman, Albert %A Homuth, Georg %A Hui, Jennie %A Igl, Wilmar %A Iribarren, Carlos %A Isomaa, Bo %A Jacobs, Kevin B %A Jarick, Ivonne %A Jewell, Elizabeth %A John, Ulrich %A Jørgensen, Torben %A Jousilahti, Pekka %A Jula, Antti %A Kaakinen, Marika %A Kajantie, Eero %A Kaplan, Lee M %A Kathiresan, Sekar %A Kettunen, Johannes %A Kinnunen, Leena %A Knowles, Joshua W %A Kolcic, Ivana %A König, Inke R %A Koskinen, Seppo %A Kovacs, Peter %A Kuusisto, Johanna %A Kraft, Peter %A Kvaløy, Kirsti %A Laitinen, Jaana %A Lantieri, Olivier %A Lanzani, Chiara %A Launer, Lenore J %A Lecoeur, Cécile %A Lehtimäki, Terho %A Lettre, Guillaume %A Liu, Jianjun %A Lokki, Marja-Liisa %A Lorentzon, Mattias %A Luben, Robert N %A Ludwig, Barbara %A Manunta, Paolo %A Marek, Diana %A Marre, Michel %A Martin, Nicholas G %A McArdle, Wendy L %A McCarthy, Anne %A McKnight, Barbara %A Meitinger, Thomas %A Melander, Olle %A Meyre, David %A Midthjell, Kristian %A Montgomery, Grant W %A Morken, Mario A %A Morris, Andrew P %A Mulic, Rosanda %A Ngwa, Julius S %A Nelis, Mari %A Neville, Matt J %A Nyholt, Dale R %A O'Donnell, Christopher J %A O'Rahilly, Stephen %A Ong, Ken K %A Oostra, Ben %A Paré, Guillaume %A Parker, Alex N %A Perola, Markus %A Pichler, Irene %A Pietiläinen, Kirsi H %A Platou, Carl G P %A Polasek, Ozren %A Pouta, Anneli %A Rafelt, Suzanne %A Raitakari, Olli %A Rayner, Nigel W %A Ridderstråle, Martin %A Rief, Winfried %A Ruokonen, Aimo %A Robertson, Neil R %A Rzehak, Peter %A Salomaa, Veikko %A Sanders, Alan R %A Sandhu, Manjinder S %A Sanna, Serena %A Saramies, Jouko %A Savolainen, Markku J %A Scherag, Susann %A Schipf, Sabine %A Schreiber, Stefan %A Schunkert, Heribert %A Silander, Kaisa %A Sinisalo, Juha %A Siscovick, David S %A Smit, Jan H %A Soranzo, Nicole %A Sovio, Ulla %A Stephens, Jonathan %A Surakka, Ida %A Swift, Amy J %A Tammesoo, Mari-Liis %A Tardif, Jean-Claude %A Teder-Laving, Maris %A Teslovich, Tanya M %A Thompson, John R %A Thomson, Brian %A Tönjes, Anke %A Tuomi, Tiinamaija %A van Meurs, Joyce B J %A van Ommen, Gert-Jan %A Vatin, Vincent %A Viikari, Jorma %A Visvikis-Siest, Sophie %A Vitart, Veronique %A Vogel, Carla I G %A Voight, Benjamin F %A Waite, Lindsay L %A Wallaschofski, Henri %A Walters, G Bragi %A Widen, Elisabeth %A Wiegand, Susanna %A Wild, Sarah H %A Willemsen, Gonneke %A Witte, Daniel R %A Witteman, Jacqueline C %A Xu, Jianfeng %A Zhang, Qunyuan %A Zgaga, Lina %A Ziegler, Andreas %A Zitting, Paavo %A Beilby, John P %A Farooqi, I Sadaf %A Hebebrand, Johannes %A Huikuri, Heikki V %A James, Alan L %A Kähönen, Mika %A Levinson, Douglas F %A Macciardi, Fabio %A Nieminen, Markku S %A Ohlsson, Claes %A Palmer, Lyle J %A Ridker, Paul M %A Stumvoll, Michael %A Beckmann, Jacques S %A Boeing, Heiner %A Boerwinkle, Eric %A Boomsma, Dorret I %A Caulfield, Mark J %A Chanock, Stephen J %A Collins, Francis S %A Cupples, L Adrienne %A Smith, George Davey %A Erdmann, Jeanette %A Froguel, Philippe %A Grönberg, Henrik %A Gyllensten, Ulf %A Hall, Per %A Hansen, Torben %A Harris, Tamara B %A Hattersley, Andrew T %A Hayes, Richard B %A Heinrich, Joachim %A Hu, Frank B %A Hveem, Kristian %A Illig, Thomas %A Jarvelin, Marjo-Riitta %A Kaprio, Jaakko %A Karpe, Fredrik %A Khaw, Kay-Tee %A Kiemeney, Lambertus A %A Krude, Heiko %A Laakso, Markku %A Lawlor, Debbie A %A Metspalu, Andres %A Munroe, Patricia B %A Ouwehand, Willem H %A Pedersen, Oluf %A Penninx, Brenda W %A Peters, Annette %A Pramstaller, Peter P %A Quertermous, Thomas %A Reinehr, Thomas %A Rissanen, Aila %A Rudan, Igor %A Samani, Nilesh J %A Schwarz, Peter E H %A Shuldiner, Alan R %A Spector, Timothy D %A Tuomilehto, Jaakko %A Uda, Manuela %A Uitterlinden, Andre %A Valle, Timo T %A Wabitsch, Martin %A Waeber, Gérard %A Wareham, Nicholas J %A Watkins, Hugh %A Wilson, James F %A Wright, Alan F %A Zillikens, M Carola %A Chatterjee, Nilanjan %A McCarroll, Steven A %A Purcell, Shaun %A Schadt, Eric E %A Visscher, Peter M %A Assimes, Themistocles L %A Borecki, Ingrid B %A Deloukas, Panos %A Fox, Caroline S %A Groop, Leif C %A Haritunians, Talin %A Hunter, David J %A Kaplan, Robert C %A Mohlke, Karen L %A O'Connell, Jeffrey R %A Peltonen, Leena %A Schlessinger, David %A Strachan, David P %A van Duijn, Cornelia M %A Wichmann, H-Erich %A Frayling, Timothy M %A Thorsteinsdottir, Unnur %A Abecasis, Goncalo R %A Barroso, Inês %A Boehnke, Michael %A Stefansson, Kari %A North, Kari E %A McCarthy, Mark I %A Hirschhorn, Joel N %A Ingelsson, Erik %A Loos, Ruth J F %K Body Height %K Body Mass Index %K Body Size %K Body Weight %K Chromosome Mapping %K European Continental Ancestry Group %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Obesity %K Polymorphism, Single Nucleotide %X

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index 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 body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.

%B Nat Genet %V 42 %P 937-48 %8 2010 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/20935630?dopt=Abstract %R 10.1038/ng.686 %0 Journal Article %J Nature %D 2010 %T Hundreds of variants clustered in genomic loci and biological pathways affect human height. %A Lango Allen, Hana %A Estrada, Karol %A Lettre, Guillaume %A Berndt, Sonja I %A Weedon, Michael N %A Rivadeneira, Fernando %A Willer, Cristen J %A Jackson, Anne U %A Vedantam, Sailaja %A Raychaudhuri, Soumya %A Ferreira, Teresa %A Wood, Andrew R %A Weyant, Robert J %A Segrè, Ayellet V %A Speliotes, Elizabeth K %A Wheeler, Eleanor %A Soranzo, Nicole %A Park, Ju-Hyun %A Yang, Jian %A Gudbjartsson, Daniel %A Heard-Costa, Nancy L %A Randall, Joshua C %A Qi, Lu %A Vernon Smith, Albert %A Mägi, Reedik %A Pastinen, Tomi %A Liang, Liming %A Heid, Iris M %A Luan, Jian'an %A Thorleifsson, Gudmar %A Winkler, Thomas W %A Goddard, Michael E %A Sin Lo, Ken %A Palmer, Cameron %A Workalemahu, Tsegaselassie %A Aulchenko, Yurii S %A Johansson, Asa %A Zillikens, M Carola %A Feitosa, Mary F %A Esko, Tõnu %A Johnson, Toby %A Ketkar, Shamika %A Kraft, Peter %A Mangino, Massimo %A Prokopenko, Inga %A Absher, Devin %A Albrecht, Eva %A Ernst, Florian %A Glazer, Nicole L %A Hayward, Caroline %A Hottenga, Jouke-Jan %A Jacobs, Kevin B %A Knowles, Joshua W %A Kutalik, Zoltán %A Monda, Keri L %A Polasek, Ozren %A Preuss, Michael %A Rayner, Nigel W %A Robertson, Neil R %A Steinthorsdottir, Valgerdur %A Tyrer, Jonathan P %A Voight, Benjamin F %A Wiklund, Fredrik %A Xu, Jianfeng %A Zhao, Jing Hua %A Nyholt, Dale R %A Pellikka, Niina %A Perola, Markus %A Perry, John R B %A Surakka, Ida %A Tammesoo, Mari-Liis %A Altmaier, Elizabeth L %A Amin, Najaf %A Aspelund, Thor %A Bhangale, Tushar %A Boucher, Gabrielle %A Chasman, Daniel I %A Chen, Constance %A Coin, Lachlan %A Cooper, Matthew N %A Dixon, Anna L %A Gibson, Quince %A Grundberg, Elin %A Hao, Ke %A Juhani Junttila, M %A Kaplan, Lee M %A Kettunen, Johannes %A König, Inke R %A Kwan, Tony %A Lawrence, Robert W %A Levinson, Douglas F %A Lorentzon, Mattias %A McKnight, Barbara %A Morris, Andrew P %A Müller, Martina %A Suh Ngwa, Julius %A Purcell, Shaun %A Rafelt, Suzanne %A Salem, Rany M %A Salvi, Erika %A Sanna, Serena %A Shi, Jianxin %A Sovio, Ulla %A Thompson, John R %A Turchin, Michael C %A Vandenput, Liesbeth %A Verlaan, Dominique J %A Vitart, Veronique %A White, Charles C %A Ziegler, Andreas %A Almgren, Peter %A Balmforth, Anthony J %A Campbell, Harry %A Citterio, Lorena %A De Grandi, Alessandro %A Dominiczak, Anna %A Duan, Jubao %A Elliott, Paul %A Elosua, Roberto %A Eriksson, Johan G %A Freimer, Nelson B %A Geus, Eco J C %A Glorioso, Nicola %A Haiqing, Shen %A Hartikainen, Anna-Liisa %A Havulinna, Aki S %A Hicks, Andrew A %A Hui, Jennie %A Igl, Wilmar %A Illig, Thomas %A Jula, Antti %A Kajantie, Eero %A Kilpeläinen, Tuomas O %A Koiranen, Markku %A Kolcic, Ivana %A Koskinen, Seppo %A Kovacs, Peter %A Laitinen, Jaana %A Liu, Jianjun %A Lokki, Marja-Liisa %A Marusic, Ana %A Maschio, Andrea %A Meitinger, Thomas %A Mulas, Antonella %A Paré, Guillaume %A Parker, Alex N %A Peden, John F %A Petersmann, Astrid %A Pichler, Irene %A Pietiläinen, Kirsi H %A Pouta, Anneli %A Ridderstråle, Martin %A Rotter, Jerome I %A Sambrook, Jennifer G %A Sanders, Alan R %A Schmidt, Carsten Oliver %A Sinisalo, Juha %A Smit, Jan H %A Stringham, Heather M %A Bragi Walters, G %A Widen, Elisabeth %A Wild, Sarah H %A Willemsen, Gonneke %A Zagato, Laura %A Zgaga, Lina %A Zitting, Paavo %A Alavere, Helene %A Farrall, Martin %A McArdle, Wendy L %A Nelis, Mari %A Peters, Marjolein J %A Ripatti, Samuli %A van Meurs, Joyce B J %A Aben, Katja K %A Ardlie, Kristin G %A Beckmann, Jacques S %A Beilby, John P %A Bergman, Richard N %A Bergmann, Sven %A Collins, Francis S %A Cusi, Daniele %A den Heijer, Martin %A Eiriksdottir, Gudny %A Gejman, Pablo V %A Hall, Alistair S %A Hamsten, Anders %A Huikuri, Heikki V %A Iribarren, Carlos %A Kähönen, Mika %A Kaprio, Jaakko %A Kathiresan, Sekar %A Kiemeney, Lambertus %A Kocher, Thomas %A Launer, Lenore J %A Lehtimäki, Terho %A Melander, Olle %A Mosley, Tom H %A Musk, Arthur W %A Nieminen, Markku S %A O'Donnell, Christopher J %A Ohlsson, Claes %A Oostra, Ben %A Palmer, Lyle J %A Raitakari, Olli %A Ridker, Paul M %A Rioux, John D %A Rissanen, Aila %A Rivolta, Carlo %A Schunkert, Heribert %A Shuldiner, Alan R %A Siscovick, David S %A Stumvoll, Michael %A Tönjes, Anke %A Tuomilehto, Jaakko %A van Ommen, Gert-Jan %A Viikari, Jorma %A Heath, Andrew C %A Martin, Nicholas G %A Montgomery, Grant W %A Province, Michael A %A Kayser, Manfred %A Arnold, Alice M %A Atwood, Larry D %A Boerwinkle, Eric %A Chanock, Stephen J %A Deloukas, Panos %A Gieger, Christian %A Grönberg, Henrik %A Hall, Per %A Hattersley, Andrew T %A Hengstenberg, Christian %A Hoffman, Wolfgang %A Lathrop, G Mark %A Salomaa, Veikko %A Schreiber, Stefan %A Uda, Manuela %A Waterworth, Dawn %A Wright, Alan F %A Assimes, Themistocles L %A Barroso, Inês %A Hofman, Albert %A Mohlke, Karen L %A Boomsma, Dorret I %A Caulfield, Mark J %A Cupples, L Adrienne %A Erdmann, Jeanette %A Fox, Caroline S %A Gudnason, Vilmundur %A Gyllensten, Ulf %A Harris, Tamara B %A Hayes, Richard B %A Jarvelin, Marjo-Riitta %A Mooser, Vincent %A Munroe, Patricia B %A Ouwehand, Willem H %A Penninx, Brenda W %A Pramstaller, Peter P %A Quertermous, Thomas %A Rudan, Igor %A Samani, Nilesh J %A Spector, Timothy D %A Völzke, Henry %A Watkins, Hugh %A Wilson, James F %A Groop, Leif C %A Haritunians, Talin %A Hu, Frank B %A Kaplan, Robert C %A Metspalu, Andres %A North, Kari E %A Schlessinger, David %A Wareham, Nicholas J %A Hunter, David J %A O'Connell, Jeffrey R %A Strachan, David P %A Wichmann, H-Erich %A Borecki, Ingrid B %A van Duijn, Cornelia M %A Schadt, Eric E %A Thorsteinsdottir, Unnur %A Peltonen, Leena %A Uitterlinden, André G %A Visscher, Peter M %A Chatterjee, Nilanjan %A Loos, Ruth J F %A Boehnke, Michael %A McCarthy, Mark I %A Ingelsson, Erik %A Lindgren, Cecilia M %A Abecasis, Goncalo R %A Stefansson, Kari %A Frayling, Timothy M %A Hirschhorn, Joel N %K Body Height %K Chromosomes, Human, Pair 3 %K Genetic Loci %K Genetic Predisposition to Disease %K Genome, Human %K Genome-Wide Association Study %K Humans %K Metabolic Networks and Pathways %K Multifactorial Inheritance %K Phenotype %K Polymorphism, Single Nucleotide %X

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

%B Nature %V 467 %P 832-8 %8 2010 Oct 14 %G eng %N 7317 %1 http://www.ncbi.nlm.nih.gov/pubmed/20881960?dopt=Abstract %R 10.1038/nature09410 %0 Journal Article %J Nat Genet %D 2010 %T Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. %A Heid, Iris M %A Jackson, Anne U %A Randall, Joshua C %A Winkler, Thomas W %A Qi, Lu %A Steinthorsdottir, Valgerdur %A Thorleifsson, Gudmar %A Zillikens, M Carola %A Speliotes, Elizabeth K %A Mägi, Reedik %A Workalemahu, Tsegaselassie %A White, Charles C %A Bouatia-Naji, Nabila %A Harris, Tamara B %A Berndt, Sonja I %A Ingelsson, Erik %A Willer, Cristen J %A Weedon, Michael N %A Luan, Jian'an %A Vedantam, Sailaja %A Esko, Tõnu %A Kilpeläinen, Tuomas O %A Kutalik, Zoltán %A Li, Shengxu %A Monda, Keri L %A Dixon, Anna L %A Holmes, Christopher C %A Kaplan, Lee M %A Liang, Liming %A Min, Josine L %A Moffatt, Miriam F %A Molony, Cliona %A Nicholson, George %A Schadt, Eric E %A Zondervan, Krina T %A Feitosa, Mary F %A Ferreira, Teresa %A Lango Allen, Hana %A Weyant, Robert J %A Wheeler, Eleanor %A Wood, Andrew R %A Estrada, Karol %A Goddard, Michael E %A Lettre, Guillaume %A Mangino, Massimo %A Nyholt, Dale R %A Purcell, Shaun %A Smith, Albert Vernon %A Visscher, Peter M %A Yang, Jian %A McCarroll, Steven A %A Nemesh, James %A Voight, Benjamin F %A Absher, Devin %A Amin, Najaf %A Aspelund, Thor %A Coin, Lachlan %A Glazer, Nicole L %A Hayward, Caroline %A Heard-Costa, Nancy L %A Hottenga, Jouke-Jan %A Johansson, Asa %A Johnson, Toby %A Kaakinen, Marika %A Kapur, Karen %A Ketkar, Shamika %A Knowles, Joshua W %A Kraft, Peter %A Kraja, Aldi T %A Lamina, Claudia %A Leitzmann, Michael F %A McKnight, Barbara %A Morris, Andrew P %A Ong, Ken K %A Perry, John R B %A Peters, Marjolein J %A Polasek, Ozren %A Prokopenko, Inga %A Rayner, Nigel W %A Ripatti, Samuli %A Rivadeneira, Fernando %A Robertson, Neil R %A Sanna, Serena %A Sovio, Ulla %A Surakka, Ida %A Teumer, Alexander %A van Wingerden, Sophie %A Vitart, Veronique %A Zhao, Jing Hua %A Cavalcanti-Proença, Christine %A Chines, Peter S %A Fisher, Eva %A Kulzer, Jennifer R %A Lecoeur, Cécile %A Narisu, Narisu %A Sandholt, Camilla %A Scott, Laura J %A Silander, Kaisa %A Stark, Klaus %A Tammesoo, Mari-Liis %A Teslovich, Tanya M %A Timpson, Nicholas John %A Watanabe, Richard M %A Welch, Ryan %A Chasman, Daniel I %A Cooper, Matthew N %A Jansson, John-Olov %A Kettunen, Johannes %A Lawrence, Robert W %A Pellikka, Niina %A Perola, Markus %A Vandenput, Liesbeth %A Alavere, Helene %A Almgren, Peter %A Atwood, Larry D %A Bennett, Amanda J %A Biffar, Reiner %A Bonnycastle, Lori L %A Bornstein, Stefan R %A Buchanan, Thomas A %A Campbell, Harry %A Day, Ian N M %A Dei, Mariano %A Dörr, Marcus %A Elliott, Paul %A Erdos, Michael R %A Eriksson, Johan G %A Freimer, Nelson B %A Fu, Mao %A Gaget, Stefan %A Geus, Eco J C %A Gjesing, Anette P %A Grallert, Harald %A Grässler, Jürgen %A Groves, Christopher J %A Guiducci, Candace %A Hartikainen, Anna-Liisa %A Hassanali, Neelam %A Havulinna, Aki S %A Herzig, Karl-Heinz %A Hicks, Andrew A %A Hui, Jennie %A Igl, Wilmar %A Jousilahti, Pekka %A Jula, Antti %A Kajantie, Eero %A Kinnunen, Leena %A Kolcic, Ivana %A Koskinen, Seppo %A Kovacs, Peter %A Kroemer, Heyo K %A Krzelj, Vjekoslav %A Kuusisto, Johanna %A Kvaloy, Kirsti %A Laitinen, Jaana %A Lantieri, Olivier %A Lathrop, G Mark %A Lokki, Marja-Liisa %A Luben, Robert N %A Ludwig, Barbara %A McArdle, Wendy L %A McCarthy, Anne %A Morken, Mario A %A Nelis, Mari %A Neville, Matt J %A Paré, Guillaume %A Parker, Alex N %A Peden, John F %A Pichler, Irene %A Pietiläinen, Kirsi H %A Platou, Carl G P %A Pouta, Anneli %A Ridderstråle, Martin %A Samani, Nilesh J %A Saramies, Jouko %A Sinisalo, Juha %A Smit, Jan H %A Strawbridge, Rona J %A Stringham, Heather M %A Swift, Amy J %A Teder-Laving, Maris %A Thomson, Brian %A Usala, Gianluca %A van Meurs, Joyce B J %A van Ommen, Gert-Jan %A Vatin, Vincent %A Volpato, Claudia B %A Wallaschofski, Henri %A Walters, G Bragi %A Widen, Elisabeth %A Wild, Sarah H %A Willemsen, Gonneke %A Witte, Daniel R %A Zgaga, Lina %A Zitting, Paavo %A Beilby, John P %A James, Alan L %A Kähönen, Mika %A Lehtimäki, Terho %A Nieminen, Markku S %A Ohlsson, Claes %A Palmer, Lyle J %A Raitakari, Olli %A Ridker, Paul M %A Stumvoll, Michael %A Tönjes, Anke %A Viikari, Jorma %A Balkau, Beverley %A Ben-Shlomo, Yoav %A Bergman, Richard N %A Boeing, Heiner %A Smith, George Davey %A Ebrahim, Shah %A Froguel, Philippe %A Hansen, Torben %A Hengstenberg, Christian %A Hveem, Kristian %A Isomaa, Bo %A Jørgensen, Torben %A Karpe, Fredrik %A Khaw, Kay-Tee %A Laakso, Markku %A Lawlor, Debbie A %A Marre, Michel %A Meitinger, Thomas %A Metspalu, Andres %A Midthjell, Kristian %A Pedersen, Oluf %A Salomaa, Veikko %A Schwarz, Peter E H %A Tuomi, Tiinamaija %A Tuomilehto, Jaakko %A Valle, Timo T %A Wareham, Nicholas J %A Arnold, Alice M %A Beckmann, Jacques S %A Bergmann, Sven %A Boerwinkle, Eric %A Boomsma, Dorret I %A Caulfield, Mark J %A Collins, Francis S %A Eiriksdottir, Gudny %A Gudnason, Vilmundur %A Gyllensten, Ulf %A Hamsten, Anders %A Hattersley, Andrew T %A Hofman, Albert %A Hu, Frank B %A Illig, Thomas %A Iribarren, Carlos %A Jarvelin, Marjo-Riitta %A Kao, W H Linda %A Kaprio, Jaakko %A Launer, Lenore J %A Munroe, Patricia B %A Oostra, Ben %A Penninx, Brenda W %A Pramstaller, Peter P %A Psaty, Bruce M %A Quertermous, Thomas %A Rissanen, Aila %A Rudan, Igor %A Shuldiner, Alan R %A Soranzo, Nicole %A Spector, Timothy D %A Syvänen, Ann-Christine %A Uda, Manuela %A Uitterlinden, Andre %A Völzke, Henry %A Vollenweider, Peter %A Wilson, James F %A Witteman, Jacqueline C %A Wright, Alan F %A Abecasis, Goncalo R %A Boehnke, Michael %A Borecki, Ingrid B %A Deloukas, Panos %A Frayling, Timothy M %A Groop, Leif C %A Haritunians, Talin %A Hunter, David J %A Kaplan, Robert C %A North, Kari E %A O'Connell, Jeffrey R %A Peltonen, Leena %A Schlessinger, David %A Strachan, David P %A Hirschhorn, Joel N %A Assimes, Themistocles L %A Wichmann, H-Erich %A Thorsteinsdottir, Unnur %A van Duijn, Cornelia M %A Stefansson, Kari %A Cupples, L Adrienne %A Loos, Ruth J F %A Barroso, Inês %A McCarthy, Mark I %A Fox, Caroline S %A Mohlke, Karen L %A Lindgren, Cecilia M %K Adipose Tissue %K Age Factors %K Chromosome Mapping %K Female %K Genome, Human %K Genome-Wide Association Study %K Humans %K Male %K Meta-Analysis as Topic %K Polymorphism, Single Nucleotide %K Sex Characteristics %K Waist-Hip Ratio %X

Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.

%B Nat Genet %V 42 %P 949-60 %8 2010 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/20935629?dopt=Abstract %R 10.1038/ng.685 %0 Journal Article %J Nat Genet %D 2012 %T Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. %A Estrada, Karol %A Styrkarsdottir, Unnur %A Evangelou, Evangelos %A Hsu, Yi-Hsiang %A Duncan, Emma L %A Ntzani, Evangelia E %A Oei, Ling %A Albagha, Omar M E %A Amin, Najaf %A Kemp, John P %A Koller, Daniel L %A Li, Guo %A Liu, Ching-Ti %A Minster, Ryan L %A Moayyeri, Alireza %A Vandenput, Liesbeth %A Willner, Dana %A Xiao, Su-Mei %A Yerges-Armstrong, Laura M %A Zheng, Hou-Feng %A Alonso, Nerea %A Eriksson, Joel %A Kammerer, Candace M %A Kaptoge, Stephen K %A Leo, Paul J %A Thorleifsson, Gudmar %A Wilson, Scott G %A Wilson, James F %A Aalto, Ville %A Alen, Markku %A Aragaki, Aaron K %A Aspelund, Thor %A Center, Jacqueline R %A Dailiana, Zoe %A Duggan, David J %A Garcia, Melissa %A García-Giralt, Natalia %A Giroux, Sylvie %A Hallmans, Göran %A Hocking, Lynne J %A Husted, Lise Bjerre %A Jameson, Karen A %A Khusainova, Rita %A Kim, Ghi Su %A Kooperberg, Charles %A Koromila, Theodora %A Kruk, Marcin %A Laaksonen, Marika %A LaCroix, Andrea Z %A Lee, Seung Hun %A Leung, Ping C %A Lewis, Joshua R %A Masi, Laura %A Mencej-Bedrac, Simona %A Nguyen, Tuan V %A Nogues, Xavier %A Patel, Millan S %A Prezelj, Janez %A Rose, Lynda M %A Scollen, Serena %A Siggeirsdottir, Kristin %A Smith, Albert V %A Svensson, Olle %A Trompet, Stella %A Trummer, Olivia %A van Schoor, Natasja M %A Woo, Jean %A Zhu, Kun %A Balcells, Susana %A Brandi, Maria Luisa %A Buckley, Brendan M %A Cheng, Sulin %A Christiansen, Claus %A Cooper, Cyrus %A Dedoussis, George %A Ford, Ian %A Frost, Morten %A Goltzman, David %A González-Macías, Jesús %A Kähönen, Mika %A Karlsson, Magnus %A Khusnutdinova, Elza %A Koh, Jung-Min %A Kollia, Panagoula %A Langdahl, Bente Lomholt %A Leslie, William D %A Lips, Paul %A Ljunggren, Osten %A Lorenc, Roman S %A Marc, Janja %A Mellström, Dan %A Obermayer-Pietsch, Barbara %A Olmos, José M %A Pettersson-Kymmer, Ulrika %A Reid, David M %A Riancho, José A %A Ridker, Paul M %A Rousseau, François %A Slagboom, P Eline %A Tang, Nelson L S %A Urreizti, Roser %A Van Hul, Wim %A Viikari, Jorma %A Zarrabeitia, María T %A Aulchenko, Yurii S %A Castano-Betancourt, Martha %A Grundberg, Elin %A Herrera, Lizbeth %A Ingvarsson, Thorvaldur %A Johannsdottir, Hrefna %A Kwan, Tony %A Li, Rui %A Luben, Robert %A Medina-Gómez, Carolina %A Palsson, Stefan Th %A Reppe, Sjur %A Rotter, Jerome I %A Sigurdsson, Gunnar %A van Meurs, Joyce B J %A Verlaan, Dominique %A Williams, Frances M K %A Wood, Andrew R %A Zhou, Yanhua %A Gautvik, Kaare M %A Pastinen, Tomi %A Raychaudhuri, Soumya %A Cauley, Jane A %A Chasman, Daniel I %A Clark, Graeme R %A Cummings, Steven R %A Danoy, Patrick %A Dennison, Elaine M %A Eastell, Richard %A Eisman, John A %A Gudnason, Vilmundur %A Hofman, Albert %A Jackson, Rebecca D %A Jones, Graeme %A Jukema, J Wouter %A Khaw, Kay-Tee %A Lehtimäki, Terho %A Liu, Yongmei %A Lorentzon, Mattias %A McCloskey, Eugene %A Mitchell, Braxton D %A Nandakumar, Kannabiran %A Nicholson, Geoffrey C %A Oostra, Ben A %A Peacock, Munro %A Pols, Huibert A P %A Prince, Richard L %A Raitakari, Olli %A Reid, Ian R %A Robbins, John %A Sambrook, Philip N %A Sham, Pak Chung %A Shuldiner, Alan R %A Tylavsky, Frances A %A van Duijn, Cornelia M %A Wareham, Nick J %A Cupples, L Adrienne %A Econs, Michael J %A Evans, David M %A Harris, Tamara B %A Kung, Annie Wai Chee %A Psaty, Bruce M %A Reeve, Jonathan %A Spector, Timothy D %A Streeten, Elizabeth A %A Zillikens, M Carola %A Thorsteinsdottir, Unnur %A Ohlsson, Claes %A Karasik, David %A Richards, J Brent %A Brown, Matthew A %A Stefansson, Kari %A Uitterlinden, André G %A Ralston, Stuart H %A Ioannidis, John P A %A Kiel, Douglas P %A Rivadeneira, Fernando %K Bone Density %K Computational Biology %K European Continental Ancestry Group %K Extracellular Matrix Proteins %K Female %K Femur Neck %K Fractures, Bone %K Gene Expression Profiling %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Glycoproteins %K Humans %K Intercellular Signaling Peptides and Proteins %K Low Density Lipoprotein Receptor-Related Protein-5 %K Lumbar Vertebrae %K Male %K Mitochondrial Membrane Transport Proteins %K Osteoporosis %K Phosphoproteins %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Risk Factors %K Spectrin %X

Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

%B Nat Genet %V 44 %P 491-501 %8 2012 Apr 15 %G eng %N 5 %R 10.1038/ng.2249 %0 Journal Article %J Am J Clin Nutr %D 2013 %T Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease. %A van Meurs, Joyce B J %A Paré, Guillaume %A Schwartz, Stephen M %A Hazra, Aditi %A Tanaka, Toshiko %A Vermeulen, Sita H %A Cotlarciuc, Ioana %A Yuan, Xin %A Mälarstig, Anders %A Bandinelli, Stefania %A Bis, Joshua C %A Blom, Henk %A Brown, Morris J %A Chen, Constance %A Chen, Yii-Der %A Clarke, Robert J %A Dehghan, Abbas %A Erdmann, Jeanette %A Ferrucci, Luigi %A Hamsten, Anders %A Hofman, Albert %A Hunter, David J %A Goel, Anuj %A Johnson, Andrew D %A Kathiresan, Sekar %A Kampman, Ellen %A Kiel, Douglas P %A Kiemeney, Lambertus A L M %A Chambers, John C %A Kraft, Peter %A Lindemans, Jan %A McKnight, Barbara %A Nelson, Christopher P %A O'Donnell, Christopher J %A Psaty, Bruce M %A Ridker, Paul M %A Rivadeneira, Fernando %A Rose, Lynda M %A Seedorf, Udo %A Siscovick, David S %A Schunkert, Heribert %A Selhub, Jacob %A Ueland, Per M %A Vollenweider, Peter %A Waeber, Gérard %A Waterworth, Dawn M %A Watkins, Hugh %A Witteman, Jacqueline C M %A den Heijer, Martin %A Jacques, Paul %A Uitterlinden, André G %A Kooner, Jaspal S %A Rader, Dan J %A Reilly, Muredach P %A Mooser, Vincent %A Chasman, Daniel I %A Samani, Nilesh J %A Ahmadi, Kourosh R %K Coronary Artery Disease %K Genes %K Genetic Loci %K Genetic Predisposition to Disease %K Genotype %K Homocysteine %K Humans %K Polymorphism, Genetic %K Risk Factors %X

BACKGROUND: The strong observational association between total homocysteine (tHcy) concentrations and risk of coronary artery disease (CAD) and the null associations in the homocysteine-lowering trials have prompted the need to identify genetic variants associated with homocysteine concentrations and risk of CAD.

OBJECTIVE: We tested whether common genetic polymorphisms associated with variation in tHcy are also associated with CAD.

DESIGN: We conducted a meta-analysis of genome-wide association studies (GWAS) on tHcy concentrations in 44,147 individuals of European descent. Polymorphisms associated with tHcy (P < 10(⁻⁸) were tested for association with CAD in 31,400 cases and 92,927 controls.

RESULTS: Common variants at 13 loci, explaining 5.9% of the variation in tHcy, were associated with tHcy concentrations, including 6 novel loci in or near MMACHC (2.1 × 10⁻⁹), SLC17A3 (1.0 × 10⁻⁸), GTPB10 (1.7 × 10⁻⁸), CUBN (7.5 × 10⁻¹⁰), HNF1A (1.2 × 10⁻¹²)), and FUT2 (6.6 × 10⁻⁹), and variants previously reported at or near the MTHFR, MTR, CPS1, MUT, NOX4, DPEP1, and CBS genes. Individuals within the highest 10% of the genotype risk score (GRS) had 3-μmol/L higher mean tHcy concentrations than did those within the lowest 10% of the GRS (P = 1 × 10⁻³⁶). The GRS was not associated with risk of CAD (OR: 1.01; 95% CI: 0.98, 1.04; P = 0.49).

CONCLUSIONS: We identified several novel loci that influence plasma tHcy concentrations. Overall, common genetic variants that influence plasma tHcy concentrations are not associated with risk of CAD in white populations, which further refutes the causal relevance of moderately elevated tHcy concentrations and tHcy-related pathways for CAD.

%B Am J Clin Nutr %V 98 %P 668-76 %8 2013 Sep %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/23824729?dopt=Abstract %R 10.3945/ajcn.112.044545 %0 Journal Article %J Nat Genet %D 2013 %T Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture. %A Berndt, Sonja I %A Gustafsson, Stefan %A Mägi, Reedik %A Ganna, Andrea %A Wheeler, Eleanor %A Feitosa, Mary F %A Justice, Anne E %A Monda, Keri L %A Croteau-Chonka, Damien C %A Day, Felix R %A Esko, Tõnu %A Fall, Tove %A Ferreira, Teresa %A Gentilini, Davide %A Jackson, Anne U %A Luan, Jian'an %A Randall, Joshua C %A Vedantam, Sailaja %A Willer, Cristen J %A Winkler, Thomas W %A Wood, Andrew R %A Workalemahu, Tsegaselassie %A Hu, Yi-Juan %A Lee, Sang Hong %A Liang, Liming %A Lin, Dan-Yu %A Min, Josine L %A Neale, Benjamin M %A Thorleifsson, Gudmar %A Yang, Jian %A Albrecht, Eva %A Amin, Najaf %A Bragg-Gresham, Jennifer L %A Cadby, Gemma %A den Heijer, Martin %A Eklund, Niina %A Fischer, Krista %A Goel, Anuj %A Hottenga, Jouke-Jan %A Huffman, Jennifer E %A Jarick, Ivonne %A Johansson, Asa %A Johnson, Toby %A Kanoni, Stavroula %A Kleber, Marcus E %A König, Inke R %A Kristiansson, Kati %A Kutalik, Zoltán %A Lamina, Claudia %A Lecoeur, Cécile %A Li, Guo %A Mangino, Massimo %A McArdle, Wendy L %A Medina-Gómez, Carolina %A Müller-Nurasyid, Martina %A Ngwa, Julius S %A Nolte, Ilja M %A Paternoster, Lavinia %A Pechlivanis, Sonali %A Perola, Markus %A Peters, Marjolein J %A Preuss, Michael %A Rose, Lynda M %A Shi, Jianxin %A Shungin, Dmitry %A Smith, Albert Vernon %A Strawbridge, Rona J %A Surakka, Ida %A Teumer, Alexander %A Trip, Mieke D %A Tyrer, Jonathan %A van Vliet-Ostaptchouk, Jana V %A Vandenput, Liesbeth %A Waite, Lindsay L %A Zhao, Jing Hua %A Absher, Devin %A Asselbergs, Folkert W %A Atalay, Mustafa %A Attwood, Antony P %A Balmforth, Anthony J %A Basart, Hanneke %A Beilby, John %A Bonnycastle, Lori L %A Brambilla, Paolo %A Bruinenberg, Marcel %A Campbell, Harry %A Chasman, Daniel I %A Chines, Peter S %A Collins, Francis S %A Connell, John M %A Cookson, William O %A de Faire, Ulf %A de Vegt, Femmie %A Dei, Mariano %A Dimitriou, Maria %A Edkins, Sarah %A Estrada, Karol %A Evans, David M %A Farrall, Martin %A Ferrario, Marco M %A Ferrieres, Jean %A Franke, Lude %A Frau, Francesca %A Gejman, Pablo V %A Grallert, Harald %A Grönberg, Henrik %A Gudnason, Vilmundur %A Hall, Alistair S %A Hall, Per %A Hartikainen, Anna-Liisa %A Hayward, Caroline %A Heard-Costa, Nancy L %A Heath, Andrew C %A Hebebrand, Johannes %A Homuth, Georg %A Hu, Frank B %A Hunt, Sarah E %A Hyppönen, Elina %A Iribarren, Carlos %A Jacobs, Kevin B %A Jansson, John-Olov %A Jula, Antti %A Kähönen, Mika %A Kathiresan, Sekar %A Kee, Frank %A Khaw, Kay-Tee %A Kivimaki, Mika %A Koenig, Wolfgang %A Kraja, Aldi T %A Kumari, Meena %A Kuulasmaa, Kari %A Kuusisto, Johanna %A Laitinen, Jaana H %A Lakka, Timo A %A Langenberg, Claudia %A Launer, Lenore J %A Lind, Lars %A Lindström, Jaana %A Liu, Jianjun %A Liuzzi, Antonio %A Lokki, Marja-Liisa %A Lorentzon, Mattias %A Madden, Pamela A %A Magnusson, Patrik K %A Manunta, Paolo %A Marek, Diana %A März, Winfried %A Mateo Leach, Irene %A McKnight, Barbara %A Medland, Sarah E %A Mihailov, Evelin %A Milani, Lili %A Montgomery, Grant W %A Mooser, Vincent %A Mühleisen, Thomas W %A Munroe, Patricia B %A Musk, Arthur W %A Narisu, Narisu %A Navis, Gerjan %A Nicholson, George %A Nohr, Ellen A %A Ong, Ken K %A Oostra, Ben A %A Palmer, Colin N A %A Palotie, Aarno %A Peden, John F %A Pedersen, Nancy %A Peters, Annette %A Polasek, Ozren %A Pouta, Anneli %A Pramstaller, Peter P %A Prokopenko, Inga %A Pütter, Carolin %A Radhakrishnan, Aparna %A Raitakari, Olli %A Rendon, Augusto %A Rivadeneira, Fernando %A Rudan, Igor %A Saaristo, Timo E %A Sambrook, Jennifer G %A Sanders, Alan R %A Sanna, Serena %A Saramies, Jouko %A Schipf, Sabine %A Schreiber, Stefan %A Schunkert, Heribert %A Shin, So-Youn %A Signorini, Stefano %A Sinisalo, Juha %A Skrobek, Boris %A Soranzo, Nicole %A Stančáková, Alena %A Stark, Klaus %A Stephens, Jonathan C %A Stirrups, Kathleen %A Stolk, Ronald P %A Stumvoll, Michael %A Swift, Amy J %A Theodoraki, Eirini V %A Thorand, Barbara %A Trégouët, David-Alexandre %A Tremoli, Elena %A van der Klauw, Melanie M %A van Meurs, Joyce B J %A Vermeulen, Sita H %A Viikari, Jorma %A Virtamo, Jarmo %A Vitart, Veronique %A Waeber, Gérard %A Wang, Zhaoming %A Widen, Elisabeth %A Wild, Sarah H %A Willemsen, Gonneke %A Winkelmann, Bernhard R %A Witteman, Jacqueline C M %A Wolffenbuttel, Bruce H R %A Wong, Andrew %A Wright, Alan F %A Zillikens, M Carola %A Amouyel, Philippe %A Boehm, Bernhard O %A Boerwinkle, Eric %A Boomsma, Dorret I %A Caulfield, Mark J %A Chanock, Stephen J %A Cupples, L Adrienne %A Cusi, Daniele %A Dedoussis, George V %A Erdmann, Jeanette %A Eriksson, Johan G %A Franks, Paul W %A Froguel, Philippe %A Gieger, Christian %A Gyllensten, Ulf %A Hamsten, Anders %A Harris, Tamara B %A Hengstenberg, Christian %A Hicks, Andrew A %A Hingorani, Aroon %A Hinney, Anke %A Hofman, Albert %A Hovingh, Kees G %A Hveem, Kristian %A Illig, Thomas %A Jarvelin, Marjo-Riitta %A Jöckel, Karl-Heinz %A Keinanen-Kiukaanniemi, Sirkka M %A Kiemeney, Lambertus A %A Kuh, Diana %A Laakso, Markku %A Lehtimäki, Terho %A Levinson, Douglas F %A Martin, Nicholas G %A Metspalu, Andres %A Morris, Andrew D %A Nieminen, Markku S %A Njølstad, Inger %A Ohlsson, Claes %A Oldehinkel, Albertine J %A Ouwehand, Willem H %A Palmer, Lyle J %A Penninx, Brenda %A Power, Chris %A Province, Michael A %A Psaty, Bruce M %A Qi, Lu %A Rauramaa, Rainer %A Ridker, Paul M %A Ripatti, Samuli %A Salomaa, Veikko %A Samani, Nilesh J %A Snieder, Harold %A Sørensen, Thorkild I A %A Spector, Timothy D %A Stefansson, Kari %A Tönjes, Anke %A Tuomilehto, Jaakko %A Uitterlinden, André G %A Uusitupa, Matti %A van der Harst, Pim %A Vollenweider, Peter %A Wallaschofski, Henri %A Wareham, Nicholas J %A Watkins, Hugh %A Wichmann, H-Erich %A Wilson, James F %A Abecasis, Goncalo R %A Assimes, Themistocles L %A Barroso, Inês %A Boehnke, Michael %A Borecki, Ingrid B %A Deloukas, Panos %A Fox, Caroline S %A Frayling, Timothy %A Groop, Leif C %A Haritunian, Talin %A Heid, Iris M %A Hunter, David %A Kaplan, Robert C %A Karpe, Fredrik %A Moffatt, Miriam F %A Mohlke, Karen L %A O'Connell, Jeffrey R %A Pawitan, Yudi %A Schadt, Eric E %A Schlessinger, David %A Steinthorsdottir, Valgerdur %A Strachan, David P %A Thorsteinsdottir, Unnur %A van Duijn, Cornelia M %A Visscher, Peter M %A Di Blasio, Anna Maria %A Hirschhorn, Joel N %A Lindgren, Cecilia M %A Morris, Andrew P %A Meyre, David %A Scherag, Andre %A McCarthy, Mark I %A Speliotes, Elizabeth K %A North, Kari E %A Loos, Ruth J F %A Ingelsson, Erik %K Anthropometry %K Body Height %K Body Mass Index %K Case-Control Studies %K European Continental Ancestry Group %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Meta-Analysis as Topic %K Obesity %K Phenotype %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Waist-Hip Ratio %X

Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.

%B Nat Genet %V 45 %P 501-12 %8 2013 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/23563607?dopt=Abstract %R 10.1038/ng.2606 %0 Journal Article %J Stroke %D 2014 %T Effect of genetic variants associated with plasma homocysteine levels on stroke risk. %A Cotlarciuc, Ioana %A Malik, Rainer %A Holliday, Elizabeth G %A Ahmadi, Kourosh R %A Paré, Guillaume %A Psaty, Bruce M %A Fornage, Myriam %A Hasan, Nazeeha %A Rinne, Paul E %A Ikram, M Arfan %A Markus, Hugh S %A Rosand, Jonathan %A Mitchell, Braxton D %A Kittner, Steven J %A Meschia, James F %A van Meurs, Joyce B J %A Uitterlinden, André G %A Worrall, Bradford B %A Dichgans, Martin %A Sharma, Pankaj %K Brain Ischemia %K Cohort Studies %K Europe %K Genetic Association Studies %K Genetic Loci %K Genetic Predisposition to Disease %K Genetic Variation %K Genome %K Homocysteine %K Humans %K Polymorphism, Single Nucleotide %K Risk %K Stroke %X

BACKGROUND AND PURPOSE: Elevated total plasma homocysteine (tHcy) levels are known to be associated with increased risk of ischemic stroke (IS). Given that both tHcy and IS are heritable traits, we investigated a potential genetic relationship between homocysteine levels and stroke risk by assessing 18 polymorphisms previously associated with tHcy levels for their association with IS and its subtypes.

METHODS: Previous meta-analysis results from an international stroke collaborative network, METASTROKE, were used to assess association of the 18 tHcy-associated single-nucleotide polymorphisms (SNPs) in 12 389 IS cases and 62 004 controls. We also investigated the associations in regions located within 50 kb from the 18 tHcy-related SNPs and the association of a genetic risk score, including the 18 SNPs.

RESULTS: One SNP located in the RASIP1 gene and a cluster of 3 SNPs located at and near SLC17A3 were significantly associated with IS (P<0.0003) after correcting for multiple testing. For stroke subtypes, the sentinel SNP located upstream of MUT was significantly associated with small-vessel disease (P=0.0022), whereas 1 SNP located in MTHFR was significantly associated with large-vessel disease (P=0.00019). A genetic risk score, including the 18 SNPs, did not show significant association with IS or its subtypes.

CONCLUSIONS: This study found several potential associations with IS and its subtypes: an association of an MUT variant with small-vessel disease, an MTHFR variant with large-vessel disease, and associations of RASIP1 and SLC17A3 variants with overall IS.

%B Stroke %V 45 %P 1920-4 %8 2014 Jul %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/24846872?dopt=Abstract %R 10.1161/STROKEAHA.114.005208 %0 Journal Article %J Nat Genet %D 2014 %T Genome-wide association analysis identifies six new loci associated with forced vital capacity. %A Loth, Daan W %A Soler Artigas, Maria %A Gharib, Sina A %A Wain, Louise V %A Franceschini, Nora %A Koch, Beate %A Pottinger, Tess D %A Smith, Albert Vernon %A Duan, Qing %A Oldmeadow, Chris %A Lee, Mi Kyeong %A Strachan, David P %A James, Alan L %A Huffman, Jennifer E %A Vitart, Veronique %A Ramasamy, Adaikalavan %A Wareham, Nicholas J %A Kaprio, Jaakko %A Wang, Xin-Qun %A Trochet, Holly %A Kähönen, Mika %A Flexeder, Claudia %A Albrecht, Eva %A Lopez, Lorna M %A de Jong, Kim %A Thyagarajan, Bharat %A Alves, Alexessander Couto %A Enroth, Stefan %A Omenaas, Ernst %A Joshi, Peter K %A Fall, Tove %A Viñuela, Ana %A Launer, Lenore J %A Loehr, Laura R %A Fornage, Myriam %A Li, Guo %A Wilk, Jemma B %A Tang, Wenbo %A Manichaikul, Ani %A Lahousse, Lies %A Harris, Tamara B %A North, Kari E %A Rudnicka, Alicja R %A Hui, Jennie %A Gu, Xiangjun %A Lumley, Thomas %A Wright, Alan F %A Hastie, Nicholas D %A Campbell, Susan %A Kumar, Rajesh %A Pin, Isabelle %A Scott, Robert A %A Pietiläinen, Kirsi H %A Surakka, Ida %A Liu, Yongmei %A Holliday, Elizabeth G %A Schulz, Holger %A Heinrich, Joachim %A Davies, Gail %A Vonk, Judith M %A Wojczynski, Mary %A Pouta, Anneli %A Johansson, Asa %A Wild, Sarah H %A Ingelsson, Erik %A Rivadeneira, Fernando %A Völzke, Henry %A Hysi, Pirro G %A Eiriksdottir, Gudny %A Morrison, Alanna C %A Rotter, Jerome I %A Gao, Wei %A Postma, Dirkje S %A White, Wendy B %A Rich, Stephen S %A Hofman, Albert %A Aspelund, Thor %A Couper, David %A Smith, Lewis J %A Psaty, Bruce M %A Lohman, Kurt %A Burchard, Esteban G %A Uitterlinden, André G %A Garcia, Melissa %A Joubert, Bonnie R %A McArdle, Wendy L %A Musk, A Bill %A Hansel, Nadia %A Heckbert, Susan R %A Zgaga, Lina %A van Meurs, Joyce B J %A Navarro, Pau %A Rudan, Igor %A Oh, Yeon-Mok %A Redline, Susan %A Jarvis, Deborah L %A Zhao, Jing Hua %A Rantanen, Taina %A O'Connor, George T %A Ripatti, Samuli %A Scott, Rodney J %A Karrasch, Stefan %A Grallert, Harald %A Gaddis, Nathan C %A Starr, John M %A Wijmenga, Cisca %A Minster, Ryan L %A Lederer, David J %A Pekkanen, Juha %A Gyllensten, Ulf %A Campbell, Harry %A Morris, Andrew P %A Gläser, Sven %A Hammond, Christopher J %A Burkart, Kristin M %A Beilby, John %A Kritchevsky, Stephen B %A Gudnason, Vilmundur %A Hancock, Dana B %A Williams, O Dale %A Polasek, Ozren %A Zemunik, Tatijana %A Kolcic, Ivana %A Petrini, Marcy F %A Wjst, Matthias %A Kim, Woo Jin %A Porteous, David J %A Scotland, Generation %A Smith, Blair H %A Viljanen, Anne %A Heliövaara, Markku %A Attia, John R %A Sayers, Ian %A Hampel, Regina %A Gieger, Christian %A Deary, Ian J %A Boezen, H Marike %A Newman, Anne %A Jarvelin, Marjo-Riitta %A Wilson, James F %A Lind, Lars %A Stricker, Bruno H %A Teumer, Alexander %A Spector, Timothy D %A Melén, Erik %A Peters, Marjolein J %A Lange, Leslie A %A Barr, R Graham %A Bracke, Ken R %A Verhamme, Fien M %A Sung, Joohon %A Hiemstra, Pieter S %A Cassano, Patricia A %A Sood, Akshay %A Hayward, Caroline %A Dupuis, Josée %A Hall, Ian P %A Brusselle, Guy G %A Tobin, Martin D %A London, Stephanie J %K Cohort Studies %K Databases, Genetic %K Follow-Up Studies %K Forced Expiratory Volume %K Genetic Loci %K Genetic Predisposition to Disease %K Genome, Human %K Genome-Wide Association Study %K Humans %K Lung Diseases %K Meta-Analysis as Topic %K Polymorphism, Single Nucleotide %K Prognosis %K Quantitative Trait Loci %K Respiratory Function Tests %K Spirometry %K Vital Capacity %X

Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.

%B Nat Genet %V 46 %P 669-77 %8 2014 Jul %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/24929828?dopt=Abstract %R 10.1038/ng.3011 %0 Journal Article %J Genome Biol %D 2016 %T DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases. %A Ligthart, Symen %A Marzi, Carola %A Aslibekyan, Stella %A Mendelson, Michael M %A Conneely, Karen N %A Tanaka, Toshiko %A Colicino, Elena %A Waite, Lindsay L %A Joehanes, Roby %A Guan, Weihua %A Brody, Jennifer A %A Elks, Cathy %A Marioni, Riccardo %A Jhun, Min A %A Agha, Golareh %A Bressler, Jan %A Ward-Caviness, Cavin K %A Chen, Brian H %A Huan, Tianxiao %A Bakulski, Kelly %A Salfati, Elias L %A Fiorito, Giovanni %A Wahl, Simone %A Schramm, Katharina %A Sha, Jin %A Hernandez, Dena G %A Just, Allan C %A Smith, Jennifer A %A Sotoodehnia, Nona %A Pilling, Luke C %A Pankow, James S %A Tsao, Phil S %A Liu, Chunyu %A Zhao, Wei %A Guarrera, Simonetta %A Michopoulos, Vasiliki J %A Smith, Alicia K %A Peters, Marjolein J %A Melzer, David %A Vokonas, Pantel %A Fornage, Myriam %A Prokisch, Holger %A Bis, Joshua C %A Chu, Audrey Y %A Herder, Christian %A Grallert, Harald %A Yao, Chen %A Shah, Sonia %A McRae, Allan F %A Lin, Honghuang %A Horvath, Steve %A Fallin, Daniele %A Hofman, Albert %A Wareham, Nicholas J %A Wiggins, Kerri L %A Feinberg, Andrew P %A Starr, John M %A Visscher, Peter M %A Murabito, Joanne M %A Kardia, Sharon L R %A Absher, Devin M %A Binder, Elisabeth B %A Singleton, Andrew B %A Bandinelli, Stefania %A Peters, Annette %A Waldenberger, Melanie %A Matullo, Giuseppe %A Schwartz, Joel D %A Demerath, Ellen W %A Uitterlinden, André G %A van Meurs, Joyce B J %A Franco, Oscar H %A Chen, Yii-Der Ida %A Levy, Daniel %A Turner, Stephen T %A Deary, Ian J %A Ressler, Kerry J %A Dupuis, Josée %A Ferrucci, Luigi %A Ong, Ken K %A Assimes, Themistocles L %A Boerwinkle, Eric %A Koenig, Wolfgang %A Arnett, Donna K %A Baccarelli, Andrea A %A Benjamin, Emelia J %A Dehghan, Abbas %X

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.

%B Genome Biol %V 17 %P 255 %8 2016 Dec 12 %G eng %N 1 %R 10.1186/s13059-016-1119-5 %0 Journal Article %J Circ Cardiovasc Genet %D 2016 %T Epigenetic Signatures of Cigarette Smoking. %A Joehanes, Roby %A Just, Allan C %A Marioni, Riccardo E %A Pilling, Luke C %A Reynolds, Lindsay M %A Mandaviya, Pooja R %A Guan, Weihua %A Xu, Tao %A Elks, Cathy E %A Aslibekyan, Stella %A Moreno-Macias, Hortensia %A Smith, Jennifer A %A Brody, Jennifer A %A Dhingra, Radhika %A Yousefi, Paul %A Pankow, James S %A Kunze, Sonja %A Shah, Sonia H %A McRae, Allan F %A Lohman, Kurt %A Sha, Jin %A Absher, Devin M %A Ferrucci, Luigi %A Zhao, Wei %A Demerath, Ellen W %A Bressler, Jan %A Grove, Megan L %A Huan, Tianxiao %A Liu, Chunyu %A Mendelson, Michael M %A Yao, Chen %A Kiel, Douglas P %A Peters, Annette %A Wang-Sattler, Rui %A Visscher, Peter M %A Wray, Naomi R %A Starr, John M %A Ding, Jingzhong %A Rodriguez, Carlos J %A Wareham, Nicholas J %A Irvin, Marguerite R %A Zhi, Degui %A Barrdahl, Myrto %A Vineis, Paolo %A Ambatipudi, Srikant %A Uitterlinden, André G %A Hofman, Albert %A Schwartz, Joel %A Colicino, Elena %A Hou, Lifang %A Vokonas, Pantel S %A Hernandez, Dena G %A Singleton, Andrew B %A Bandinelli, Stefania %A Turner, Stephen T %A Ware, Erin B %A Smith, Alicia K %A Klengel, Torsten %A Binder, Elisabeth B %A Psaty, Bruce M %A Taylor, Kent D %A Gharib, Sina A %A Swenson, Brenton R %A Liang, Liming %A DeMeo, Dawn L %A O'Connor, George T %A Herceg, Zdenko %A Ressler, Kerry J %A Conneely, Karen N %A Sotoodehnia, Nona %A Kardia, Sharon L R %A Melzer, David %A Baccarelli, Andrea A %A van Meurs, Joyce B J %A Romieu, Isabelle %A Arnett, Donna K %A Ong, Ken K %A Liu, Yongmei %A Waldenberger, Melanie %A Deary, Ian J %A Fornage, Myriam %A Levy, Daniel %A London, Stephanie J %X

BACKGROUND: DNA methylation leaves a long-term signature of smoking exposure and is one potential mechanism by which tobacco exposure predisposes to adverse health outcomes, such as cancers, osteoporosis, lung, and cardiovascular disorders.

METHODS AND RESULTS: To comprehensively determine the association between cigarette smoking and DNA methylation, we conducted a meta-analysis of genome-wide DNA methylation assessed using the Illumina BeadChip 450K array on 15 907 blood-derived DNA samples from participants in 16 cohorts (including 2433 current, 6518 former, and 6956 never smokers). Comparing current versus never smokers, 2623 cytosine-phosphate-guanine sites (CpGs), annotated to 1405 genes, were statistically significantly differentially methylated at Bonferroni threshold of P<1×10(-7) (18 760 CpGs at false discovery rate <0.05). Genes annotated to these CpGs were enriched for associations with several smoking-related traits in genome-wide studies including pulmonary function, cancers, inflammatory diseases, and heart disease. Comparing former versus never smokers, 185 of the CpGs that differed between current and never smokers were significant P<1×10(-7) (2623 CpGs at false discovery rate <0.05), indicating a pattern of persistent altered methylation, with attenuation, after smoking cessation. Transcriptomic integration identified effects on gene expression at many differentially methylated CpGs.

CONCLUSIONS: Cigarette smoking has a broad impact on genome-wide methylation that, at many loci, persists many years after smoking cessation. Many of the differentially methylated genes were novel genes with respect to biological effects of smoking and might represent therapeutic targets for prevention or treatment of tobacco-related diseases. Methylation at these sites could also serve as sensitive and stable biomarkers of lifetime exposure to tobacco smoke.

%B Circ Cardiovasc Genet %V 9 %P 436-447 %8 2016 Oct %G eng %N 5 %R 10.1161/CIRCGENETICS.116.001506 %0 Journal Article %J Blood %D 2018 %T DNA methylation age is associated with an altered hemostatic profile in a multi-ethnic meta-analysis. %A Ward-Caviness, Cavin K %A Huffman, Jennifer E %A Evertt, Karl %A Germain, Marine %A van Dongen, Jenny %A Hill, W David %A Jhun, Min A %A Brody, Jennifer A %A Ghanbari, Mohsen %A Du, Lei %A Roetker, Nicholas S %A de Vries, Paul S %A Waldenberger, Melanie %A Gieger, Christian %A Wolf, Petra %A Prokisch, Holger %A Koenig, Wolfgang %A O'Donnell, Christopher J %A Levy, Daniel %A Liu, Chunyu %A Truong, Vinh %A Wells, Philip S %A Trégouët, David-Alexandre %A Tang, Weihong %A Morrison, Alanna C %A Boerwinkle, Eric %A Wiggins, Kerri L %A McKnight, Barbara %A Guo, Xiuqing %A Psaty, Bruce M %A Sotoodenia, Nona %A Boomsa, Dorret I %A Willemsen, Gonneke %A Ligthart, Lannie %A Deary, Ian J %A Zhao, Wei %A Ware, Erin B %A Kardia, Sharon L R %A van Meurs, Joyce B J %A Uitterlinden, André G %A Franco, Oscar H %A Eriksson, Per %A Franco-Cereceda, Anders %A Pankow, James S %A Johnson, Andrew D %A Gagnon, France %A Morange, Pierre-Emmanuel %A de Geus, Eco J C %A Starr, John M %A Smith, Jennifer A %A Dehghan, Abbas %A Björck, Hanna M %A Smith, Nicholas L %A Peters, Annette %X

Many hemostatic factors are associated with age and age-related diseases, however much remains unknown about the biological mechanisms linking aging and hemostatic factors. DNA methylation is a novel means by which to assess epigenetic aging, which is a measure of age and the aging processes as determined by altered epigenetic states. We used a meta-analysis approach to examine the association between measures of epigenetic aging and hemostatic factors, as well as a clotting time measure. For fibrinogen, we used European and African-ancestry participants who were meta-analyzed separately and combined via a random effects meta-analysis. All other measures only included participants of European-ancestry. We found that 1-year higher extrinsic epigenetic age as compared to chronological age was associated with higher fibrinogen (0.004 g/L per year; 95% CI: 0.001, 0.007; P = 0.01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL per year; 95% CI: 0.07, 0.20; P = 6.6x10-5) concentrations as well as lower activated partial thromboplastin time, a measure of clotting time. We replicated PAI-1 associations using an independent cohort. To further elucidate potential functional mechanisms we associated epigenetic aging with expression levels of the PAI-1 protein encoding gene (SERPINE1) and the three fibrinogen subunit-encoding genes (FGA, FGG, and FGB), in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of FGG in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a pro-coagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.

%B Blood %8 2018 Jul 24 %G eng %R 10.1182/blood-2018-02-831347 %0 Journal Article %J PLoS Genet %D 2018 %T Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain. %A Suri, Pradeep %A Palmer, Melody R %A Tsepilov, Yakov A %A Freidin, Maxim B %A Boer, Cindy G %A Yau, Michelle S %A Evans, Daniel S %A Gelemanovic, Andrea %A Bartz, Traci M %A Nethander, Maria %A Arbeeva, Liubov %A Karssen, Lennart %A Neogi, Tuhina %A Campbell, Archie %A Mellström, Dan %A Ohlsson, Claes %A Marshall, Lynn M %A Orwoll, Eric %A Uitterlinden, Andre %A Rotter, Jerome I %A Lauc, Gordan %A Psaty, Bruce M %A Karlsson, Magnus K %A Lane, Nancy E %A Jarvik, Gail P %A Polasek, Ozren %A Hochberg, Marc %A Jordan, Joanne M %A van Meurs, Joyce B J %A Jackson, Rebecca %A Nielson, Carrie M %A Mitchell, Braxton D %A Smith, Blair H %A Hayward, Caroline %A Smith, Nicholas L %A Aulchenko, Yurii S %A Williams, Frances M K %X

Back pain is the #1 cause of years lived with disability worldwide, yet surprisingly little is known regarding the biology underlying this symptom. We conducted a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP). Adults of European ancestry were included from 15 cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and from the UK Biobank interim data release. CBP cases were defined as those reporting back pain present for ≥3-6 months; non-cases were included as comparisons ("controls"). Each cohort conducted genotyping using commercially available arrays followed by imputation. GWAS used logistic regression models with additive genetic effects, adjusting for age, sex, study-specific covariates, and population substructure. The threshold for genome-wide significance in the fixed-effect inverse-variance weighted meta-analysis was p<5×10-8. Suggestive (p<5×10-7) and genome-wide significant (p<5×10-8) variants were carried forward for replication or further investigation in the remaining UK Biobank participants not included in the discovery sample. The discovery sample comprised 158,025 individuals, including 29,531 CBP cases. A genome-wide significant association was found for the intronic variant rs12310519 in SOX5 (OR 1.08, p = 7.2×10-10). This was subsequently replicated in 283,752 UK Biobank participants not included in the discovery sample, including 50,915 cases (OR 1.06, p = 5.3×10-11), and exceeded genome-wide significance in joint meta-analysis (OR 1.07, p = 4.5×10-19). We found suggestive associations at three other loci in the discovery sample, two of which exceeded genome-wide significance in joint meta-analysis: an intergenic variant, rs7833174, located between CCDC26 and GSDMC (OR 1.05, p = 4.4×10-13), and an intronic variant, rs4384683, in DCC (OR 0.97, p = 2.4×10-10). In this first reported meta-analysis of GWAS for CBP, we identified and replicated a genetic locus associated with CBP (SOX5). We also identified 2 other loci that reached genome-wide significance in a 2-stage joint meta-analysis (CCDC26/GSDMC and DCC).

%B PLoS Genet %V 14 %P e1007601 %8 2018 Sep %G eng %N 9 %R 10.1371/journal.pgen.1007601 %0 Journal Article %J Nat Commun %D 2021 %T Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus. %A Tin, Adrienne %A Schlosser, Pascal %A Matias-Garcia, Pamela R %A Thio, Chris H L %A Joehanes, Roby %A Liu, Hongbo %A Yu, Zhi %A Weihs, Antoine %A Hoppmann, Anselm %A Grundner-Culemann, Franziska %A Min, Josine L %A Kuhns, Victoria L Halperin %A Adeyemo, Adebowale A %A Agyemang, Charles %A Arnlöv, Johan %A Aziz, Nasir A %A Baccarelli, Andrea %A Bochud, Murielle %A Brenner, Hermann %A Bressler, Jan %A Breteler, Monique M B %A Carmeli, Cristian %A Chaker, Layal %A Coresh, Josef %A Corre, Tanguy %A Correa, Adolfo %A Cox, Simon R %A Delgado, Graciela E %A Eckardt, Kai-Uwe %A Ekici, Arif B %A Endlich, Karlhans %A Floyd, James S %A Fraszczyk, Eliza %A Gao, Xu %A Gào, Xīn %A Gelber, Allan C %A Ghanbari, Mohsen %A Ghasemi, Sahar %A Gieger, Christian %A Greenland, Philip %A Grove, Megan L %A Harris, Sarah E %A Hemani, Gibran %A Henneman, Peter %A Herder, Christian %A Horvath, Steve %A Hou, Lifang %A Hurme, Mikko A %A Hwang, Shih-Jen %A Kardia, Sharon L R %A Kasela, Silva %A Kleber, Marcus E %A Koenig, Wolfgang %A Kooner, Jaspal S %A Kronenberg, Florian %A Kuhnel, Brigitte %A Ladd-Acosta, Christine %A Lehtimäki, Terho %A Lind, Lars %A Liu, Dan %A Lloyd-Jones, Donald M %A Lorkowski, Stefan %A Lu, Ake T %A Marioni, Riccardo E %A März, Winfried %A McCartney, Daniel L %A Meeks, Karlijn A C %A Milani, Lili %A Mishra, Pashupati P %A Nauck, Matthias %A Nowak, Christoph %A Peters, Annette %A Prokisch, Holger %A Psaty, Bruce M %A Raitakari, Olli T %A Ratliff, Scott M %A Reiner, Alex P %A Schöttker, Ben %A Schwartz, Joel %A Sedaghat, Sanaz %A Smith, Jennifer A %A Sotoodehnia, Nona %A Stocker, Hannah R %A Stringhini, Silvia %A Sundström, Johan %A Swenson, Brenton R %A van Meurs, Joyce B J %A van Vliet-Ostaptchouk, Jana V %A Venema, Andrea %A Völker, Uwe %A Winkelmann, Juliane %A Wolffenbuttel, Bruce H R %A Zhao, Wei %A Zheng, Yinan %A Loh, Marie %A Snieder, Harold %A Waldenberger, Melanie %A Levy, Daniel %A Akilesh, Shreeram %A Woodward, Owen M %A Susztak, Katalin %A Teumer, Alexander %A Köttgen, Anna %K Amino Acid Transport System y+ %K Cohort Studies %K CpG Islands %K DNA Methylation %K Epigenome %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Glucose Transport Proteins, Facilitative %K Gout %K Humans %K Male %K Uric Acid %X

Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E-7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.

%B Nat Commun %V 12 %P 7173 %8 2021 12 09 %G eng %N 1 %R 10.1038/s41467-021-27198-4 %0 Journal Article %J Nature %D 2021 %T Genetic insights into biological mechanisms governing human ovarian ageing. %A Ruth, Katherine S %A Day, Felix R %A Hussain, Jazib %A Martínez-Marchal, Ana %A Aiken, Catherine E %A Azad, Ajuna %A Thompson, Deborah J %A Knoblochova, Lucie %A Abe, Hironori %A Tarry-Adkins, Jane L %A Gonzalez, Javier Martin %A Fontanillas, Pierre %A Claringbould, Annique %A Bakker, Olivier B %A Sulem, Patrick %A Walters, Robin G %A Terao, Chikashi %A Turon, Sandra %A Horikoshi, Momoko %A Lin, Kuang %A Onland-Moret, N Charlotte %A Sankar, Aditya %A Hertz, Emil Peter Thrane %A Timshel, Pascal N %A Shukla, Vallari %A Borup, Rehannah %A Olsen, Kristina W %A Aguilera, Paula %A Ferrer-Roda, Mònica %A Huang, Yan %A Stankovic, Stasa %A Timmers, Paul R H J %A Ahearn, Thomas U %A Alizadeh, Behrooz Z %A Naderi, Elnaz %A Andrulis, Irene L %A Arnold, Alice M %A Aronson, Kristan J %A Augustinsson, Annelie %A Bandinelli, Stefania %A Barbieri, Caterina M %A Beaumont, Robin N %A Becher, Heiko %A Beckmann, Matthias W %A Benonisdottir, Stefania %A Bergmann, Sven %A Bochud, Murielle %A Boerwinkle, Eric %A Bojesen, Stig E %A Bolla, Manjeet K %A Boomsma, Dorret I %A Bowker, Nicholas %A Brody, Jennifer A %A Broer, Linda %A Buring, Julie E %A Campbell, Archie %A Campbell, Harry %A Castelao, Jose E %A Catamo, Eulalia %A Chanock, Stephen J %A Chenevix-Trench, Georgia %A Ciullo, Marina %A Corre, Tanguy %A Couch, Fergus J %A Cox, Angela %A Crisponi, Laura %A Cross, Simon S %A Cucca, Francesco %A Czene, Kamila %A Smith, George Davey %A de Geus, Eco J C N %A de Mutsert, Renée %A De Vivo, Immaculata %A Demerath, Ellen W %A Dennis, Joe %A Dunning, Alison M %A Dwek, Miriam %A Eriksson, Mikael %A Esko, Tõnu %A Fasching, Peter A %A Faul, Jessica D %A Ferrucci, Luigi %A Franceschini, Nora %A Frayling, Timothy M %A Gago-Dominguez, Manuela %A Mezzavilla, Massimo %A García-Closas, Montserrat %A Gieger, Christian %A Giles, Graham G %A Grallert, Harald %A Gudbjartsson, Daniel F %A Gudnason, Vilmundur %A Guénel, Pascal %A Haiman, Christopher A %A Håkansson, Niclas %A Hall, Per %A Hayward, Caroline %A He, Chunyan %A He, Wei %A Heiss, Gerardo %A Høffding, Miya K %A Hopper, John L %A Hottenga, Jouke J %A Hu, Frank %A Hunter, David %A Ikram, Mohammad A %A Jackson, Rebecca D %A Joaquim, Micaella D R %A John, Esther M %A Joshi, Peter K %A Karasik, David %A Kardia, Sharon L R %A Kartsonaki, Christiana %A Karlsson, Robert %A Kitahara, Cari M %A Kolcic, Ivana %A Kooperberg, Charles %A Kraft, Peter %A Kurian, Allison W %A Kutalik, Zoltán %A La Bianca, Martina %A Lachance, Genevieve %A Langenberg, Claudia %A Launer, Lenore J %A Laven, Joop S E %A Lawlor, Deborah A %A Le Marchand, Loïc %A Li, Jingmei %A Lindblom, Annika %A Lindström, Sara %A Lindstrom, Tricia %A Linet, Martha %A Liu, Yongmei %A Liu, Simin %A Luan, Jian'an %A Mägi, Reedik %A Magnusson, Patrik K E %A Mangino, Massimo %A Mannermaa, Arto %A Marco, Brumat %A Marten, Jonathan %A Martin, Nicholas G %A Mbarek, Hamdi %A McKnight, Barbara %A Medland, Sarah E %A Meisinger, Christa %A Meitinger, Thomas %A Menni, Cristina %A Metspalu, Andres %A Milani, Lili %A Milne, Roger L %A Montgomery, Grant W %A Mook-Kanamori, Dennis O %A Mulas, Antonella %A Mulligan, Anna M %A Murray, Alison %A Nalls, Mike A %A Newman, Anne %A Noordam, Raymond %A Nutile, Teresa %A Nyholt, Dale R %A Olshan, Andrew F %A Olsson, Håkan %A Painter, Jodie N %A Patel, Alpa V %A Pedersen, Nancy L %A Perjakova, Natalia %A Peters, Annette %A Peters, Ulrike %A Pharoah, Paul D P %A Polasek, Ozren %A Porcu, Eleonora %A Psaty, Bruce M %A Rahman, Iffat %A Rennert, Gad %A Rennert, Hedy S %A Ridker, Paul M %A Ring, Susan M %A Robino, Antonietta %A Rose, Lynda M %A Rosendaal, Frits R %A Rossouw, Jacques %A Rudan, Igor %A Rueedi, Rico %A Ruggiero, Daniela %A Sala, Cinzia F %A Saloustros, Emmanouil %A Sandler, Dale P %A Sanna, Serena %A Sawyer, Elinor J %A Sarnowski, Chloe %A Schlessinger, David %A Schmidt, Marjanka K %A Schoemaker, Minouk J %A Schraut, Katharina E %A Scott, Christopher %A Shekari, Saleh %A Shrikhande, Amruta %A Smith, Albert V %A Smith, Blair H %A Smith, Jennifer A %A Sorice, Rossella %A Southey, Melissa C %A Spector, Tim D %A Spinelli, John J %A Stampfer, Meir %A Stöckl, Doris %A van Meurs, Joyce B J %A Strauch, Konstantin %A Styrkarsdottir, Unnur %A Swerdlow, Anthony J %A Tanaka, Toshiko %A Teras, Lauren R %A Teumer, Alexander %A Þorsteinsdottir, Unnur %A Timpson, Nicholas J %A Toniolo, Daniela %A Traglia, Michela %A Troester, Melissa A %A Truong, Thérèse %A Tyrrell, Jessica %A Uitterlinden, André G %A Ulivi, Sheila %A Vachon, Celine M %A Vitart, Veronique %A Völker, Uwe %A Vollenweider, Peter %A Völzke, Henry %A Wang, Qin %A Wareham, Nicholas J %A Weinberg, Clarice R %A Weir, David R %A Wilcox, Amber N %A van Dijk, Ko Willems %A Willemsen, Gonneke %A Wilson, James F %A Wolffenbuttel, Bruce H R %A Wolk, Alicja %A Wood, Andrew R %A Zhao, Wei %A Zygmunt, Marek %A Chen, Zhengming %A Li, Liming %A Franke, Lude %A Burgess, Stephen %A Deelen, Patrick %A Pers, Tune H %A Grøndahl, Marie Louise %A Andersen, Claus Yding %A Pujol, Anna %A Lopez-Contreras, Andres J %A Daniel, Jeremy A %A Stefansson, Kari %A Chang-Claude, Jenny %A van der Schouw, Yvonne T %A Lunetta, Kathryn L %A Chasman, Daniel I %A Easton, Douglas F %A Visser, Jenny A %A Ozanne, Susan E %A Namekawa, Satoshi H %A Solc, Petr %A Murabito, Joanne M %A Ong, Ken K %A Hoffmann, Eva R %A Murray, Anna %A Roig, Ignasi %A Perry, John R B %X

Reproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

%B Nature %V 596 %P 393-397 %8 2021 Aug %G eng %N 7872 %R 10.1038/s41586-021-03779-7 %0 Journal Article %J Nat Commun %D 2021 %T Meta-analyses identify DNA methylation associated with kidney function and damage. %A Schlosser, Pascal %A Tin, Adrienne %A Matias-Garcia, Pamela R %A Thio, Chris H L %A Joehanes, Roby %A Liu, Hongbo %A Weihs, Antoine %A Yu, Zhi %A Hoppmann, Anselm %A Grundner-Culemann, Franziska %A Min, Josine L %A Adeyemo, Adebowale A %A Agyemang, Charles %A Arnlöv, Johan %A Aziz, Nasir A %A Baccarelli, Andrea %A Bochud, Murielle %A Brenner, Hermann %A Breteler, Monique M B %A Carmeli, Cristian %A Chaker, Layal %A Chambers, John C %A Cole, Shelley A %A Coresh, Josef %A Corre, Tanguy %A Correa, Adolfo %A Cox, Simon R %A de Klein, Niek %A Delgado, Graciela E %A Domingo-Relloso, Arce %A Eckardt, Kai-Uwe %A Ekici, Arif B %A Endlich, Karlhans %A Evans, Kathryn L %A Floyd, James S %A Fornage, Myriam %A Franke, Lude %A Fraszczyk, Eliza %A Gao, Xu %A Gào, Xīn %A Ghanbari, Mohsen %A Ghasemi, Sahar %A Gieger, Christian %A Greenland, Philip %A Grove, Megan L %A Harris, Sarah E %A Hemani, Gibran %A Henneman, Peter %A Herder, Christian %A Horvath, Steve %A Hou, Lifang %A Hurme, Mikko A %A Hwang, Shih-Jen %A Jarvelin, Marjo-Riitta %A Kardia, Sharon L R %A Kasela, Silva %A Kleber, Marcus E %A Koenig, Wolfgang %A Kooner, Jaspal S %A Kramer, Holly %A Kronenberg, Florian %A Kuhnel, Brigitte %A Lehtimäki, Terho %A Lind, Lars %A Liu, Dan %A Liu, Yongmei %A Lloyd-Jones, Donald M %A Lohman, Kurt %A Lorkowski, Stefan %A Lu, Ake T %A Marioni, Riccardo E %A März, Winfried %A McCartney, Daniel L %A Meeks, Karlijn A C %A Milani, Lili %A Mishra, Pashupati P %A Nauck, Matthias %A Navas-Acien, Ana %A Nowak, Christoph %A Peters, Annette %A Prokisch, Holger %A Psaty, Bruce M %A Raitakari, Olli T %A Ratliff, Scott M %A Reiner, Alex P %A Rosas, Sylvia E %A Schöttker, Ben %A Schwartz, Joel %A Sedaghat, Sanaz %A Smith, Jennifer A %A Sotoodehnia, Nona %A Stocker, Hannah R %A Stringhini, Silvia %A Sundström, Johan %A Swenson, Brenton R %A Tellez-Plaza, Maria %A van Meurs, Joyce B J %A van Vliet-Ostaptchouk, Jana V %A Venema, Andrea %A Verweij, Niek %A Walker, Rosie M %A Wielscher, Matthias %A Winkelmann, Juliane %A Wolffenbuttel, Bruce H R %A Zhao, Wei %A Zheng, Yinan %A Loh, Marie %A Snieder, Harold %A Levy, Daniel %A Waldenberger, Melanie %A Susztak, Katalin %A Köttgen, Anna %A Teumer, Alexander %K Adult %K Aged %K CpG Islands %K DNA Methylation %K Female %K Glomerular Filtration Rate %K Humans %K Interferon Regulatory Factors %K Kidney %K Kidney Function Tests %K LIM Domain Proteins %K Male %K Membrane Proteins %K Middle Aged %K Renal Insufficiency, Chronic %K Transcription Factors %X

Chronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. To extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated glomerular filtration rate (n = 33,605) and urinary albumin-to-creatinine ratio (n = 15,068) and detected 69 and seven CpG sites where DNA methylation was associated with the respective trait. The majority of these findings showed directionally consistent associations with the respective clinical outcomes chronic kidney disease and moderately increased albuminuria. Associations of DNA methylation with kidney function, such as CpGs at JAZF1, PELI1 and CHD2 were validated in kidney tissue. Methylation at PHRF1, LDB2, CSRNP1 and IRF5 indicated causal effects on kidney function. Enrichment analyses revealed pathways related to hemostasis and blood cell migration for estimated glomerular filtration rate, and immune cell activation and response for urinary albumin-to-creatinineratio-associated CpGs.

%B Nat Commun %V 12 %P 7174 %8 2021 12 09 %G eng %N 1 %R 10.1038/s41467-021-27234-3 %0 Journal Article %J Aging Cell %D 2022 %T Integrative analysis of clinical and epigenetic biomarkers of mortality. %A Huan, Tianxiao %A Nguyen, Steve %A Colicino, Elena %A Ochoa-Rosales, Carolina %A Hill, W David %A Brody, Jennifer A %A Soerensen, Mette %A Zhang, Yan %A Baldassari, Antoine %A Elhadad, Mohamed Ahmed %A Toshiko, Tanaka %A Zheng, Yinan %A Domingo-Relloso, Arce %A Lee, Dong Heon %A Ma, Jiantao %A Yao, Chen %A Liu, Chunyu %A Hwang, Shih-Jen %A Joehanes, Roby %A Fornage, Myriam %A Bressler, Jan %A van Meurs, Joyce B J %A Debrabant, Birgit %A Mengel-From, Jonas %A Hjelmborg, Jacob %A Christensen, Kaare %A Vokonas, Pantel %A Schwartz, Joel %A Gahrib, Sina A %A Sotoodehnia, Nona %A Sitlani, Colleen M %A Kunze, Sonja %A Gieger, Christian %A Peters, Annette %A Waldenberger, Melanie %A Deary, Ian J %A Ferrucci, Luigi %A Qu, Yishu %A Greenland, Philip %A Lloyd-Jones, Donald M %A Hou, Lifang %A Bandinelli, Stefania %A Voortman, Trudy %A Hermann, Brenner %A Baccarelli, Andrea %A Whitsel, Eric %A Pankow, James S %A Levy, Daniel %K Biomarkers %K Cardiovascular Diseases %K DNA Methylation %K Epigenesis, Genetic %K Epigenomics %K Humans %K Male %K Neoplasms %X

DNA methylation (DNAm) has been reported to be associated with many diseases and with mortality. We hypothesized that the integration of DNAm with clinical risk factors would improve mortality prediction. We performed an epigenome-wide association study of whole blood DNAm in relation to mortality in 15 cohorts (n = 15,013). During a mean follow-up of 10 years, there were 4314 deaths from all causes including 1235 cardiovascular disease (CVD) deaths and 868 cancer deaths. Ancestry-stratified meta-analysis of all-cause mortality identified 163 CpGs in European ancestry (EA) and 17 in African ancestry (AA) participants at p < 1 × 10 , of which 41 (EA) and 16 (AA) were also associated with CVD death, and 15 (EA) and 9 (AA) with cancer death. We built DNAm-based prediction models for all-cause mortality that predicted mortality risk after adjusting for clinical risk factors. The mortality prediction model trained by integrating DNAm with clinical risk factors showed an improvement in prediction of cancer death with 5% increase in the C-index in a replication cohort, compared with the model including clinical risk factors alone. Mendelian randomization identified 15 putatively causal CpGs in relation to longevity, CVD, or cancer risk. For example, cg06885782 (in KCNQ4) was positively associated with risk for prostate cancer (Beta = 1.2, P  = 4.1 × 10 ) and negatively associated with longevity (Beta = -1.9, P  = 0.02). Pathway analysis revealed that genes associated with mortality-related CpGs are enriched for immune- and cancer-related pathways. We identified replicable DNAm signatures of mortality and demonstrated the potential utility of CpGs as informative biomarkers for prediction of mortality risk.

%B Aging Cell %V 21 %P e13608 %8 2022 Jun %G eng %N 6 %R 10.1111/acel.13608