@article {1141, title = {Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium.}, journal = {Nat Genet}, volume = {41}, year = {2009}, month = {2009 Nov}, pages = {1191-8}, abstract = {

Measurements of erythrocytes within the blood are important clinical traits and can indicate various hematological disorders. We report here genome-wide association studies (GWAS) for six erythrocyte traits, including hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) and red blood cell count (RBC). We performed an initial GWAS in cohorts of the CHARGE Consortium totaling 24,167 individuals of European ancestry and replication in additional independent cohorts of the HaemGen Consortium totaling 9,456 individuals. We identified 23 loci significantly associated with these traits in a meta-analysis of the discovery and replication cohorts (combined P values ranging from 5 x 10(-8) to 7 x 10(-86)). Our findings include loci previously associated with these traits (HBS1L-MYB, HFE, TMPRSS6, TFR2, SPTA1) as well as new associations (EPO, TFRC, SH2B3 and 15 other loci). This study has identified new determinants of erythrocyte traits, offering insight into common variants underlying variation in erythrocyte measures.

}, keywords = {Blood Pressure, Cell Line, Cohort Studies, Endothelial Cells, Erythrocytes, Gene Expression, Genome, Human, Genome-Wide Association Study, Humans, Hypertension, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci}, issn = {1546-1718}, doi = {10.1038/ng.466}, author = {Ganesh, Santhi K and Zakai, Neil A and van Rooij, Frank J A and Soranzo, Nicole and Smith, Albert V and Nalls, Michael A and Chen, Ming-Huei and K{\"o}ttgen, Anna and Glazer, Nicole L and Dehghan, Abbas and Kuhnel, Brigitte and Aspelund, Thor and Yang, Qiong and Tanaka, Toshiko and Jaffe, Andrew and Bis, Joshua C M and Verwoert, Germaine C and Teumer, Alexander and Fox, Caroline S and Guralnik, Jack M and Ehret, Georg B and Rice, Kenneth and Felix, Janine F and Rendon, Augusto and Eiriksdottir, Gudny and Levy, Daniel and Patel, Kushang V and Boerwinkle, Eric and Rotter, Jerome I and Hofman, Albert and Sambrook, Jennifer G and Hernandez, Dena G and Zheng, Gang and Bandinelli, Stefania and Singleton, Andrew B and Coresh, Josef and Lumley, Thomas and Uitterlinden, Andr{\'e} G and Vangils, Janine M and Launer, Lenore J and Cupples, L Adrienne and Oostra, Ben A and Zwaginga, Jaap-Jan and Ouwehand, Willem H and Thein, Swee-Lay and Meisinger, Christa and Deloukas, Panos and Nauck, Matthias and Spector, Tim D and Gieger, Christian and Gudnason, Vilmundur and van Duijn, Cornelia M and Psaty, Bruce M and Ferrucci, Luigi and Chakravarti, Aravinda and Greinacher, Andreas and O{\textquoteright}Donnell, Christopher J and Witteman, Jacqueline C M and Furth, Susan and Cushman, Mary and Harris, Tamara B and Lin, Jing-Ping} } @article {1237, title = {Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index.}, journal = {Nat Genet}, volume = {42}, year = {2010}, month = {2010 Nov}, pages = {937-48}, abstract = {

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 {\texttimes} 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.

}, keywords = {Body Height, Body Mass Index, Body Size, Body Weight, Chromosome Mapping, European Continental Ancestry Group, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Obesity, Polymorphism, Single Nucleotide}, issn = {1546-1718}, doi = {10.1038/ng.686}, author = {Speliotes, Elizabeth K and Willer, Cristen J and Berndt, Sonja I and Monda, Keri L and Thorleifsson, Gudmar and Jackson, Anne U and Lango Allen, Hana and Lindgren, Cecilia M and Luan, Jian{\textquoteright}an and M{\"a}gi, Reedik and Randall, Joshua C and Vedantam, Sailaja and Winkler, Thomas W and Qi, Lu and Workalemahu, Tsegaselassie and Heid, Iris M and Steinthorsdottir, Valgerdur and Stringham, Heather M and Weedon, Michael N and Wheeler, Eleanor and Wood, Andrew R and Ferreira, Teresa and Weyant, Robert J and Segr{\`e}, Ayellet V and Estrada, Karol and Liang, Liming and Nemesh, James and Park, Ju-Hyun and Gustafsson, Stefan and Kilpel{\"a}inen, Tuomas O and Yang, Jian and Bouatia-Naji, Nabila and Esko, T{\~o}nu and Feitosa, Mary F and Kutalik, Zolt{\'a}n and Mangino, Massimo and Raychaudhuri, Soumya and Scherag, Andre and Smith, Albert Vernon and Welch, Ryan and Zhao, Jing Hua and Aben, Katja K and Absher, Devin M and Amin, Najaf and Dixon, Anna L and Fisher, Eva and Glazer, Nicole L and Goddard, Michael E and Heard-Costa, Nancy L and Hoesel, Volker and Hottenga, Jouke-Jan and Johansson, Asa and Johnson, Toby and Ketkar, Shamika and Lamina, Claudia and Li, Shengxu and Moffatt, Miriam F and Myers, Richard H and Narisu, Narisu and Perry, John R B and Peters, Marjolein J and Preuss, Michael and Ripatti, Samuli and Rivadeneira, Fernando and Sandholt, Camilla and Scott, Laura J and Timpson, Nicholas J and Tyrer, Jonathan P and van Wingerden, Sophie and Watanabe, Richard M and White, Charles C and Wiklund, Fredrik and Barlassina, Christina and Chasman, Daniel I and Cooper, Matthew N and Jansson, John-Olov and Lawrence, Robert W and Pellikka, Niina and Prokopenko, Inga and Shi, Jianxin and Thiering, Elisabeth and Alavere, Helene and Alibrandi, Maria T S and Almgren, Peter and Arnold, Alice M and Aspelund, Thor and Atwood, Larry D and Balkau, Beverley and Balmforth, Anthony J and Bennett, Amanda J and Ben-Shlomo, Yoav and Bergman, Richard N and Bergmann, Sven and Biebermann, Heike and Blakemore, Alexandra I F and Boes, Tanja and Bonnycastle, Lori L and Bornstein, Stefan R and Brown, Morris J and Buchanan, Thomas A and Busonero, Fabio and Campbell, Harry and Cappuccio, Francesco P and Cavalcanti-Proen{\c c}a, Christine and Chen, Yii-Der Ida and Chen, Chih-Mei and Chines, Peter S and Clarke, Robert and Coin, Lachlan and Connell, John and Day, Ian N M and den Heijer, Martin and Duan, Jubao and Ebrahim, Shah and Elliott, Paul and Elosua, Roberto and Eiriksdottir, Gudny and Erdos, Michael R and Eriksson, Johan G and Facheris, Maurizio F and Felix, Stephan B and Fischer-Posovszky, Pamela and Folsom, Aaron R and Friedrich, Nele and Freimer, Nelson B and Fu, Mao and Gaget, Stefan and Gejman, Pablo V and Geus, Eco J C and Gieger, Christian and Gjesing, Anette P and Goel, Anuj and Goyette, Philippe and Grallert, Harald and Gr{\"a}ssler, J{\"u}rgen and Greenawalt, Danielle M and Groves, Christopher J and Gudnason, Vilmundur and Guiducci, Candace and Hartikainen, Anna-Liisa and Hassanali, Neelam and Hall, Alistair S and Havulinna, Aki S and Hayward, Caroline and Heath, Andrew C and Hengstenberg, Christian and Hicks, Andrew A and Hinney, Anke and Hofman, Albert and Homuth, Georg and Hui, Jennie and Igl, Wilmar and Iribarren, Carlos and Isomaa, Bo and Jacobs, Kevin B and Jarick, Ivonne and Jewell, Elizabeth and John, Ulrich and J{\o}rgensen, Torben and Jousilahti, Pekka and Jula, Antti and Kaakinen, Marika and Kajantie, Eero and Kaplan, Lee M and Kathiresan, Sekar and Kettunen, Johannes and Kinnunen, Leena and Knowles, Joshua W and Kolcic, Ivana and K{\"o}nig, Inke R and Koskinen, Seppo and Kovacs, Peter and Kuusisto, Johanna and Kraft, Peter and Kval{\o}y, Kirsti and Laitinen, Jaana and Lantieri, Olivier and Lanzani, Chiara and Launer, Lenore J and Lecoeur, C{\'e}cile and Lehtim{\"a}ki, Terho and Lettre, Guillaume and Liu, Jianjun and Lokki, Marja-Liisa and Lorentzon, Mattias and Luben, Robert N and Ludwig, Barbara and Manunta, Paolo and Marek, Diana and Marre, Michel and Martin, Nicholas G and McArdle, Wendy L and McCarthy, Anne and McKnight, Barbara and Meitinger, Thomas and Melander, Olle and Meyre, David and Midthjell, Kristian and Montgomery, Grant W and Morken, Mario A and Morris, Andrew P and Mulic, Rosanda and Ngwa, Julius S and Nelis, Mari and Neville, Matt J and Nyholt, Dale R and O{\textquoteright}Donnell, Christopher J and O{\textquoteright}Rahilly, Stephen and Ong, Ken K and Oostra, Ben and Par{\'e}, Guillaume and Parker, Alex N and Perola, Markus and Pichler, Irene and Pietil{\"a}inen, Kirsi H and Platou, Carl G P and Polasek, Ozren and Pouta, Anneli and Rafelt, Suzanne and Raitakari, Olli and Rayner, Nigel W and Ridderstr{\r a}le, Martin and Rief, Winfried and Ruokonen, Aimo and Robertson, Neil R and Rzehak, Peter and Salomaa, Veikko and Sanders, Alan R and Sandhu, Manjinder S and Sanna, Serena and Saramies, Jouko and Savolainen, Markku J and Scherag, Susann and Schipf, Sabine and Schreiber, Stefan and Schunkert, Heribert and Silander, Kaisa and Sinisalo, Juha and Siscovick, David S and Smit, Jan H and Soranzo, Nicole and Sovio, Ulla and Stephens, Jonathan and Surakka, Ida and Swift, Amy J and Tammesoo, Mari-Liis and Tardif, Jean-Claude and Teder-Laving, Maris and Teslovich, Tanya M and Thompson, John R and Thomson, Brian and T{\"o}njes, Anke and Tuomi, Tiinamaija and van Meurs, Joyce B J and van Ommen, Gert-Jan and Vatin, Vincent and Viikari, Jorma and Visvikis-Siest, Sophie and Vitart, Veronique and Vogel, Carla I G and Voight, Benjamin F and Waite, Lindsay L and Wallaschofski, Henri and Walters, G Bragi and Widen, Elisabeth and Wiegand, Susanna and Wild, Sarah H and Willemsen, Gonneke and Witte, Daniel R and Witteman, Jacqueline C and Xu, Jianfeng and Zhang, Qunyuan and Zgaga, Lina and Ziegler, Andreas and Zitting, Paavo and Beilby, John P and Farooqi, I Sadaf and Hebebrand, Johannes and Huikuri, Heikki V and James, Alan L and K{\"a}h{\"o}nen, Mika and Levinson, Douglas F and Macciardi, Fabio and Nieminen, Markku S and Ohlsson, Claes and Palmer, Lyle J and Ridker, Paul M and Stumvoll, Michael and Beckmann, Jacques S and Boeing, Heiner and Boerwinkle, Eric and Boomsma, Dorret I and Caulfield, Mark J and Chanock, Stephen J and Collins, Francis S and Cupples, L Adrienne and Smith, George Davey and Erdmann, Jeanette and Froguel, Philippe and Gr{\"o}nberg, Henrik and Gyllensten, Ulf and Hall, Per and Hansen, Torben and Harris, Tamara B and Hattersley, Andrew T and Hayes, Richard B and Heinrich, Joachim and Hu, Frank B and Hveem, Kristian and Illig, Thomas and Jarvelin, Marjo-Riitta and Kaprio, Jaakko and Karpe, Fredrik and Khaw, Kay-Tee and Kiemeney, Lambertus A and Krude, Heiko and Laakso, Markku and Lawlor, Debbie A and Metspalu, Andres and Munroe, Patricia B and Ouwehand, Willem H and Pedersen, Oluf and Penninx, Brenda W and Peters, Annette and Pramstaller, Peter P and Quertermous, Thomas and Reinehr, Thomas and Rissanen, Aila and Rudan, Igor and Samani, Nilesh J and Schwarz, Peter E H and Shuldiner, Alan R and Spector, Timothy D and Tuomilehto, Jaakko and Uda, Manuela and Uitterlinden, Andre and Valle, Timo T and Wabitsch, Martin and Waeber, G{\'e}rard and Wareham, Nicholas J and Watkins, Hugh and Wilson, James F and Wright, Alan F and Zillikens, M Carola and Chatterjee, Nilanjan and McCarroll, Steven A and Purcell, Shaun and Schadt, Eric E and Visscher, Peter M and Assimes, Themistocles L and Borecki, Ingrid B and Deloukas, Panos and Fox, Caroline S and Groop, Leif C and Haritunians, Talin and Hunter, David J and Kaplan, Robert C and Mohlke, Karen L and O{\textquoteright}Connell, Jeffrey R and Peltonen, Leena and Schlessinger, David and Strachan, David P and van Duijn, Cornelia M and Wichmann, H-Erich and Frayling, Timothy M and Thorsteinsdottir, Unnur and Abecasis, Goncalo R and Barroso, In{\^e}s and Boehnke, Michael and Stefansson, Kari and North, Kari E and McCarthy, Mark I and Hirschhorn, Joel N and Ingelsson, Erik and Loos, Ruth J F} } @article {1221, title = {Biological, clinical and population relevance of 95 loci for blood lipids.}, journal = {Nature}, volume = {466}, year = {2010}, month = {2010 Aug 05}, pages = {707-13}, abstract = {

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

}, keywords = {African Americans, Animals, Asian Continental Ancestry Group, Cholesterol, HDL, Cholesterol, LDL, Coronary Artery Disease, Europe, European Continental Ancestry Group, Female, Genetic Loci, Genome-Wide Association Study, Genotype, Humans, Lipid Metabolism, Lipids, Liver, Male, Mice, N-Acetylgalactosaminyltransferases, Phenotype, Polymorphism, Single Nucleotide, Protein Phosphatase 1, Reproducibility of Results, Triglycerides}, issn = {1476-4687}, doi = {10.1038/nature09270}, author = {Teslovich, Tanya M and Musunuru, Kiran and Smith, Albert V and Edmondson, Andrew C and Stylianou, Ioannis M and Koseki, Masahiro and Pirruccello, James P and Ripatti, Samuli and Chasman, Daniel I and Willer, Cristen J and Johansen, Christopher T and Fouchier, Sigrid W and Isaacs, Aaron and Peloso, Gina M and Barbalic, Maja and Ricketts, Sally L and Bis, Joshua C and Aulchenko, Yurii S and Thorleifsson, Gudmar and Feitosa, Mary F and Chambers, John and Orho-Melander, Marju and Melander, Olle and Johnson, Toby and Li, Xiaohui and Guo, Xiuqing and Li, Mingyao and Shin Cho, Yoon and Jin Go, Min and Jin Kim, Young and Lee, Jong-Young and Park, Taesung and Kim, Kyunga and Sim, Xueling and Twee-Hee Ong, Rick and Croteau-Chonka, Damien C and Lange, Leslie A and Smith, Joshua D and Song, Kijoung and Hua Zhao, Jing and Yuan, Xin and Luan, Jian{\textquoteright}an and Lamina, Claudia and Ziegler, Andreas and Zhang, Weihua and Zee, Robert Y L and Wright, Alan F and Witteman, Jacqueline C M and Wilson, James F and Willemsen, Gonneke and Wichmann, H-Erich and Whitfield, John B and Waterworth, Dawn M and Wareham, Nicholas J and Waeber, G{\'e}rard and Vollenweider, Peter and Voight, Benjamin F and Vitart, Veronique and Uitterlinden, Andr{\'e} G and Uda, Manuela and Tuomilehto, Jaakko and Thompson, John R and Tanaka, Toshiko and Surakka, Ida and Stringham, Heather M and Spector, Tim D and Soranzo, Nicole and Smit, Johannes H and Sinisalo, Juha and Silander, Kaisa and Sijbrands, Eric J G and Scuteri, Angelo and Scott, James and Schlessinger, David and Sanna, Serena and Salomaa, Veikko and Saharinen, Juha and Sabatti, Chiara and Ruokonen, Aimo and Rudan, Igor and Rose, Lynda M and Roberts, Robert and Rieder, Mark and Psaty, Bruce M and Pramstaller, Peter P and Pichler, Irene and Perola, Markus and Penninx, Brenda W J H and Pedersen, Nancy L and Pattaro, Cristian and Parker, Alex N and Par{\'e}, Guillaume and Oostra, Ben A and O{\textquoteright}Donnell, Christopher J and Nieminen, Markku S and Nickerson, Deborah A and Montgomery, Grant W and Meitinger, Thomas and McPherson, Ruth and McCarthy, Mark I and McArdle, Wendy and Masson, David and Martin, Nicholas G and Marroni, Fabio and Mangino, Massimo and Magnusson, Patrik K E and Lucas, Gavin and Luben, Robert and Loos, Ruth J F and Lokki, Marja-Liisa and Lettre, Guillaume and Langenberg, Claudia and Launer, Lenore J and Lakatta, Edward G and Laaksonen, Reijo and Kyvik, Kirsten O and Kronenberg, Florian and K{\"o}nig, Inke R and Khaw, Kay-Tee and Kaprio, Jaakko and Kaplan, Lee M and Johansson, Asa and Jarvelin, Marjo-Riitta and Janssens, A Cecile J W and Ingelsson, Erik and Igl, Wilmar and Kees Hovingh, G and Hottenga, Jouke-Jan and Hofman, Albert and Hicks, Andrew A and Hengstenberg, Christian and Heid, Iris M and Hayward, Caroline and Havulinna, Aki S and Hastie, Nicholas D and Harris, Tamara B and Haritunians, Talin and Hall, Alistair S and Gyllensten, Ulf and Guiducci, Candace and Groop, Leif C and Gonzalez, Elena and Gieger, Christian and Freimer, Nelson B and Ferrucci, Luigi and Erdmann, Jeanette and Elliott, Paul and Ejebe, Kenechi G and D{\"o}ring, Angela and Dominiczak, Anna F and Demissie, Serkalem and Deloukas, Panagiotis and de Geus, Eco J C and de Faire, Ulf and Crawford, Gabriel and Collins, Francis S and Chen, Yii-der I and Caulfield, Mark J and Campbell, Harry and Burtt, Noel P and Bonnycastle, Lori L and Boomsma, Dorret I and Boekholdt, S Matthijs and Bergman, Richard N and Barroso, In{\^e}s and Bandinelli, Stefania and Ballantyne, Christie M and Assimes, Themistocles L and Quertermous, Thomas and Altshuler, David and Seielstad, Mark and Wong, Tien Y and Tai, E-Shyong and Feranil, Alan B and Kuzawa, Christopher W and Adair, Linda S and Taylor, Herman A and Borecki, Ingrid B and Gabriel, Stacey B and Wilson, James G and Holm, Hilma and Thorsteinsdottir, Unnur and Gudnason, Vilmundur and Krauss, Ronald M and Mohlke, Karen L and Ordovas, Jose M and Munroe, Patricia B and Kooner, Jaspal S and Tall, Alan R and Hegele, Robert A and Kastelein, John J P and Schadt, Eric E and Rotter, Jerome I and Boerwinkle, Eric and Strachan, David P and Mooser, Vincent and Stefansson, Kari and Reilly, Muredach P and Samani, Nilesh J and Schunkert, Heribert and Cupples, L Adrienne and Sandhu, Manjinder S and Ridker, Paul M and Rader, Daniel J and van Duijn, Cornelia M and Peltonen, Leena and Abecasis, Goncalo R and Boehnke, Michael and Kathiresan, Sekar} } @article {1204, title = {Common genetic determinants of vitamin D insufficiency: a genome-wide association study.}, journal = {Lancet}, volume = {376}, year = {2010}, month = {2010 Jul 17}, pages = {180-8}, abstract = {

BACKGROUND: Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency.

METHODS: We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z-score-weighted meta-analysis. Genotype scores were constructed for confirmed variants.

FINDINGS: Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1.9x10(-109) for rs2282679, in GC); 11q12 (p=2.1x10(-27) for rs12785878, near DHCR7); and 11p15 (p=3.3x10(-20) for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6.0x10(-10) for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2.47, 95\% CI 2.20-2.78, p=2.3x10(-48)) or lower than 50 nmol/L (1.92, 1.70-2.16, p=1.0x10(-26)) compared with those in the lowest quartile.

INTERPRETATION: Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency.

FUNDING: Full funding sources listed at end of paper (see Acknowledgments).

}, keywords = {Canada, Chromosomes, Human, Pair 11, Chromosomes, Human, Pair 4, Cohort Studies, Dietary Supplements, Europe, European Continental Ancestry Group, Genetic Predisposition to Disease, Genome-Wide Association Study, Heterozygote, Homozygote, Humans, Immunoassay, International Cooperation, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Seasons, United States, Vitamin D, Vitamin D Deficiency}, issn = {1474-547X}, doi = {10.1016/S0140-6736(10)60588-0}, author = {Wang, Thomas J and Zhang, Feng and Richards, J Brent and Kestenbaum, Bryan and van Meurs, Joyce B and Berry, Diane and Kiel, Douglas P and Streeten, Elizabeth A and Ohlsson, Claes and Koller, Daniel L and Peltonen, Leena and Cooper, Jason D and O{\textquoteright}Reilly, Paul F and Houston, Denise K and Glazer, Nicole L and Vandenput, Liesbeth and Peacock, Munro and Shi, Julia and Rivadeneira, Fernando and McCarthy, Mark I and Anneli, Pouta and de Boer, Ian H and Mangino, Massimo and Kato, Bernet and Smyth, Deborah J and Booth, Sarah L and Jacques, Paul F and Burke, Greg L and Goodarzi, Mark and Cheung, Ching-Lung and Wolf, Myles and Rice, Kenneth and Goltzman, David and Hidiroglou, Nick and Ladouceur, Martin and Wareham, Nicholas J and Hocking, Lynne J and Hart, Deborah and Arden, Nigel K and Cooper, Cyrus and Malik, Suneil and Fraser, William D and Hartikainen, Anna-Liisa and Zhai, Guangju and Macdonald, Helen M and Forouhi, Nita G and Loos, Ruth J F and Reid, David M and Hakim, Alan and Dennison, Elaine and Liu, Yongmei and Power, Chris and Stevens, Helen E and Jaana, Laitinen and Vasan, Ramachandran S and Soranzo, Nicole and Bojunga, J{\"o}rg and Psaty, Bruce M and Lorentzon, Mattias and Foroud, Tatiana and Harris, Tamara B and Hofman, Albert and Jansson, John-Olov and Cauley, Jane A and Uitterlinden, Andr{\'e} G and Gibson, Quince and Jarvelin, Marjo-Riitta and Karasik, David and Siscovick, David S and Econs, Michael J and Kritchevsky, Stephen B and Florez, Jose C and Todd, John A and Dupuis, Jos{\'e}e and Hypp{\"o}nen, Elina and Spector, Timothy D} } @article {1192, title = {Genome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology.}, journal = {Proc Natl Acad Sci U S A}, volume = {107}, year = {2010}, month = {2010 May 18}, pages = {9293-8}, abstract = {

Telomeres are engaged in a host of cellular functions, and their length is regulated by multiple genes. Telomere shortening, in the course of somatic cell replication, ultimately leads to replicative senescence. In humans, rare mutations in genes that regulate telomere length have been identified in monogenic diseases such as dyskeratosis congenita and idiopathic pulmonary fibrosis, which are associated with shortened leukocyte telomere length (LTL) and increased risk for aplastic anemia. Shortened LTL is observed in a host of aging-related complex genetic diseases and is associated with diminished survival in the elderly. We report results of a genome-wide association study of LTL in a consortium of four observational studies (n = 3,417 participants with LTL and genome-wide genotyping). SNPs in the regions of the oligonucleotide/oligosaccharide-binding folds containing one gene (OBFC1; rs4387287; P = 3.9 x 10(-9)) and chemokine (C-X-C motif) receptor 4 gene (CXCR4; rs4452212; P = 2.9 x 10(-8)) were associated with LTL at a genome-wide significance level (P < 5 x 10(-8)). We attempted replication of the top SNPs at these loci through de novo genotyping of 1,893 additional individuals and in silico lookup in another observational study (n = 2,876), and we confirmed the association findings for OBFC1 but not CXCR4. In addition, we confirmed the telomerase RNA component (TERC) as a gene associated with LTL (P = 1.1 x 10(-5)). The identification of OBFC1 through genome-wide association as a locus for interindividual variation in LTL in the general population advances the understanding of telomere biology in humans and may provide insights into aging-related disorders linked to altered LTL dynamics.

}, keywords = {Cohort Studies, Genome-Wide Association Study, Genotype, Humans, Leukocytes, Polymorphism, Single Nucleotide, Receptors, CXCR4, Telomere, Telomere-Binding Proteins}, issn = {1091-6490}, doi = {10.1073/pnas.0911494107}, author = {Levy, Daniel and Neuhausen, Susan L and Hunt, Steven C and Kimura, Masayuki and Hwang, Shih-Jen and Chen, Wei and Bis, Joshua C and Fitzpatrick, Annette L and Smith, Erin and Johnson, Andrew D and Gardner, Jeffrey P and Srinivasan, Sathanur R and Schork, Nicholas and Rotter, Jerome I and Herbig, Utz and Psaty, Bruce M and Sastrasinh, Malinee and Murray, Sarah S and Vasan, Ramachandran S and Province, Michael A and Glazer, Nicole L and Lu, Xiaobin and Cao, Xiaojian and Kronmal, Richard and Mangino, Massimo and Soranzo, Nicole and Spector, Tim D and Berenson, Gerald S and Aviv, Abraham} } @article {1234, title = {Hundreds of variants clustered in genomic loci and biological pathways affect human height.}, journal = {Nature}, volume = {467}, year = {2010}, month = {2010 Oct 14}, pages = {832-8}, abstract = {

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.

}, keywords = {Body Height, Chromosomes, Human, Pair 3, Genetic Loci, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Metabolic Networks and Pathways, Multifactorial Inheritance, Phenotype, Polymorphism, Single Nucleotide}, issn = {1476-4687}, doi = {10.1038/nature09410}, author = {Lango Allen, Hana and Estrada, Karol and Lettre, Guillaume and Berndt, Sonja I and Weedon, Michael N and Rivadeneira, Fernando and Willer, Cristen J and Jackson, Anne U and Vedantam, Sailaja and Raychaudhuri, Soumya and Ferreira, Teresa and Wood, Andrew R and Weyant, Robert J and Segr{\`e}, Ayellet V and Speliotes, Elizabeth K and Wheeler, Eleanor and Soranzo, Nicole and Park, Ju-Hyun and Yang, Jian and Gudbjartsson, Daniel and Heard-Costa, Nancy L and Randall, Joshua C and Qi, Lu and Vernon Smith, Albert and M{\"a}gi, Reedik and Pastinen, Tomi and Liang, Liming and Heid, Iris M and Luan, Jian{\textquoteright}an and Thorleifsson, Gudmar and Winkler, Thomas W and Goddard, Michael E and Sin Lo, Ken and Palmer, Cameron and Workalemahu, Tsegaselassie and Aulchenko, Yurii S and Johansson, Asa and Zillikens, M Carola and Feitosa, Mary F and Esko, T{\~o}nu and Johnson, Toby and Ketkar, Shamika and Kraft, Peter and Mangino, Massimo and Prokopenko, Inga and Absher, Devin and Albrecht, Eva and Ernst, Florian and Glazer, Nicole L and Hayward, Caroline and Hottenga, Jouke-Jan and Jacobs, Kevin B and Knowles, Joshua W and Kutalik, Zolt{\'a}n and Monda, Keri L and Polasek, Ozren and Preuss, Michael and Rayner, Nigel W and Robertson, Neil R and Steinthorsdottir, Valgerdur and Tyrer, Jonathan P and Voight, Benjamin F and Wiklund, Fredrik and Xu, Jianfeng and Zhao, Jing Hua and Nyholt, Dale R and Pellikka, Niina and Perola, Markus and Perry, John R B and Surakka, Ida and Tammesoo, Mari-Liis and Altmaier, Elizabeth L and Amin, Najaf and Aspelund, Thor and Bhangale, Tushar and Boucher, Gabrielle and Chasman, Daniel I and Chen, Constance and Coin, Lachlan and Cooper, Matthew N and Dixon, Anna L and Gibson, Quince and Grundberg, Elin and Hao, Ke and Juhani Junttila, M and Kaplan, Lee M and Kettunen, Johannes and K{\"o}nig, Inke R and Kwan, Tony and Lawrence, Robert W and Levinson, Douglas F and Lorentzon, Mattias and McKnight, Barbara and Morris, Andrew P and M{\"u}ller, Martina and Suh Ngwa, Julius and Purcell, Shaun and Rafelt, Suzanne and Salem, Rany M and Salvi, Erika and Sanna, Serena and Shi, Jianxin and Sovio, Ulla and Thompson, John R and Turchin, Michael C and Vandenput, Liesbeth and Verlaan, Dominique J and Vitart, Veronique and White, Charles C and Ziegler, Andreas and Almgren, Peter and Balmforth, Anthony J and Campbell, Harry and Citterio, Lorena and De Grandi, Alessandro and Dominiczak, Anna and Duan, Jubao and Elliott, Paul and Elosua, Roberto and Eriksson, Johan G and Freimer, Nelson B and Geus, Eco J C and Glorioso, Nicola and Haiqing, Shen and Hartikainen, Anna-Liisa and Havulinna, Aki S and Hicks, Andrew A and Hui, Jennie and Igl, Wilmar and Illig, Thomas and Jula, Antti and Kajantie, Eero and Kilpel{\"a}inen, Tuomas O and Koiranen, Markku and Kolcic, Ivana and Koskinen, Seppo and Kovacs, Peter and Laitinen, Jaana and Liu, Jianjun and Lokki, Marja-Liisa and Marusic, Ana and Maschio, Andrea and Meitinger, Thomas and Mulas, Antonella and Par{\'e}, Guillaume and Parker, Alex N and Peden, John F and Petersmann, Astrid and Pichler, Irene and Pietil{\"a}inen, Kirsi H and Pouta, Anneli and Ridderstr{\r a}le, Martin and Rotter, Jerome I and Sambrook, Jennifer G and Sanders, Alan R and Schmidt, Carsten Oliver and Sinisalo, Juha and Smit, Jan H and Stringham, Heather M and Bragi Walters, G and Widen, Elisabeth and Wild, Sarah H and Willemsen, Gonneke and Zagato, Laura and Zgaga, Lina and Zitting, Paavo and Alavere, Helene and Farrall, Martin and McArdle, Wendy L and Nelis, Mari and Peters, Marjolein J and Ripatti, Samuli and van Meurs, Joyce B J and Aben, Katja K and Ardlie, Kristin G and Beckmann, Jacques S and Beilby, John P and Bergman, Richard N and Bergmann, Sven and Collins, Francis S and Cusi, Daniele and den Heijer, Martin and Eiriksdottir, Gudny and Gejman, Pablo V and Hall, Alistair S and Hamsten, Anders and Huikuri, Heikki V and Iribarren, Carlos and K{\"a}h{\"o}nen, Mika and Kaprio, Jaakko and Kathiresan, Sekar and Kiemeney, Lambertus and Kocher, Thomas and Launer, Lenore J and Lehtim{\"a}ki, Terho and Melander, Olle and Mosley, Tom H and Musk, Arthur W and Nieminen, Markku S and O{\textquoteright}Donnell, Christopher J and Ohlsson, Claes and Oostra, Ben and Palmer, Lyle J and Raitakari, Olli and Ridker, Paul M and Rioux, John D and Rissanen, Aila and Rivolta, Carlo and Schunkert, Heribert and Shuldiner, Alan R and Siscovick, David S and Stumvoll, Michael and T{\"o}njes, Anke and Tuomilehto, Jaakko and van Ommen, Gert-Jan and Viikari, Jorma and Heath, Andrew C and Martin, Nicholas G and Montgomery, Grant W and Province, Michael A and Kayser, Manfred and Arnold, Alice M and Atwood, Larry D and Boerwinkle, Eric and Chanock, Stephen J and Deloukas, Panos and Gieger, Christian and Gr{\"o}nberg, Henrik and Hall, Per and Hattersley, Andrew T and Hengstenberg, Christian and Hoffman, Wolfgang and Lathrop, G Mark and Salomaa, Veikko and Schreiber, Stefan and Uda, Manuela and Waterworth, Dawn and Wright, Alan F and Assimes, Themistocles L and Barroso, In{\^e}s and Hofman, Albert and Mohlke, Karen L and Boomsma, Dorret I and Caulfield, Mark J and Cupples, L Adrienne and Erdmann, Jeanette and Fox, Caroline S and Gudnason, Vilmundur and Gyllensten, Ulf and Harris, Tamara B and Hayes, Richard B and Jarvelin, Marjo-Riitta and Mooser, Vincent and Munroe, Patricia B and Ouwehand, Willem H and Penninx, Brenda W and Pramstaller, Peter P and Quertermous, Thomas and Rudan, Igor and Samani, Nilesh J and Spector, Timothy D and V{\"o}lzke, Henry and Watkins, Hugh and Wilson, James F and Groop, Leif C and Haritunians, Talin and Hu, Frank B and Kaplan, Robert C and Metspalu, Andres and North, Kari E and Schlessinger, David and Wareham, Nicholas J and Hunter, David J and O{\textquoteright}Connell, Jeffrey R and Strachan, David P and Wichmann, H-Erich and Borecki, Ingrid B and van Duijn, Cornelia M and Schadt, Eric E and Thorsteinsdottir, Unnur and Peltonen, Leena and Uitterlinden, Andr{\'e} G and Visscher, Peter M and Chatterjee, Nilanjan and Loos, Ruth J F and Boehnke, Michael and McCarthy, Mark I and Ingelsson, Erik and Lindgren, Cecilia M and Abecasis, Goncalo R and Stefansson, Kari and Frayling, Timothy M and Hirschhorn, Joel N} } @article {1236, title = {Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution.}, journal = {Nat Genet}, volume = {42}, year = {2010}, month = {2010 Nov}, pages = {949-60}, abstract = {

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 {\texttimes} 10$^{-}$$^{9}$ to P = 1.8 {\texttimes} 10$^{-}$$^{4}$$^{0}$) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 {\texttimes} 10$^{-}${\textthreesuperior} to P = 1.2 {\texttimes} 10$^{-}${\textonesuperior}{\textthreesuperior}). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.

}, keywords = {Adipose Tissue, Age Factors, Chromosome Mapping, Female, Genome, Human, Genome-Wide Association Study, Humans, Male, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Sex Characteristics, Waist-Hip Ratio}, issn = {1546-1718}, doi = {10.1038/ng.685}, author = {Heid, Iris M and Jackson, Anne U and Randall, Joshua C and Winkler, Thomas W and Qi, Lu and Steinthorsdottir, Valgerdur and Thorleifsson, Gudmar and Zillikens, M Carola and Speliotes, Elizabeth K and M{\"a}gi, Reedik and Workalemahu, Tsegaselassie and White, Charles C and Bouatia-Naji, Nabila and Harris, Tamara B and Berndt, Sonja I and Ingelsson, Erik and Willer, Cristen J and Weedon, Michael N and Luan, Jian{\textquoteright}an and Vedantam, Sailaja and Esko, T{\~o}nu and Kilpel{\"a}inen, Tuomas O and Kutalik, Zolt{\'a}n and Li, Shengxu and Monda, Keri L and Dixon, Anna L and Holmes, Christopher C and Kaplan, Lee M and Liang, Liming and Min, Josine L and Moffatt, Miriam F and Molony, Cliona and Nicholson, George and Schadt, Eric E and Zondervan, Krina T and Feitosa, Mary F and Ferreira, Teresa and Lango Allen, Hana and Weyant, Robert J and Wheeler, Eleanor and Wood, Andrew R and Estrada, Karol and Goddard, Michael E and Lettre, Guillaume and Mangino, Massimo and Nyholt, Dale R and Purcell, Shaun and Smith, Albert Vernon and Visscher, Peter M and Yang, Jian and McCarroll, Steven A and Nemesh, James and Voight, Benjamin F and Absher, Devin and Amin, Najaf and Aspelund, Thor and Coin, Lachlan and Glazer, Nicole L and Hayward, Caroline and Heard-Costa, Nancy L and Hottenga, Jouke-Jan and Johansson, Asa and Johnson, Toby and Kaakinen, Marika and Kapur, Karen and Ketkar, Shamika and Knowles, Joshua W and Kraft, Peter and Kraja, Aldi T and Lamina, Claudia and Leitzmann, Michael F and McKnight, Barbara and Morris, Andrew P and Ong, Ken K and Perry, John R B and Peters, Marjolein J and Polasek, Ozren and Prokopenko, Inga and Rayner, Nigel W and Ripatti, Samuli and Rivadeneira, Fernando and Robertson, Neil R and Sanna, Serena and Sovio, Ulla and Surakka, Ida and Teumer, Alexander and van Wingerden, Sophie and Vitart, Veronique and Zhao, Jing Hua and Cavalcanti-Proen{\c c}a, Christine and Chines, Peter S and Fisher, Eva and Kulzer, Jennifer R and Lecoeur, C{\'e}cile and Narisu, Narisu and Sandholt, Camilla and Scott, Laura J and Silander, Kaisa and Stark, Klaus and Tammesoo, Mari-Liis and Teslovich, Tanya M and Timpson, Nicholas John and Watanabe, Richard M and Welch, Ryan and Chasman, Daniel I and Cooper, Matthew N and Jansson, John-Olov and Kettunen, Johannes and Lawrence, Robert W and Pellikka, Niina and Perola, Markus and Vandenput, Liesbeth and Alavere, Helene and Almgren, Peter and Atwood, Larry D and Bennett, Amanda J and Biffar, Reiner and Bonnycastle, Lori L and Bornstein, Stefan R and Buchanan, Thomas A and Campbell, Harry and Day, Ian N M and Dei, Mariano and D{\"o}rr, Marcus and Elliott, Paul and Erdos, Michael R and Eriksson, Johan G and Freimer, Nelson B and Fu, Mao and Gaget, Stefan and Geus, Eco J C and Gjesing, Anette P and Grallert, Harald and Gr{\"a}ssler, J{\"u}rgen and Groves, Christopher J and Guiducci, Candace and Hartikainen, Anna-Liisa and Hassanali, Neelam and Havulinna, Aki S and Herzig, Karl-Heinz and Hicks, Andrew A and Hui, Jennie and Igl, Wilmar and Jousilahti, Pekka and Jula, Antti and Kajantie, Eero and Kinnunen, Leena and Kolcic, Ivana and Koskinen, Seppo and Kovacs, Peter and Kroemer, Heyo K and Krzelj, Vjekoslav and Kuusisto, Johanna and Kvaloy, Kirsti and Laitinen, Jaana and Lantieri, Olivier and Lathrop, G Mark and Lokki, Marja-Liisa and Luben, Robert N and Ludwig, Barbara and McArdle, Wendy L and McCarthy, Anne and Morken, Mario A and Nelis, Mari and Neville, Matt J and Par{\'e}, Guillaume and Parker, Alex N and Peden, John F and Pichler, Irene and Pietil{\"a}inen, Kirsi H and Platou, Carl G P and Pouta, Anneli and Ridderstr{\r a}le, Martin and Samani, Nilesh J and Saramies, Jouko and Sinisalo, Juha and Smit, Jan H and Strawbridge, Rona J and Stringham, Heather M and Swift, Amy J and Teder-Laving, Maris and Thomson, Brian and Usala, Gianluca and van Meurs, Joyce B J and van Ommen, Gert-Jan and Vatin, Vincent and Volpato, Claudia B and Wallaschofski, Henri and Walters, G Bragi and Widen, Elisabeth and Wild, Sarah H and Willemsen, Gonneke and Witte, Daniel R and Zgaga, Lina and Zitting, Paavo and Beilby, John P and James, Alan L and K{\"a}h{\"o}nen, Mika and Lehtim{\"a}ki, Terho and Nieminen, Markku S and Ohlsson, Claes and Palmer, Lyle J and Raitakari, Olli and Ridker, Paul M and Stumvoll, Michael and T{\"o}njes, Anke and Viikari, Jorma and Balkau, Beverley and Ben-Shlomo, Yoav and Bergman, Richard N and Boeing, Heiner and Smith, George Davey and Ebrahim, Shah and Froguel, Philippe and Hansen, Torben and Hengstenberg, Christian and Hveem, Kristian and Isomaa, Bo and J{\o}rgensen, Torben and Karpe, Fredrik and Khaw, Kay-Tee and Laakso, Markku and Lawlor, Debbie A and Marre, Michel and Meitinger, Thomas and Metspalu, Andres and Midthjell, Kristian and Pedersen, Oluf and Salomaa, Veikko and Schwarz, Peter E H and Tuomi, Tiinamaija and Tuomilehto, Jaakko and Valle, Timo T and Wareham, Nicholas J and Arnold, Alice M and Beckmann, Jacques S and Bergmann, Sven and Boerwinkle, Eric and Boomsma, Dorret I and Caulfield, Mark J and Collins, Francis S and Eiriksdottir, Gudny and Gudnason, Vilmundur and Gyllensten, Ulf and Hamsten, Anders and Hattersley, Andrew T and Hofman, Albert and Hu, Frank B and Illig, Thomas and Iribarren, Carlos and Jarvelin, Marjo-Riitta and Kao, W H Linda and Kaprio, Jaakko and Launer, Lenore J and Munroe, Patricia B and Oostra, Ben and Penninx, Brenda W and Pramstaller, Peter P and Psaty, Bruce M and Quertermous, Thomas and Rissanen, Aila and Rudan, Igor and Shuldiner, Alan R and Soranzo, Nicole and Spector, Timothy D and Syv{\"a}nen, Ann-Christine and Uda, Manuela and Uitterlinden, Andre and V{\"o}lzke, Henry and Vollenweider, Peter and Wilson, James F and Witteman, Jacqueline C and Wright, Alan F and Abecasis, Goncalo R and Boehnke, Michael and Borecki, Ingrid B and Deloukas, Panos and Frayling, Timothy M and Groop, Leif C and Haritunians, Talin and Hunter, David J and Kaplan, Robert C and North, Kari E and O{\textquoteright}Connell, Jeffrey R and Peltonen, Leena and Schlessinger, David and Strachan, David P and Hirschhorn, Joel N and Assimes, Themistocles L and Wichmann, H-Erich and Thorsteinsdottir, Unnur and van Duijn, Cornelia M and Stefansson, Kari and Cupples, L Adrienne and Loos, Ruth J F and Barroso, In{\^e}s and McCarthy, Mark I and Fox, Caroline S and Mohlke, Karen L and Lindgren, Cecilia M} } @article {1160, title = {New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.}, journal = {Nat Genet}, volume = {42}, year = {2010}, month = {2010 Feb}, pages = {105-16}, abstract = {

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. 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 type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

}, keywords = {Adolescent, Adult, Alleles, Blood Glucose, Child, Databases, Genetic, Diabetes Mellitus, Type 2, DNA Copy Number Variations, Fasting, Gene Expression Regulation, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Homeostasis, Humans, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Quantitative Trait, Heritable, Reproducibility of Results}, issn = {1546-1718}, doi = {10.1038/ng.520}, author = {Dupuis, Jos{\'e}e and Langenberg, Claudia and Prokopenko, Inga and Saxena, Richa and Soranzo, Nicole and Jackson, Anne U and Wheeler, Eleanor and Glazer, Nicole L and Bouatia-Naji, Nabila and Gloyn, Anna L and Lindgren, Cecilia M and M{\"a}gi, Reedik and Morris, Andrew P and Randall, Joshua and Johnson, Toby and Elliott, Paul and Rybin, Denis and Thorleifsson, Gudmar and Steinthorsdottir, Valgerdur and Henneman, Peter and Grallert, Harald and Dehghan, Abbas and Hottenga, Jouke Jan and Franklin, Christopher S and Navarro, Pau and Song, Kijoung and Goel, Anuj and Perry, John R B and Egan, Josephine M and Lajunen, Taina and Grarup, Niels and Spars{\o}, Thomas and Doney, Alex and Voight, Benjamin F and Stringham, Heather M and Li, Man and Kanoni, Stavroula and Shrader, Peter and Cavalcanti-Proen{\c c}a, Christine and Kumari, Meena and Qi, Lu and Timpson, Nicholas J and Gieger, Christian and Zabena, Carina and Rocheleau, Ghislain and Ingelsson, Erik and An, Ping and O{\textquoteright}Connell, Jeffrey and Luan, Jian{\textquoteright}an and Elliott, Amanda and McCarroll, Steven A and Payne, Felicity and Roccasecca, Rosa Maria and Pattou, Fran{\c c}ois and Sethupathy, Praveen and Ardlie, Kristin and Ariyurek, Yavuz and Balkau, Beverley and Barter, Philip and Beilby, John P and Ben-Shlomo, Yoav and Benediktsson, Rafn and Bennett, Amanda J and Bergmann, Sven and Bochud, Murielle and Boerwinkle, Eric and Bonnefond, Am{\'e}lie and Bonnycastle, Lori L and Borch-Johnsen, Knut and B{\"o}ttcher, Yvonne and Brunner, Eric and Bumpstead, Suzannah J and Charpentier, Guillaume and Chen, Yii-Der Ida and Chines, Peter and Clarke, Robert and Coin, Lachlan J M and Cooper, Matthew N and Cornelis, Marilyn and Crawford, Gabe and Crisponi, Laura and Day, Ian N M and de Geus, Eco J C and Delplanque, Jerome and Dina, Christian and Erdos, Michael R and Fedson, Annette C and Fischer-Rosinsky, Antje and Forouhi, Nita G and Fox, Caroline S and Frants, Rune and Franzosi, Maria Grazia and Galan, Pilar and Goodarzi, Mark O and Graessler, J{\"u}rgen and Groves, Christopher J and Grundy, Scott and Gwilliam, Rhian and Gyllensten, Ulf and Hadjadj, Samy and Hallmans, G{\"o}ran and Hammond, Naomi and Han, Xijing and Hartikainen, Anna-Liisa and Hassanali, Neelam and Hayward, Caroline and Heath, Simon C and Hercberg, Serge and Herder, Christian and Hicks, Andrew A and Hillman, David R and Hingorani, Aroon D and Hofman, Albert and Hui, Jennie and Hung, Joe and Isomaa, Bo and Johnson, Paul R V and J{\o}rgensen, Torben and Jula, Antti and Kaakinen, Marika and Kaprio, Jaakko and Kesaniemi, Y Antero and Kivimaki, Mika and Knight, Beatrice and Koskinen, Seppo and Kovacs, Peter and Kyvik, Kirsten Ohm and Lathrop, G Mark and Lawlor, Debbie A and Le Bacquer, Olivier and Lecoeur, C{\'e}cile and Li, Yun and Lyssenko, Valeriya and Mahley, Robert and Mangino, Massimo and Manning, Alisa K and Mart{\'\i}nez-Larrad, Mar{\'\i}a Teresa and McAteer, Jarred B and McCulloch, Laura J and McPherson, Ruth and Meisinger, Christa and Melzer, David and Meyre, David and Mitchell, Braxton D and Morken, Mario A and Mukherjee, Sutapa and Naitza, Silvia and Narisu, Narisu and Neville, Matthew J and Oostra, Ben A and Orr{\`u}, Marco and Pakyz, Ruth and Palmer, Colin N A and Paolisso, Giuseppe and Pattaro, Cristian and Pearson, Daniel and Peden, John F and Pedersen, Nancy L and Perola, Markus and Pfeiffer, Andreas F H and Pichler, Irene and Polasek, Ozren and Posthuma, Danielle and Potter, Simon C and Pouta, Anneli and Province, Michael A and Psaty, Bruce M and Rathmann, Wolfgang and Rayner, Nigel W and Rice, Kenneth and Ripatti, Samuli and Rivadeneira, Fernando and Roden, Michael and Rolandsson, Olov and Sandbaek, Annelli and Sandhu, Manjinder and Sanna, Serena and Sayer, Avan Aihie and Scheet, Paul and Scott, Laura J and Seedorf, Udo and Sharp, Stephen J and Shields, Beverley and Sigurethsson, Gunnar and Sijbrands, Eric J G and Silveira, Angela and Simpson, Laila and Singleton, Andrew and Smith, Nicholas L and Sovio, Ulla and Swift, Amy and Syddall, Holly and Syv{\"a}nen, Ann-Christine and Tanaka, Toshiko and Thorand, Barbara and Tichet, Jean and T{\"o}njes, Anke and Tuomi, Tiinamaija and Uitterlinden, Andr{\'e} G and van Dijk, Ko Willems and van Hoek, Mandy and Varma, Dhiraj and Visvikis-Siest, Sophie and Vitart, Veronique and Vogelzangs, Nicole and Waeber, G{\'e}rard and Wagner, Peter J and Walley, Andrew and Walters, G Bragi and Ward, Kim L and Watkins, Hugh and Weedon, Michael N and Wild, Sarah H and Willemsen, Gonneke and Witteman, Jaqueline C M and Yarnell, John W G and Zeggini, Eleftheria and Zelenika, Diana and Zethelius, Bj{\"o}rn and Zhai, Guangju and Zhao, Jing Hua and Zillikens, M Carola and Borecki, Ingrid B and Loos, Ruth J F and Meneton, Pierre and Magnusson, Patrik K E and Nathan, David M and Williams, Gordon H and Hattersley, Andrew T and Silander, Kaisa and Salomaa, Veikko and Smith, George Davey and Bornstein, Stefan R and Schwarz, Peter and Spranger, Joachim and Karpe, Fredrik and Shuldiner, Alan R and Cooper, Cyrus and Dedoussis, George V and Serrano-R{\'\i}os, Manuel and Morris, Andrew D and Lind, Lars and Palmer, Lyle J and Hu, Frank B and Franks, Paul W and Ebrahim, Shah and Marmot, Michael and Kao, W H Linda and Pankow, James S and Sampson, Michael J and Kuusisto, Johanna and Laakso, Markku and Hansen, Torben and Pedersen, Oluf and Pramstaller, Peter Paul and Wichmann, H Erich and Illig, Thomas and Rudan, Igor and Wright, Alan F and Stumvoll, Michael and Campbell, Harry and Wilson, James F and Bergman, Richard N and Buchanan, Thomas A and Collins, Francis S and Mohlke, Karen L and Tuomilehto, Jaakko and Valle, Timo T and Altshuler, David and Rotter, Jerome I and Siscovick, David S and Penninx, Brenda W J H and Boomsma, Dorret I and Deloukas, Panos and Spector, Timothy D and Frayling, Timothy M and Ferrucci, Luigi and Kong, Augustine and Thorsteinsdottir, Unnur and Stefansson, Kari and van Duijn, Cornelia M and Aulchenko, Yurii S and Cao, Antonio and Scuteri, Angelo and Schlessinger, David and Uda, Manuela and Ruokonen, Aimo and Jarvelin, Marjo-Riitta and Waterworth, Dawn M and Vollenweider, Peter and Peltonen, Leena and Mooser, Vincent and Abecasis, Goncalo R and Wareham, Nicholas J and Sladek, Robert and Froguel, Philippe and Watanabe, Richard M and Meigs, James B and Groop, Leif and Boehnke, Michael and McCarthy, Mark I and Florez, Jose C and Barroso, In{\^e}s} } @article {1176, title = {Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium.}, journal = {Circulation}, volume = {121}, year = {2010}, month = {2010 Mar 30}, pages = {1382-92}, abstract = {

BACKGROUND: Plasma levels of coagulation factors VII (FVII), VIII (FVIII), and von Willebrand factor (vWF) influence risk of hemorrhage and thrombosis. We conducted genome-wide association studies to identify new loci associated with plasma levels.

METHODS AND RESULTS: The setting of the study included 5 community-based studies for discovery comprising 23 608 European-ancestry participants: Atherosclerosis Risk In Communities Study, Cardiovascular Health Study, British 1958 Birth Cohort, Framingham Heart Study, and Rotterdam Study. All subjects had genome-wide single-nucleotide polymorphism (SNP) scans and at least 1 phenotype measured: FVII activity/antigen, FVIII activity, and vWF antigen. Each study used its genotype data to impute to HapMap SNPs and independently conducted association analyses of hemostasis measures using an additive genetic model. Study findings were combined by meta-analysis. Replication was conducted in 7604 participants not in the discovery cohort. For FVII, 305 SNPs exceeded the genome-wide significance threshold of 5.0x10(-8) and comprised 5 loci on 5 chromosomes: 2p23 (smallest P value 6.2x10(-24)), 4q25 (3.6x10(-12)), 11q12 (2.0x10(-10)), 13q34 (9.0x10(-259)), and 20q11.2 (5.7x10(-37)). Loci were within or near genes, including 4 new candidate genes and F7 (13q34). For vWF, 400 SNPs exceeded the threshold and marked 8 loci on 6 chromosomes: 6q24 (1.2x10(-22)), 8p21 (1.3x10(-16)), 9q34 (<5.0x10(-324)), 12p13 (1.7x10(-32)), 12q23 (7.3x10(-10)), 12q24.3 (3.8x10(-11)), 14q32 (2.3x10(-10)), and 19p13.2 (1.3x10(-9)). All loci were within genes, including 6 new candidate genes, as well as ABO (9q34) and VWF (12p13). For FVIII, 5 loci were identified and overlapped vWF findings. Nine of the 10 new findings were replicated.

CONCLUSIONS: New genetic associations were discovered outside previously known biological pathways and may point to novel prevention and treatment targets of hemostasis disorders.

}, keywords = {Adult, Factor VII, Factor VIII, Female, Genome-Wide Association Study, Hemostasis, Humans, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Thrombosis, von Willebrand Factor}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.109.869156}, author = {Smith, Nicholas L and Chen, Ming-Huei and Dehghan, Abbas and Strachan, David P and Basu, Saonli and Soranzo, Nicole and Hayward, Caroline and Rudan, Igor and Sabater-Lleal, Maria and Bis, Joshua C and de Maat, Moniek P M and Rumley, Ann and Kong, Xiaoxiao and Yang, Qiong and Williams, Frances M K and Vitart, Veronique and Campbell, Harry and M{\"a}larstig, Anders and Wiggins, Kerri L and van Duijn, Cornelia M and McArdle, Wendy L and Pankow, James S and Johnson, Andrew D and Silveira, Angela and McKnight, Barbara and Uitterlinden, Andr{\'e} G and Aleksic, Nena and Meigs, James B and Peters, Annette and Koenig, Wolfgang and Cushman, Mary and Kathiresan, Sekar and Rotter, Jerome I and Bovill, Edwin G and Hofman, Albert and Boerwinkle, Eric and Tofler, Geoffrey H and Peden, John F and Psaty, Bruce M and Leebeek, Frank and Folsom, Aaron R and Larson, Martin G and Spector, Timothy D and Wright, Alan F and Wilson, James F and Hamsten, Anders and Lumley, Thomas and Witteman, Jacqueline C M and Tang, Weihong and O{\textquoteright}Donnell, Christopher J} } @article {1284, title = {Genetic predictors of fibrin D-dimer levels in healthy adults.}, journal = {Circulation}, volume = {123}, year = {2011}, month = {2011 May 03}, pages = {1864-72}, abstract = {

BACKGROUND: Fibrin fragment D-dimer, one of several peptides produced when crosslinked fibrin is degraded by plasmin, is the most widely used clinical marker of activated blood coagulation. To identity genetic loci influencing D-dimer levels, we performed the first large-scale, genome-wide association search.

METHODS AND RESULTS: A genome-wide investigation of the genomic correlates of plasma D-dimer levels was conducted among 21 052 European-ancestry adults. Plasma levels of D-dimer were measured independently in each of 13 cohorts. Each study analyzed the association between ≈2.6 million genotyped and imputed variants across the 22 autosomal chromosomes and natural-log{\textendash}transformed D-dimer levels using linear regression in additive genetic models adjusted for age and sex. Among all variants, 74 exceeded the genome-wide significance threshold and marked 3 regions. At 1p22, rs12029080 (P=6.4{\texttimes}10(-52)) was 46.0 kb upstream from F3, coagulation factor III (tissue factor). At 1q24, rs6687813 (P=2.4{\texttimes}10(-14)) was 79.7 kb downstream of F5, coagulation factor V. At 4q32, rs13109457 (P=2.9{\texttimes}10(-18)) was located between 2 fibrinogen genes: 10.4 kb downstream from FGG and 3.0 kb upstream from FGA. Variants were associated with a 0.099-, 0.096-, and 0.061-unit difference, respectively, in natural-log{\textendash}transformed D-dimer and together accounted for 1.8\% of the total variance. When adjusted for nonsynonymous substitutions in F5 and FGA loci known to be associated with D-dimer levels, there was no evidence of an additional association at either locus.

CONCLUSIONS: Three genes were associated with fibrin D-dimer levels. Of these 3, the F3 association was the strongest, and has not been previously reported.

}, keywords = {Adult, Aged, Blood Coagulation, European Continental Ancestry Group, Factor V, Female, Fibrin Fibrinogen Degradation Products, Fibrinogen, Genetic Testing, Genome-Wide Association Study, Humans, Male, Middle Aged, Reference Values, Thromboplastin}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.110.009480}, author = {Smith, Nicholas L and Huffman, Jennifer E and Strachan, David P and Huang, Jie and Dehghan, Abbas and Trompet, Stella and Lopez, Lorna M and Shin, So-Youn and Baumert, Jens and Vitart, Veronique and Bis, Joshua C and Wild, Sarah H and Rumley, Ann and Yang, Qiong and Uitterlinden, Andr{\'e} G and Stott, David J and Davies, Gail and Carter, Angela M and Thorand, Barbara and Polasek, Ozren and McKnight, Barbara and Campbell, Harry and Rudnicka, Alicja R and Chen, Ming-Huei and Buckley, Brendan M and Harris, Sarah E and Peters, Annette and Pulanic, Drazen and Lumley, Thomas and de Craen, Anton J M and Liewald, David C and Gieger, Christian and Campbell, Susan and Ford, Ian and Gow, Alan J and Luciano, Michelle and Porteous, David J and Guo, Xiuqing and Sattar, Naveed and Tenesa, Albert and Cushman, Mary and Slagboom, P Eline and Visscher, Peter M and Spector, Tim D and Illig, Thomas and Rudan, Igor and Bovill, Edwin G and Wright, Alan F and McArdle, Wendy L and Tofler, Geoffrey and Hofman, Albert and Westendorp, Rudi G J and Starr, John M and Grant, Peter J and Karakas, Mahir and Hastie, Nicholas D and Psaty, Bruce M and Wilson, James F and Lowe, Gordon D O and O{\textquoteright}Donnell, Christopher J and Witteman, Jacqueline C M and Jukema, J Wouter and Deary, Ian J and Soranzo, Nicole and Koenig, Wolfgang and Hayward, Caroline} } @article {1325, title = {Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.}, journal = {Nature}, volume = {478}, year = {2011}, month = {2011 Sep 11}, pages = {103-9}, abstract = {

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (>=140 mm Hg systolic blood pressure or >=90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

}, keywords = {Africa, Asia, Blood Pressure, Cardiovascular Diseases, Coronary Artery Disease, Europe, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Hypertension, Kidney Diseases, Polymorphism, Single Nucleotide, Stroke}, issn = {1476-4687}, doi = {10.1038/nature10405}, author = {Ehret, Georg B and Munroe, Patricia B and Rice, Kenneth M and Bochud, Murielle and Johnson, Andrew D and Chasman, Daniel I and Smith, Albert V and Tobin, Martin D and Verwoert, Germaine C and Hwang, Shih-Jen and Pihur, Vasyl and Vollenweider, Peter and O{\textquoteright}Reilly, Paul F and Amin, Najaf and Bragg-Gresham, Jennifer L and Teumer, Alexander and Glazer, Nicole L and Launer, Lenore and Zhao, Jing Hua and Aulchenko, Yurii and Heath, Simon and S{\~o}ber, Siim and Parsa, Afshin and Luan, Jian{\textquoteright}an and Arora, Pankaj and Dehghan, Abbas and Zhang, Feng and Lucas, Gavin and Hicks, Andrew A and Jackson, Anne U and Peden, John F and Tanaka, Toshiko and Wild, Sarah H and Rudan, Igor and Igl, Wilmar and Milaneschi, Yuri and Parker, Alex N and Fava, Cristiano and Chambers, John C and Fox, Ervin R and Kumari, Meena and Go, Min Jin and van der Harst, Pim and Kao, Wen Hong Linda and Sj{\"o}gren, Marketa and Vinay, D G and Alexander, Myriam and Tabara, Yasuharu and Shaw-Hawkins, Sue and Whincup, Peter H and Liu, Yongmei and Shi, Gang and Kuusisto, Johanna and Tayo, Bamidele and Seielstad, Mark and Sim, Xueling and Nguyen, Khanh-Dung Hoang and Lehtim{\"a}ki, Terho and Matullo, Giuseppe and Wu, Ying and Gaunt, Tom R and Onland-Moret, N Charlotte and Cooper, Matthew N and Platou, Carl G P and Org, Elin and Hardy, Rebecca and Dahgam, Santosh and Palmen, Jutta and Vitart, Veronique and Braund, Peter S and Kuznetsova, Tatiana and Uiterwaal, Cuno S P M and Adeyemo, Adebowale and Palmas, Walter and Campbell, Harry and Ludwig, Barbara and Tomaszewski, Maciej and Tzoulaki, Ioanna and Palmer, Nicholette D and Aspelund, Thor and Garcia, Melissa and Chang, Yen-Pei C and O{\textquoteright}Connell, Jeffrey R and Steinle, Nanette I and Grobbee, Diederick E and Arking, Dan E and Kardia, Sharon L and Morrison, Alanna C and Hernandez, Dena and Najjar, Samer and McArdle, Wendy L and Hadley, David and Brown, Morris J and Connell, John M and Hingorani, Aroon D and Day, Ian N M and Lawlor, Debbie A and Beilby, John P and Lawrence, Robert W and Clarke, Robert and Hopewell, Jemma C and Ongen, Halit and Dreisbach, Albert W and Li, Yali and Young, J Hunter and Bis, Joshua C and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and Adair, Linda S and Lee, Nanette R and Chen, Ming-Huei and Olden, Matthias and Pattaro, Cristian and Bolton, Judith A Hoffman and K{\"o}ttgen, Anna and Bergmann, Sven and Mooser, Vincent and Chaturvedi, Nish and Frayling, Timothy M and Islam, Muhammad and Jafar, Tazeen H and Erdmann, Jeanette and Kulkarni, Smita R and Bornstein, Stefan R and Gr{\"a}ssler, J{\"u}rgen and Groop, Leif and Voight, Benjamin F and Kettunen, Johannes and Howard, Philip and Taylor, Andrew and Guarrera, Simonetta and Ricceri, Fulvio and Emilsson, Valur and Plump, Andrew and Barroso, In{\^e}s and Khaw, Kay-Tee and Weder, Alan B and Hunt, Steven C and Sun, Yan V and Bergman, Richard N and Collins, Francis S and Bonnycastle, Lori L and Scott, Laura J and Stringham, Heather M and Peltonen, Leena and Perola, Markus and Vartiainen, Erkki and Brand, Stefan-Martin and Staessen, Jan A and Wang, Thomas J and Burton, Paul R and Soler Artigas, Maria and Dong, Yanbin and Snieder, Harold and Wang, Xiaoling and Zhu, Haidong and Lohman, Kurt K and Rudock, Megan E and Heckbert, Susan R and Smith, Nicholas L and Wiggins, Kerri L and Doumatey, Ayo and Shriner, Daniel and Veldre, Gudrun and Viigimaa, Margus and Kinra, Sanjay and Prabhakaran, Dorairaj and Tripathy, Vikal and Langefeld, Carl D and Rosengren, Annika and Thelle, Dag S and Corsi, Anna Maria and Singleton, Andrew and Forrester, Terrence and Hilton, Gina and McKenzie, Colin A and Salako, Tunde and Iwai, Naoharu and Kita, Yoshikuni and Ogihara, Toshio and Ohkubo, Takayoshi and Okamura, Tomonori and Ueshima, Hirotsugu and Umemura, Satoshi and Eyheramendy, Susana and Meitinger, Thomas and Wichmann, H-Erich and Cho, Yoon Shin and Kim, Hyung-Lae and Lee, Jong-Young and Scott, James and Sehmi, Joban S and Zhang, Weihua and Hedblad, Bo and Nilsson, Peter and Smith, George Davey and Wong, Andrew and Narisu, Narisu and Stan{\v c}{\'a}kov{\'a}, Alena and Raffel, Leslie J and Yao, Jie and Kathiresan, Sekar and O{\textquoteright}Donnell, Christopher J and Schwartz, Stephen M and Ikram, M Arfan and Longstreth, W T and Mosley, Thomas H and Seshadri, Sudha and Shrine, Nick R G and Wain, Louise V and Morken, Mario A and Swift, Amy J and Laitinen, Jaana and Prokopenko, Inga and Zitting, Paavo and Cooper, Jackie A and Humphries, Steve E and Danesh, John and Rasheed, Asif and Goel, Anuj and Hamsten, Anders and Watkins, Hugh and Bakker, Stephan J L and van Gilst, Wiek H and Janipalli, Charles S and Mani, K Radha and Yajnik, Chittaranjan S and Hofman, Albert and Mattace-Raso, Francesco U S and Oostra, Ben A and Demirkan, Ayse and Isaacs, Aaron and Rivadeneira, Fernando and Lakatta, Edward G and Orr{\`u}, Marco and Scuteri, Angelo and Ala-Korpela, Mika and Kangas, Antti J and Lyytik{\"a}inen, Leo-Pekka and Soininen, Pasi and Tukiainen, Taru and W{\"u}rtz, Peter and Ong, Rick Twee-Hee and D{\"o}rr, Marcus and Kroemer, Heyo K and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Galan, Pilar and Hercberg, Serge and Lathrop, Mark and Zelenika, Diana and Deloukas, Panos and Mangino, Massimo and Spector, Tim D and Zhai, Guangju and Meschia, James F and Nalls, Michael A and Sharma, Pankaj and Terzic, Janos and Kumar, M V Kranthi and Denniff, Matthew and Zukowska-Szczechowska, Ewa and Wagenknecht, Lynne E and Fowkes, F Gerald R and Charchar, Fadi J and Schwarz, Peter E H and Hayward, Caroline and Guo, Xiuqing and Rotimi, Charles and Bots, Michiel L and Brand, Eva and Samani, Nilesh J and Polasek, Ozren and Talmud, Philippa J and Nyberg, Fredrik and Kuh, Diana and Laan, Maris and Hveem, Kristian and Palmer, Lyle J and van der Schouw, Yvonne T and Casas, Juan P and Mohlke, Karen L and Vineis, Paolo and Raitakari, Olli and Ganesh, Santhi K and Wong, Tien Y and Tai, E Shyong and Cooper, Richard S and Laakso, Markku and Rao, Dabeeru C and Harris, Tamara B and Morris, Richard W and Dominiczak, Anna F and Kivimaki, Mika and Marmot, Michael G and Miki, Tetsuro and Saleheen, Danish and Chandak, Giriraj R and Coresh, Josef and Navis, Gerjan and Salomaa, Veikko and Han, Bok-Ghee and Zhu, Xiaofeng and Kooner, Jaspal S and Melander, Olle and Ridker, Paul M and Bandinelli, Stefania and Gyllensten, Ulf B and Wright, Alan F and Wilson, James F and Ferrucci, Luigi and Farrall, Martin and Tuomilehto, Jaakko and Pramstaller, Peter P and Elosua, Roberto and Soranzo, Nicole and Sijbrands, Eric J G and Altshuler, David and Loos, Ruth J F and Shuldiner, Alan R and Gieger, Christian and Meneton, Pierre and Uitterlinden, Andr{\'e} G and Wareham, Nicholas J and Gudnason, Vilmundur and Rotter, Jerome I and Rettig, Rainer and Uda, Manuela and Strachan, David P and Witteman, Jacqueline C M and Hartikainen, Anna-Liisa and Beckmann, Jacques S and Boerwinkle, Eric and Vasan, Ramachandran S and Boehnke, Michael and Larson, Martin G and Jarvelin, Marjo-Riitta and Psaty, Bruce M and Abecasis, Goncalo R and Chakravarti, Aravinda and Elliott, Paul and van Duijn, Cornelia M and Newton-Cheh, Christopher and Levy, Daniel and Caulfield, Mark J and Johnson, Toby} } @article {1301, title = {Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile.}, journal = {Nat Genet}, volume = {43}, year = {2011}, month = {2011 Jun 26}, pages = {753-60}, abstract = {

Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between \~{}2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 {\texttimes} 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 {\texttimes} 10(-11)) and one near SPRY2 (P = 3 {\texttimes} 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.

}, keywords = {Adiponectin, Adiposity, Alleles, Body Fat Distribution, Body Mass Index, Body Weight, Female, Genetic Variation, Genome-Wide Association Study, Humans, Insulin Receptor Substrate Proteins, Intracellular Signaling Peptides and Proteins, Male, Membrane Proteins, Meta-Analysis as Topic, Metabolome, Obesity, Polymorphism, Single Nucleotide, Subcutaneous Fat}, issn = {1546-1718}, doi = {10.1038/ng.866}, author = {Kilpel{\"a}inen, Tuomas O and Zillikens, M Carola and Stan{\v c}{\'a}kov{\'a}, Alena and Finucane, Francis M and Ried, Janina S and Langenberg, Claudia and Zhang, Weihua and Beckmann, Jacques S and Luan, Jian{\textquoteright}an and Vandenput, Liesbeth and Styrkarsdottir, Unnur and Zhou, Yanhua and Smith, Albert Vernon and Zhao, Jing-Hua and Amin, Najaf and Vedantam, Sailaja and Shin, So-Youn and Haritunians, Talin and Fu, Mao and Feitosa, Mary F and Kumari, Meena and Halldorsson, Bjarni V and Tikkanen, Emmi and Mangino, Massimo and Hayward, Caroline and Song, Ci and Arnold, Alice M and Aulchenko, Yurii S and Oostra, Ben A and Campbell, Harry and Cupples, L Adrienne and Davis, Kathryn E and D{\"o}ring, Angela and Eiriksdottir, Gudny and Estrada, Karol and Fern{\'a}ndez-Real, Jos{\'e} Manuel and Garcia, Melissa and Gieger, Christian and Glazer, Nicole L and Guiducci, Candace and Hofman, Albert and Humphries, Steve E and Isomaa, Bo and Jacobs, Leonie C and Jula, Antti and Karasik, David and Karlsson, Magnus K and Khaw, Kay-Tee and Kim, Lauren J and Kivimaki, Mika and Klopp, Norman and Kuhnel, Brigitte and Kuusisto, Johanna and Liu, Yongmei and Ljunggren, Osten and Lorentzon, Mattias and Luben, Robert N and McKnight, Barbara and Mellstr{\"o}m, Dan and Mitchell, Braxton D and Mooser, Vincent and Moreno, Jos{\'e} Maria and M{\"a}nnist{\"o}, Satu and O{\textquoteright}Connell, Jeffery R and Pascoe, Laura and Peltonen, Leena and Peral, Bel{\'e}n and Perola, Markus and Psaty, Bruce M and Salomaa, Veikko and Savage, David B and Semple, Robert K and Skaric-Juric, Tatjana and Sigurdsson, Gunnar and Song, Kijoung S and Spector, Timothy D and Syv{\"a}nen, Ann-Christine and Talmud, Philippa J and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Uitterlinden, Andr{\'e} G and van Duijn, Cornelia M and Vidal-Puig, Antonio and Wild, Sarah H and Wright, Alan F and Clegg, Deborah J and Schadt, Eric and Wilson, James F and Rudan, Igor and Ripatti, Samuli and Borecki, Ingrid B and Shuldiner, Alan R and Ingelsson, Erik and Jansson, John-Olov and Kaplan, Robert C and Gudnason, Vilmundur and Harris, Tamara B and Groop, Leif and Kiel, Douglas P and Rivadeneira, Fernando and Walker, Mark and Barroso, In{\^e}s and Vollenweider, Peter and Waeber, G{\'e}rard and Chambers, John C and Kooner, Jaspal S and Soranzo, Nicole and Hirschhorn, Joel N and Stefansson, Kari and Wichmann, H-Erich and Ohlsson, Claes and O{\textquoteright}Rahilly, Stephen and Wareham, Nicholas J and Speliotes, Elizabeth K and Fox, Caroline S and Laakso, Markku and Loos, Ruth J F} } @article {1324, title = {Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.}, journal = {Nat Genet}, volume = {43}, year = {2011}, month = {2011 Sep 11}, pages = {1005-11}, abstract = {

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 {\texttimes} 10(-8) to P = 2.3 {\texttimes} 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.

}, keywords = {Arteries, Blood Pressure, Case-Control Studies, Follow-Up Studies, Genetic Loci, Genome-Wide Association Study, Humans, Hypertension, Linkage Disequilibrium, Polymorphism, Single Nucleotide}, issn = {1546-1718}, doi = {10.1038/ng.922}, author = {Wain, Louise V and Verwoert, Germaine C and O{\textquoteright}Reilly, Paul F and Shi, Gang and Johnson, Toby and Johnson, Andrew D and Bochud, Murielle and Rice, Kenneth M and Henneman, Peter and Smith, Albert V and Ehret, Georg B and Amin, Najaf and Larson, Martin G and Mooser, Vincent and Hadley, David and D{\"o}rr, Marcus and Bis, Joshua C and Aspelund, Thor and Esko, T{\~o}nu and Janssens, A Cecile J W and Zhao, Jing Hua and Heath, Simon and Laan, Maris and Fu, Jingyuan and Pistis, Giorgio and Luan, Jian{\textquoteright}an and Arora, Pankaj and Lucas, Gavin and Pirastu, Nicola and Pichler, Irene and Jackson, Anne U and Webster, Rebecca J and Zhang, Feng and Peden, John F and Schmidt, Helena and Tanaka, Toshiko and Campbell, Harry and Igl, Wilmar and Milaneschi, Yuri and Hottenga, Jouke-Jan and Vitart, Veronique and Chasman, Daniel I and Trompet, Stella and Bragg-Gresham, Jennifer L and Alizadeh, Behrooz Z and Chambers, John C and Guo, Xiuqing and Lehtim{\"a}ki, Terho and Kuhnel, Brigitte and Lopez, Lorna M and Polasek, Ozren and Boban, Mladen and Nelson, Christopher P and Morrison, Alanna C and Pihur, Vasyl and Ganesh, Santhi K and Hofman, Albert and Kundu, Suman and Mattace-Raso, Francesco U S and Rivadeneira, Fernando and Sijbrands, Eric J G and Uitterlinden, Andr{\'e} G and Hwang, Shih-Jen and Vasan, Ramachandran S and Wang, Thomas J and Bergmann, Sven and Vollenweider, Peter and Waeber, G{\'e}rard and Laitinen, Jaana and Pouta, Anneli and Zitting, Paavo and McArdle, Wendy L and Kroemer, Heyo K and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Glazer, Nicole L and Taylor, Kent D and Harris, Tamara B and Alavere, Helene and Haller, Toomas and Keis, Aime and Tammesoo, Mari-Liis and Aulchenko, Yurii and Barroso, In{\^e}s and Khaw, Kay-Tee and Galan, Pilar and Hercberg, Serge and Lathrop, Mark and Eyheramendy, Susana and Org, Elin and S{\~o}ber, Siim and Lu, Xiaowen and Nolte, Ilja M and Penninx, Brenda W and Corre, Tanguy and Masciullo, Corrado and Sala, Cinzia and Groop, Leif and Voight, Benjamin F and Melander, Olle and O{\textquoteright}Donnell, Christopher J and Salomaa, Veikko and d{\textquoteright}Adamo, Adamo Pio and Fabretto, Antonella and Faletra, Flavio and Ulivi, Sheila and Del Greco, Fabiola M and Facheris, Maurizio and Collins, Francis S and Bergman, Richard N and Beilby, John P and Hung, Joseph and Musk, A William and Mangino, Massimo and Shin, So-Youn and Soranzo, Nicole and Watkins, Hugh and Goel, Anuj and Hamsten, Anders and Gider, Pierre and Loitfelder, Marisa and Zeginigg, Marion and Hernandez, Dena and Najjar, Samer S and Navarro, Pau and Wild, Sarah H and Corsi, Anna Maria and Singleton, Andrew and de Geus, Eco J C and Willemsen, Gonneke and Parker, Alex N and Rose, Lynda M and Buckley, Brendan and Stott, David and Orr{\`u}, Marco and Uda, Manuela and van der Klauw, Melanie M and Zhang, Weihua and Li, Xinzhong and Scott, James and Chen, Yii-Der Ida and Burke, Gregory L and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and D{\"o}ring, Angela and Meitinger, Thomas and Davies, Gail and Starr, John M and Emilsson, Valur and Plump, Andrew and Lindeman, Jan H and Hoen, Peter A C {\textquoteright}t and K{\"o}nig, Inke R and Felix, Janine F and Clarke, Robert and Hopewell, Jemma C and Ongen, Halit and Breteler, Monique and Debette, Stephanie and DeStefano, Anita L and Fornage, Myriam and Mitchell, Gary F and Smith, Nicholas L and Holm, Hilma and Stefansson, Kari and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Samani, Nilesh J and Preuss, Michael and Rudan, Igor and Hayward, Caroline and Deary, Ian J and Wichmann, H-Erich and Raitakari, Olli T and Palmas, Walter and Kooner, Jaspal S and Stolk, Ronald P and Jukema, J Wouter and Wright, Alan F and Boomsma, Dorret I and Bandinelli, Stefania and Gyllensten, Ulf B and Wilson, James F and Ferrucci, Luigi and Schmidt, Reinhold and Farrall, Martin and Spector, Tim D and Palmer, Lyle J and Tuomilehto, Jaakko and Pfeufer, Arne and Gasparini, Paolo and Siscovick, David and Altshuler, David and Loos, Ruth J F and Toniolo, Daniela and Snieder, Harold and Gieger, Christian and Meneton, Pierre and Wareham, Nicholas J and Oostra, Ben A and Metspalu, Andres and Launer, Lenore and Rettig, Rainer and Strachan, David P and Beckmann, Jacques S and Witteman, Jacqueline C M and Erdmann, Jeanette and van Dijk, Ko Willems and Boerwinkle, Eric and Boehnke, Michael and Ridker, Paul M and Jarvelin, Marjo-Riitta and Chakravarti, Aravinda and Abecasis, Goncalo R and Gudnason, Vilmundur and Newton-Cheh, Christopher and Levy, Daniel and Munroe, Patricia B and Psaty, Bruce M and Caulfield, Mark J and Rao, Dabeeru C and Tobin, Martin D and Elliott, Paul and van Duijn, Cornelia M} } @article {1267, title = {Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels.}, journal = {Circulation}, volume = {123}, year = {2011}, month = {2011 Feb 22}, pages = {731-8}, abstract = {

BACKGROUND: C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We sought to identify genetic variants that are associated with CRP levels.

METHODS AND RESULTS: We performed a genome-wide association analysis of CRP in 66 185 participants from 15 population-based studies. We sought replication for the genome-wide significant and suggestive loci in a replication panel comprising 16 540 individuals from 10 independent studies. We found 18 genome-wide significant loci, and we provided evidence of replication for 8 of them. Our results confirm 7 previously known loci and introduce 11 novel loci that are implicated in pathways related to the metabolic syndrome (APOC1, HNF1A, LEPR, GCKR, HNF4A, and PTPN2) or the immune system (CRP, IL6R, NLRP3, IL1F10, and IRF1) or that reside in regions previously not known to play a role in chronic inflammation (PPP1R3B, SALL1, PABPC4, ASCL1, RORA, and BCL7B). We found a significant interaction of body mass index with LEPR (P<2.9{\texttimes}10(-6)). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained ≈5\% of the trait variance; however, there was no evidence for these genetic variants explaining the association of CRP with coronary heart disease.

CONCLUSIONS: We identified 18 loci that were associated with CRP levels. Our study highlights immune response and metabolic regulatory pathways involved in the regulation of chronic inflammation.

}, keywords = {Biomarkers, C-Reactive Protein, Cardiovascular Diseases, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Risk Factors, Vasculitis}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.110.948570}, author = {Dehghan, Abbas and Dupuis, Jos{\'e}e and Barbalic, Maja and Bis, Joshua C and Eiriksdottir, Gudny and Lu, Chen and Pellikka, Niina and Wallaschofski, Henri and Kettunen, Johannes and Henneman, Peter and Baumert, Jens and Strachan, David P and Fuchsberger, Christian and Vitart, Veronique and Wilson, James F and Par{\'e}, Guillaume and Naitza, Silvia and Rudock, Megan E and Surakka, Ida and de Geus, Eco J C and Alizadeh, Behrooz Z and Guralnik, Jack and Shuldiner, Alan and Tanaka, Toshiko and Zee, Robert Y L and Schnabel, Renate B and Nambi, Vijay and Kavousi, Maryam and Ripatti, Samuli and Nauck, Matthias and Smith, Nicholas L and Smith, Albert V and Sundvall, Jouko and Scheet, Paul and Liu, Yongmei and Ruokonen, Aimo and Rose, Lynda M and Larson, Martin G and Hoogeveen, Ron C and Freimer, Nelson B and Teumer, Alexander and Tracy, Russell P and Launer, Lenore J and Buring, Julie E and Yamamoto, Jennifer F and Folsom, Aaron R and Sijbrands, Eric J G and Pankow, James and Elliott, Paul and Keaney, John F and Sun, Wei and Sarin, Antti-Pekka and Fontes, Jo{\~a}o D and Badola, Sunita and Astor, Brad C and Hofman, Albert and Pouta, Anneli and Werdan, Karl and Greiser, Karin H and Kuss, Oliver and Meyer zu Schwabedissen, Henriette E and Thiery, Joachim and Jamshidi, Yalda and Nolte, Ilja M and Soranzo, Nicole and Spector, Timothy D and V{\"o}lzke, Henry and Parker, Alexander N and Aspelund, Thor and Bates, David and Young, Lauren and Tsui, Kim and Siscovick, David S and Guo, Xiuqing and Rotter, Jerome I and Uda, Manuela and Schlessinger, David and Rudan, Igor and Hicks, Andrew A and Penninx, Brenda W and Thorand, Barbara and Gieger, Christian and Coresh, Joe and Willemsen, Gonneke and Harris, Tamara B and Uitterlinden, Andr{\'e} G and Jarvelin, Marjo-Riitta and Rice, Kenneth and Radke, D{\"o}rte and Salomaa, Veikko and Willems van Dijk, Ko and Boerwinkle, Eric and Vasan, Ramachandran S and Ferrucci, Luigi and Gibson, Quince D and Bandinelli, Stefania and Snieder, Harold and Boomsma, Dorret I and Xiao, Xiangjun and Campbell, Harry and Hayward, Caroline and Pramstaller, Peter P and van Duijn, Cornelia M and Peltonen, Leena and Psaty, Bruce M and Gudnason, Vilmundur and Ridker, Paul M and Homuth, Georg and Koenig, Wolfgang and Ballantyne, Christie M and Witteman, Jacqueline C M and Benjamin, Emelia J and Perola, Markus and Chasman, Daniel I} } @article {1355, title = {New gene functions in megakaryopoiesis and platelet formation.}, journal = {Nature}, volume = {480}, year = {2011}, month = {2011 Nov 30}, pages = {201-8}, abstract = {

Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function.

}, keywords = {Animals, Blood Platelets, Cell Size, Drosophila melanogaster, Drosophila Proteins, Europe, Gene Expression Profiling, Gene Silencing, Genome, Human, Genome-Wide Association Study, Hematopoiesis, Humans, Megakaryocytes, Platelet Count, Protein Interaction Maps, Transcription, Genetic, Zebrafish, Zebrafish Proteins}, issn = {1476-4687}, doi = {10.1038/nature10659}, author = {Gieger, Christian and Radhakrishnan, Aparna and Cvejic, Ana and Tang, Weihong and Porcu, Eleonora and Pistis, Giorgio and Serbanovic-Canic, Jovana and Elling, Ulrich and Goodall, Alison H and Labrune, Yann and Lopez, Lorna M and M{\"a}gi, Reedik and Meacham, Stuart and Okada, Yukinori and Pirastu, Nicola and Sorice, Rossella and Teumer, Alexander and Voss, Katrin and Zhang, Weihua and Ramirez-Solis, Ramiro and Bis, Joshua C and Ellinghaus, David and G{\"o}gele, Martin and Hottenga, Jouke-Jan and Langenberg, Claudia and Kovacs, Peter and O{\textquoteright}Reilly, Paul F and Shin, So-Youn and Esko, T{\~o}nu and Hartiala, Jaana and Kanoni, Stavroula and Murgia, Federico and Parsa, Afshin and Stephens, Jonathan and van der Harst, Pim and Ellen van der Schoot, C and Allayee, Hooman and Attwood, Antony and Balkau, Beverley and Bastardot, Fran{\c c}ois and Basu, Saonli and Baumeister, Sebastian E and Biino, Ginevra and Bomba, Lorenzo and Bonnefond, Am{\'e}lie and Cambien, Francois and Chambers, John C and Cucca, Francesco and D{\textquoteright}Adamo, Pio and Davies, Gail and de Boer, Rudolf A and de Geus, Eco J C and D{\"o}ring, Angela and Elliott, Paul and Erdmann, Jeanette and Evans, David M and Falchi, Mario and Feng, Wei and Folsom, Aaron R and Frazer, Ian H and Gibson, Quince D and Glazer, Nicole L and Hammond, Chris and Hartikainen, Anna-Liisa and Heckbert, Susan R and Hengstenberg, Christian and Hersch, Micha and Illig, Thomas and Loos, Ruth J F and Jolley, Jennifer and Khaw, Kay Tee and Kuhnel, Brigitte and Kyrtsonis, Marie-Christine and Lagou, Vasiliki and Lloyd-Jones, Heather and Lumley, Thomas and Mangino, Massimo and Maschio, Andrea and Mateo Leach, Irene and McKnight, Barbara and Memari, Yasin and Mitchell, Braxton D and Montgomery, Grant W and Nakamura, Yusuke and Nauck, Matthias and Navis, Gerjan and N{\"o}thlings, Ute and Nolte, Ilja M and Porteous, David J and Pouta, Anneli and Pramstaller, Peter P and Pullat, Janne and Ring, Susan M and Rotter, Jerome I and Ruggiero, Daniela and Ruokonen, Aimo and Sala, Cinzia and Samani, Nilesh J and Sambrook, Jennifer and Schlessinger, David and Schreiber, Stefan and Schunkert, Heribert and Scott, James and Smith, Nicholas L and Snieder, Harold and Starr, John M and Stumvoll, Michael and Takahashi, Atsushi and Tang, W H Wilson and Taylor, Kent and Tenesa, Albert and Lay Thein, Swee and T{\"o}njes, Anke and Uda, Manuela and Ulivi, Sheila and van Veldhuisen, Dirk J and Visscher, Peter M and V{\"o}lker, Uwe and Wichmann, H-Erich and Wiggins, Kerri L and Willemsen, Gonneke and Yang, Tsun-Po and Hua Zhao, Jing and Zitting, Paavo and Bradley, John R and Dedoussis, George V and Gasparini, Paolo and Hazen, Stanley L and Metspalu, Andres and Pirastu, Mario and Shuldiner, Alan R and Joost van Pelt, L and Zwaginga, Jaap-Jan and Boomsma, Dorret I and Deary, Ian J and Franke, Andre and Froguel, Philippe and Ganesh, Santhi K and Jarvelin, Marjo-Riitta and Martin, Nicholas G and Meisinger, Christa and Psaty, Bruce M and Spector, Timothy D and Wareham, Nicholas J and Akkerman, Jan-Willem N and Ciullo, Marina and Deloukas, Panos and Greinacher, Andreas and Jupe, Steve and Kamatani, Naoyuki and Khadake, Jyoti and Kooner, Jaspal S and Penninger, Josef and Prokopenko, Inga and Stemple, Derek and Toniolo, Daniela and Wernisch, Lorenz and Sanna, Serena and Hicks, Andrew A and Rendon, Augusto and Ferreira, Manuel A and Ouwehand, Willem H and Soranzo, Nicole} } @article {6089, title = {Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation.}, journal = {Blood}, volume = {120}, year = {2012}, month = {2012 Dec 06}, pages = {4873-81}, abstract = {

We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P < 5 {\texttimes} 10(-8)) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P = 3.4 {\texttimes} 10(-10)); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 {\texttimes} 10(-8)); and chromosome 3p25.2 within PPARG (rs11128603, discovery P = 2.9 {\texttimes} 10(-8)). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P < .05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1.

}, keywords = {Adaptor Proteins, Signal Transducing, ARNTL Transcription Factors, ATPases Associated with Diverse Cellular Activities, Cell Line, Cell Line, Tumor, Cohort Studies, Coronary Artery Disease, Diabetes Mellitus, Type 2, Gene Expression Profiling, Gene Expression Regulation, Gene Frequency, Genome-Wide Association Study, Genotype, Humans, LIM Domain Proteins, Meta-Analysis as Topic, Monocytes, Mucin-3, Plasminogen Activator Inhibitor 1, Polymorphism, Single Nucleotide, PPAR gamma, Proteasome Endopeptidase Complex, RNA Interference, Transcription Factors}, issn = {1528-0020}, doi = {10.1182/blood-2012-06-436188}, author = {Huang, Jie and Sabater-Lleal, Maria and Asselbergs, Folkert W and Tregouet, David and Shin, So-Youn and Ding, Jingzhong and Baumert, Jens and Oudot-Mellakh, Tiphaine and Folkersen, Lasse and Johnson, Andrew D and Smith, Nicholas L and Williams, Scott M and Ikram, Mohammad A and Kleber, Marcus E and Becker, Diane M and Truong, Vinh and Mychaleckyj, Josyf C and Tang, Weihong and Yang, Qiong and Sennblad, Bengt and Moore, Jason H and Williams, Frances M K and Dehghan, Abbas and Silbernagel, G{\"u}nther and Schrijvers, Elisabeth M C and Smith, Shelly and Karakas, Mahir and Tofler, Geoffrey H and Silveira, Angela and Navis, Gerjan J and Lohman, Kurt and Chen, Ming-Huei and Peters, Annette and Goel, Anuj and Hopewell, Jemma C and Chambers, John C and Saleheen, Danish and Lundmark, Per and Psaty, Bruce M and Strawbridge, Rona J and Boehm, Bernhard O and Carter, Angela M and Meisinger, Christa and Peden, John F and Bis, Joshua C and McKnight, Barbara and Ohrvik, John and Taylor, Kent and Franzosi, Maria Grazia and Seedorf, Udo and Collins, Rory and Franco-Cereceda, Anders and Syv{\"a}nen, Ann-Christine and Goodall, Alison H and Yanek, Lisa R and Cushman, Mary and M{\"u}ller-Nurasyid, Martina and Folsom, Aaron R and Basu, Saonli and Matijevic, Nena and van Gilst, Wiek H and Kooner, Jaspal S and Hofman, Albert and Danesh, John and Clarke, Robert and Meigs, James B and Kathiresan, Sekar and Reilly, Muredach P and Klopp, Norman and Harris, Tamara B and Winkelmann, Bernhard R and Grant, Peter J and Hillege, Hans L and Watkins, Hugh and Spector, Timothy D and Becker, Lewis C and Tracy, Russell P and M{\"a}rz, Winfried and Uitterlinden, Andr{\'e} G and Eriksson, Per and Cambien, Francois and Morange, Pierre-Emmanuel and Koenig, Wolfgang and Soranzo, Nicole and van der Harst, Pim and Liu, Yongmei and O{\textquoteright}Donnell, Christopher J and Hamsten, Anders} } @article {1360, title = {Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways.}, journal = {Nat Genet}, volume = {44}, year = {2012}, month = {2012 Jan 22}, pages = {260-8}, abstract = {

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 {\texttimes} 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.

}, keywords = {Age Factors, DNA Helicases, DNA Polymerase gamma, DNA Primase, DNA Repair, DNA Repair Enzymes, DNA-Directed DNA Polymerase, European Continental Ancestry Group, Exodeoxyribonucleases, Female, Genetic Loci, Genome-Wide Association Study, Humans, Immunity, Menopause, Polymorphism, Single Nucleotide, Proteins}, issn = {1546-1718}, doi = {10.1038/ng.1051}, author = {Stolk, Lisette and Perry, John R B and Chasman, Daniel I and He, Chunyan and Mangino, Massimo and Sulem, Patrick and Barbalic, Maja and Broer, Linda and Byrne, Enda M and Ernst, Florian and Esko, T{\~o}nu and Franceschini, Nora and Gudbjartsson, Daniel F and Hottenga, Jouke-Jan and Kraft, Peter and McArdle, Patrick F and Porcu, Eleonora and Shin, So-Youn and Smith, Albert V and van Wingerden, Sophie and Zhai, Guangju and Zhuang, Wei V and Albrecht, Eva and Alizadeh, Behrooz Z and Aspelund, Thor and Bandinelli, Stefania and Lauc, Lovorka Barac and Beckmann, Jacques S and Boban, Mladen and Boerwinkle, Eric and Broekmans, Frank J and Burri, Andrea and Campbell, Harry and Chanock, Stephen J and Chen, Constance and Cornelis, Marilyn C and Corre, Tanguy and Coviello, Andrea D and D{\textquoteright}Adamo, Pio and Davies, Gail and de Faire, Ulf and de Geus, Eco J C and Deary, Ian J and Dedoussis, George V Z and Deloukas, Panagiotis and Ebrahim, Shah and Eiriksdottir, Gudny and Emilsson, Valur and Eriksson, Johan G and Fauser, Bart C J M and Ferreli, Liana and Ferrucci, Luigi and Fischer, Krista and Folsom, Aaron R and Garcia, Melissa E and Gasparini, Paolo and Gieger, Christian and Glazer, Nicole and Grobbee, Diederick E and Hall, Per and Haller, Toomas and Hankinson, Susan E and Hass, Merli and Hayward, Caroline and Heath, Andrew C and Hofman, Albert and Ingelsson, Erik and Janssens, A Cecile J W and Johnson, Andrew D and Karasik, David and Kardia, Sharon L R and Keyzer, Jules and Kiel, Douglas P and Kolcic, Ivana and Kutalik, Zolt{\'a}n and Lahti, Jari and Lai, Sandra and Laisk, Triin and Laven, Joop S E and Lawlor, Debbie A and Liu, Jianjun and Lopez, Lorna M and Louwers, Yvonne V and Magnusson, Patrik K E and Marongiu, Mara and Martin, Nicholas G and Klaric, Irena Martinovic and Masciullo, Corrado and McKnight, Barbara and Medland, Sarah E and Melzer, David and Mooser, Vincent and Navarro, Pau and Newman, Anne B and Nyholt, Dale R and Onland-Moret, N Charlotte and Palotie, Aarno and Par{\'e}, Guillaume and Parker, Alex N and Pedersen, Nancy L and Peeters, Petra H M and Pistis, Giorgio and Plump, Andrew S and Polasek, Ozren and Pop, Victor J M and Psaty, Bruce M and R{\"a}ikk{\"o}nen, Katri and Rehnberg, Emil and Rotter, Jerome I and Rudan, Igor and Sala, Cinzia and Salumets, Andres and Scuteri, Angelo and Singleton, Andrew and Smith, Jennifer A and Snieder, Harold and Soranzo, Nicole and Stacey, Simon N and Starr, John M and Stathopoulou, Maria G and Stirrups, Kathleen and Stolk, Ronald P and Styrkarsdottir, Unnur and Sun, Yan V and Tenesa, Albert and Thorand, Barbara and Toniolo, Daniela and Tryggvadottir, Laufey and Tsui, Kim and Ulivi, Sheila and van Dam, Rob M and van der Schouw, Yvonne T and van Gils, Carla H and van Nierop, Peter and Vink, Jacqueline M and Visscher, Peter M and Voorhuis, Marlies and Waeber, G{\'e}rard and Wallaschofski, Henri and Wichmann, H Erich and Widen, Elisabeth and Wijnands-van Gent, Colette J M and Willemsen, Gonneke and Wilson, James F and Wolffenbuttel, Bruce H R and Wright, Alan F and Yerges-Armstrong, Laura M and Zemunik, Tatijana and Zgaga, Lina and Zillikens, M Carola and Zygmunt, Marek and Arnold, Alice M and Boomsma, Dorret I and Buring, Julie E and Crisponi, Laura and Demerath, Ellen W and Gudnason, Vilmundur and Harris, Tamara B and Hu, Frank B and Hunter, David J and Launer, Lenore J and Metspalu, Andres and Montgomery, Grant W and Oostra, Ben A and Ridker, Paul M and Sanna, Serena and Schlessinger, David and Spector, Tim D and Stefansson, Kari and Streeten, Elizabeth A and Thorsteinsdottir, Unnur and Uda, Manuela and Uitterlinden, Andr{\'e} G and van Duijn, Cornelia M and V{\"o}lzke, Henry and Murray, Anna and Murabito, Joanne M and Visser, Jenny A and Lunetta, Kathryn L} } @article {1378, title = {Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.}, journal = {PLoS Genet}, volume = {8}, year = {2012}, month = {2012}, pages = {e1002607}, abstract = {

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5{\texttimes}10(-8)-1.2{\texttimes}10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3{\texttimes}10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3{\texttimes}10(-3), n = 22,044), increased triglycerides (p = 2.6{\texttimes}10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8{\texttimes}10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4{\texttimes}10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5{\texttimes}10(-13), n = 96,748) and decreased BMI (p = 1.4{\texttimes}10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

}, keywords = {Adiponectin, African Americans, Asian Continental Ancestry Group, Cholesterol, HDL, Diabetes Mellitus, Type 2, European Continental Ancestry Group, Female, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Glucose Tolerance Test, Humans, Insulin Resistance, Male, Metabolic Networks and Pathways, Polymorphism, Single Nucleotide, Waist-Hip Ratio}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1002607}, author = {Dastani, Zari and Hivert, Marie-France and Timpson, Nicholas and Perry, John R B and Yuan, Xin and Scott, Robert A and Henneman, Peter and Heid, Iris M and Kizer, Jorge R and Lyytik{\"a}inen, Leo-Pekka and Fuchsberger, Christian and Tanaka, Toshiko and Morris, Andrew P and Small, Kerrin and Isaacs, Aaron and Beekman, Marian and Coassin, Stefan and Lohman, Kurt and Qi, Lu and Kanoni, Stavroula and Pankow, James S and Uh, Hae-Won and Wu, Ying and Bidulescu, Aurelian and Rasmussen-Torvik, Laura J and Greenwood, Celia M T and Ladouceur, Martin and Grimsby, Jonna and Manning, Alisa K and Liu, Ching-Ti and Kooner, Jaspal and Mooser, Vincent E and Vollenweider, Peter and Kapur, Karen A and Chambers, John and Wareham, Nicholas J and Langenberg, Claudia and Frants, Rune and Willems-Vandijk, Ko and Oostra, Ben A and Willems, Sara M and Lamina, Claudia and Winkler, Thomas W and Psaty, Bruce M and Tracy, Russell P and Brody, Jennifer and Chen, Ida and Viikari, Jorma and K{\"a}h{\"o}nen, Mika and Pramstaller, Peter P and Evans, David M and St Pourcain, Beate and Sattar, Naveed and Wood, Andrew R and Bandinelli, Stefania and Carlson, Olga D and Egan, Josephine M and B{\"o}hringer, Stefan and van Heemst, Diana and Kedenko, Lyudmyla and Kristiansson, Kati and Nuotio, Marja-Liisa and Loo, Britt-Marie and Harris, Tamara and Garcia, Melissa and Kanaya, Alka and Haun, Margot and Klopp, Norman and Wichmann, H-Erich and Deloukas, Panos and Katsareli, Efi and Couper, David J and Duncan, Bruce B and Kloppenburg, Margreet and Adair, Linda S and Borja, Judith B and Wilson, James G and Musani, Solomon and Guo, Xiuqing and Johnson, Toby and Semple, Robert and Teslovich, Tanya M and Allison, Matthew A and Redline, Susan and Buxbaum, Sarah G and Mohlke, Karen L and Meulenbelt, Ingrid and Ballantyne, Christie M and Dedoussis, George V and Hu, Frank B and Liu, Yongmei and Paulweber, Bernhard and Spector, Timothy D and Slagboom, P Eline and Ferrucci, Luigi and Jula, Antti and Perola, Markus and Raitakari, Olli and Florez, Jose C and Salomaa, Veikko and Eriksson, Johan G and Frayling, Timothy M and Hicks, Andrew A and Lehtim{\"a}ki, Terho and Smith, George Davey and Siscovick, David S and Kronenberg, Florian and van Duijn, Cornelia and Loos, Ruth J F and Waterworth, Dawn M and Meigs, James B and Dupuis, Jos{\'e}e and Richards, J Brent and Voight, Benjamin F and Scott, Laura J and Steinthorsdottir, Valgerdur and Dina, Christian and Welch, Ryan P and Zeggini, Eleftheria and Huth, Cornelia and Aulchenko, Yurii S and Thorleifsson, Gudmar and McCulloch, Laura J and Ferreira, Teresa and Grallert, Harald and Amin, Najaf and Wu, Guanming and Willer, Cristen J and Raychaudhuri, Soumya and McCarroll, Steve A and Hofmann, Oliver M and Segr{\`e}, Ayellet V and van Hoek, Mandy and Navarro, Pau and Ardlie, Kristin and Balkau, Beverley and Benediktsson, Rafn and Bennett, Amanda J and Blagieva, Roza and Boerwinkle, Eric and Bonnycastle, Lori L and Bostr{\"o}m, Kristina Bengtsson and Bravenboer, Bert and Bumpstead, Suzannah and Burtt, Noel P and Charpentier, Guillaume and Chines, Peter S and Cornelis, Marilyn and Crawford, Gabe and Doney, Alex S F and Elliott, Katherine S and Elliott, Amanda L and Erdos, Michael R and Fox, Caroline S and Franklin, Christopher S and Ganser, Martha and Gieger, Christian and Grarup, Niels and Green, Todd and Griffin, Simon and Groves, Christopher J and Guiducci, Candace and Hadjadj, Samy and Hassanali, Neelam and Herder, Christian and Isomaa, Bo and Jackson, Anne U and Johnson, Paul R V and J{\o}rgensen, Torben and Kao, Wen H L and Kong, Augustine and Kraft, Peter and Kuusisto, Johanna and Lauritzen, Torsten and Li, Man and Lieverse, Aloysius and Lindgren, Cecilia M and Lyssenko, Valeriya and Marre, Michel and Meitinger, Thomas and Midthjell, Kristian and Morken, Mario A and Narisu, Narisu and Nilsson, Peter and Owen, Katharine R and Payne, Felicity and Petersen, Ann-Kristin and Platou, Carl and Proen{\c c}a, Christine and Prokopenko, Inga and Rathmann, Wolfgang and Rayner, N William and Robertson, Neil R and Rocheleau, Ghislain and Roden, Michael and Sampson, Michael J and Saxena, Richa and Shields, Beverley M and Shrader, Peter and Sigurdsson, Gunnar and Spars{\o}, Thomas and Strassburger, Klaus and Stringham, Heather M and Sun, Qi and Swift, Amy J and Thorand, Barbara and Tichet, Jean and Tuomi, Tiinamaija and van Dam, Rob M and van Haeften, Timon W and van Herpt, Thijs and van Vliet-Ostaptchouk, Jana V and Walters, G Bragi and Weedon, Michael N and Wijmenga, Cisca and Witteman, Jacqueline and Bergman, Richard N and Cauchi, Stephane and Collins, Francis S and Gloyn, Anna L and Gyllensten, Ulf and Hansen, Torben and Hide, Winston A and Hitman, Graham A and Hofman, Albert and Hunter, David J and Hveem, Kristian and Laakso, Markku and Morris, Andrew D and Palmer, Colin N A and Rudan, Igor and Sijbrands, Eric and Stein, Lincoln D and Tuomilehto, Jaakko and Uitterlinden, Andre and Walker, Mark and Watanabe, Richard M and Abecasis, Goncalo R and Boehm, Bernhard O and Campbell, Harry and Daly, Mark J and Hattersley, Andrew T and Pedersen, Oluf and Barroso, In{\^e}s and Groop, Leif and Sladek, Rob and Thorsteinsdottir, Unnur and Wilson, James F and Illig, Thomas and Froguel, Philippe and van Duijn, Cornelia M and Stefansson, Kari and Altshuler, David and Boehnke, Michael and McCarthy, Mark I and Soranzo, Nicole and Wheeler, Eleanor and Glazer, Nicole L and Bouatia-Naji, Nabila and M{\"a}gi, Reedik and Randall, Joshua and Elliott, Paul and Rybin, Denis and Dehghan, Abbas and Hottenga, Jouke Jan and Song, Kijoung and Goel, Anuj and Lajunen, Taina and Doney, Alex and Cavalcanti-Proen{\c c}a, Christine and Kumari, Meena and Timpson, Nicholas J and Zabena, Carina and Ingelsson, Erik and An, Ping and O{\textquoteright}Connell, Jeffrey and Luan, Jian{\textquoteright}an and Elliott, Amanda and McCarroll, Steven A and Roccasecca, Rosa Maria and Pattou, Fran{\c c}ois and Sethupathy, Praveen and Ariyurek, Yavuz and Barter, Philip and Beilby, John P and Ben-Shlomo, Yoav and Bergmann, Sven and Bochud, Murielle and Bonnefond, Am{\'e}lie and Borch-Johnsen, Knut and B{\"o}ttcher, Yvonne and Brunner, Eric and Bumpstead, Suzannah J and Chen, Yii-Der Ida and Chines, Peter and Clarke, Robert and Coin, Lachlan J M and Cooper, Matthew N and Crisponi, Laura and Day, Ian N M and de Geus, Eco J C and Delplanque, Jerome and Fedson, Annette C and Fischer-Rosinsky, Antje and Forouhi, Nita G and Franzosi, Maria Grazia and Galan, Pilar and Goodarzi, Mark O and Graessler, J{\"u}rgen and Grundy, Scott and Gwilliam, Rhian and Hallmans, G{\"o}ran and Hammond, Naomi and Han, Xijing and Hartikainen, Anna-Liisa and Hayward, Caroline and Heath, Simon C and Hercberg, Serge and Hillman, David R and Hingorani, Aroon D and Hui, Jennie and Hung, Joe and Kaakinen, Marika and Kaprio, Jaakko and Kesaniemi, Y Antero and Kivimaki, Mika and Knight, Beatrice and Koskinen, Seppo and Kovacs, Peter and Kyvik, Kirsten Ohm and Lathrop, G Mark and Lawlor, Debbie A and Le Bacquer, Olivier and Lecoeur, C{\'e}cile and Li, Yun and Mahley, Robert and Mangino, Massimo and Mart{\'\i}nez-Larrad, Mar{\'\i}a Teresa and McAteer, Jarred B and McPherson, Ruth and Meisinger, Christa and Melzer, David and Meyre, David and Mitchell, Braxton D and Mukherjee, Sutapa and Naitza, Silvia and Neville, Matthew J and Orr{\`u}, Marco and Pakyz, Ruth and Paolisso, Giuseppe and Pattaro, Cristian and Pearson, Daniel and Peden, John F and Pedersen, Nancy L and Pfeiffer, Andreas F H and Pichler, Irene and Polasek, Ozren and Posthuma, Danielle and Potter, Simon C and Pouta, Anneli and Province, Michael A and Rayner, Nigel W and Rice, Kenneth and Ripatti, Samuli and Rivadeneira, Fernando and Rolandsson, Olov and Sandbaek, Annelli and Sandhu, Manjinder and Sanna, Serena and Sayer, Avan Aihie and Scheet, Paul and Seedorf, Udo and Sharp, Stephen J and Shields, Beverley and Sigur{\dh}sson, Gunnar and Sijbrands, Eric J G and Silveira, Angela and Simpson, Laila and Singleton, Andrew and Smith, Nicholas L and Sovio, Ulla and Swift, Amy and Syddall, Holly and Syv{\"a}nen, Ann-Christine and T{\"o}njes, Anke and Uitterlinden, Andr{\'e} G and van Dijk, Ko Willems and Varma, Dhiraj and Visvikis-Siest, Sophie and Vitart, Veronique and Vogelzangs, Nicole and Waeber, G{\'e}rard and Wagner, Peter J and Walley, Andrew and Ward, Kim L and Watkins, Hugh and Wild, Sarah H and Willemsen, Gonneke and Witteman, Jaqueline C M and Yarnell, John W G and Zelenika, Diana and Zethelius, Bj{\"o}rn and Zhai, Guangju and Zhao, Jing Hua and Zillikens, M Carola and Borecki, Ingrid B and Meneton, Pierre and Magnusson, Patrik K E and Nathan, David M and Williams, Gordon H and Silander, Kaisa and Bornstein, Stefan R and Schwarz, Peter and Spranger, Joachim and Karpe, Fredrik and Shuldiner, Alan R and Cooper, Cyrus and Serrano-R{\'\i}os, Manuel and Lind, Lars and Palmer, Lyle J and Hu, Frank B and Franks, Paul W and Ebrahim, Shah and Marmot, Michael and Kao, W H Linda and Pramstaller, Peter Paul and Wright, Alan F and Stumvoll, Michael and Hamsten, Anders and Buchanan, Thomas A and Valle, Timo T and Rotter, Jerome I and Penninx, Brenda W J H and Boomsma, Dorret I and Cao, Antonio and Scuteri, Angelo and Schlessinger, David and Uda, Manuela and Ruokonen, Aimo and Jarvelin, Marjo-Riitta and Peltonen, Leena and Mooser, Vincent and Sladek, Robert and Musunuru, Kiran and Smith, Albert V and Edmondson, Andrew C and Stylianou, Ioannis M and Koseki, Masahiro and Pirruccello, James P and Chasman, Daniel I and Johansen, Christopher T and Fouchier, Sigrid W and Peloso, Gina M and Barbalic, Maja and Ricketts, Sally L and Bis, Joshua C and Feitosa, Mary F and Orho-Melander, Marju and Melander, Olle and Li, Xiaohui and Li, Mingyao and Cho, Yoon Shin and Go, Min Jin and Kim, Young Jin and Lee, Jong-Young and Park, Taesung and Kim, Kyunga and Sim, Xueling and Ong, Rick Twee-Hee and Croteau-Chonka, Damien C and Lange, Leslie A and Smith, Joshua D and Ziegler, Andreas and Zhang, Weihua and Zee, Robert Y L and Whitfield, John B and Thompson, John R and Surakka, Ida and Spector, Tim D and Smit, Johannes H and Sinisalo, Juha and Scott, James and Saharinen, Juha and Sabatti, Chiara and Rose, Lynda M and Roberts, Robert and Rieder, Mark and Parker, Alex N and Par{\'e}, Guillaume and O{\textquoteright}Donnell, Christopher J and Nieminen, Markku S and Nickerson, Deborah A and Montgomery, Grant W and McArdle, Wendy and Masson, David and Martin, Nicholas G and Marroni, Fabio and Lucas, Gavin and Luben, Robert and Lokki, Marja-Liisa and Lettre, Guillaume and Launer, Lenore J and Lakatta, Edward G and Laaksonen, Reijo and Kyvik, Kirsten O and K{\"o}nig, Inke R and Khaw, Kay-Tee and Kaplan, Lee M and Johansson, Asa and Janssens, A Cecile J W and Igl, Wilmar and Hovingh, G Kees and Hengstenberg, Christian and Havulinna, Aki S and Hastie, Nicholas D and Harris, Tamara B and Haritunians, Talin and Hall, Alistair S and Groop, Leif C and Gonzalez, Elena and Freimer, Nelson B and Erdmann, Jeanette and Ejebe, Kenechi G and D{\"o}ring, Angela and Dominiczak, Anna F and Demissie, Serkalem and Deloukas, Panagiotis and de Faire, Ulf and Crawford, Gabriel and Chen, Yii-der I and Caulfield, Mark J and Boekholdt, S Matthijs and Assimes, Themistocles L and Quertermous, Thomas and Seielstad, Mark and Wong, Tien Y and Tai, E-Shyong and Feranil, Alan B and Kuzawa, Christopher W and Taylor, Herman A and Gabriel, Stacey B and Holm, Hilma and Gudnason, Vilmundur and Krauss, Ronald M and Ordovas, Jose M and Munroe, Patricia B and Kooner, Jaspal S and Tall, Alan R and Hegele, Robert A and Kastelein, John J P and Schadt, Eric E and Strachan, David P and Reilly, Muredach P and Samani, Nilesh J and Schunkert, Heribert and Cupples, L Adrienne and Sandhu, Manjinder S and Ridker, Paul M and Rader, Daniel J and Kathiresan, Sekar} } @article {6075, title = {Genome-wide association analyses identify 18 new loci associated with serum urate concentrations.}, journal = {Nat Genet}, volume = {45}, year = {2013}, month = {2013 Feb}, pages = {145-54}, abstract = {

Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.

}, keywords = {Analysis of Variance, European Continental Ancestry Group, Gene Frequency, Genetic Loci, Genome-Wide Association Study, Glucose, Gout, Humans, Inhibins, Polymorphism, Single Nucleotide, Signal Transduction, Uric Acid}, issn = {1546-1718}, doi = {10.1038/ng.2500}, author = {K{\"o}ttgen, Anna and Albrecht, Eva and Teumer, Alexander and Vitart, Veronique and Krumsiek, Jan and Hundertmark, Claudia and Pistis, Giorgio and Ruggiero, Daniela and O{\textquoteright}Seaghdha, Conall M and Haller, Toomas and Yang, Qiong and Tanaka, Toshiko and Johnson, Andrew D and Kutalik, Zolt{\'a}n and Smith, Albert V and Shi, Julia and Struchalin, Maksim and Middelberg, Rita P S and Brown, Morris J and Gaffo, Angelo L and Pirastu, Nicola and Li, Guo and Hayward, Caroline and Zemunik, Tatijana and Huffman, Jennifer and Yengo, Loic and Zhao, Jing Hua and Demirkan, Ayse and Feitosa, Mary F and Liu, Xuan and Malerba, Giovanni and Lopez, Lorna M and van der Harst, Pim and Li, Xinzhong and Kleber, Marcus E and Hicks, Andrew A and Nolte, Ilja M and Johansson, Asa and Murgia, Federico and Wild, Sarah H and Bakker, Stephan J L and Peden, John F and Dehghan, Abbas and Steri, Maristella and Tenesa, Albert and Lagou, Vasiliki and Salo, Perttu and Mangino, Massimo and Rose, Lynda M and Lehtim{\"a}ki, Terho and Woodward, Owen M and Okada, Yukinori and Tin, Adrienne and M{\"u}ller, Christian and Oldmeadow, Christopher and Putku, Margus and Czamara, Darina and Kraft, Peter and Frogheri, Laura and Thun, Gian Andri and Grotevendt, Anne and Gislason, Gauti Kjartan and Harris, Tamara B and Launer, Lenore J and McArdle, Patrick and Shuldiner, Alan R and Boerwinkle, Eric and Coresh, Josef and Schmidt, Helena and Schallert, Michael and Martin, Nicholas G and Montgomery, Grant W and Kubo, Michiaki and Nakamura, Yusuke and Tanaka, Toshihiro and Munroe, Patricia B and Samani, Nilesh J and Jacobs, David R and Liu, Kiang and D{\textquoteright}Adamo, Pio and Ulivi, Sheila and Rotter, Jerome I and Psaty, Bruce M and Vollenweider, Peter and Waeber, G{\'e}rard and Campbell, Susan and Devuyst, Olivier and Navarro, Pau and Kolcic, Ivana and Hastie, Nicholas and Balkau, Beverley and Froguel, Philippe and Esko, T{\~o}nu and Salumets, Andres and Khaw, Kay Tee and Langenberg, Claudia and Wareham, Nicholas J and Isaacs, Aaron and Kraja, Aldi and Zhang, Qunyuan and Wild, Philipp S and Scott, Rodney J and Holliday, Elizabeth G and Org, Elin and Viigimaa, Margus and Bandinelli, Stefania and Metter, Jeffrey E and Lupo, Antonio and Trabetti, Elisabetta and Sorice, Rossella and D{\"o}ring, Angela and Lattka, Eva and Strauch, Konstantin and Theis, Fabian and Waldenberger, Melanie and Wichmann, H-Erich and Davies, Gail and Gow, Alan J and Bruinenberg, Marcel and Stolk, Ronald P and Kooner, Jaspal S and Zhang, Weihua and Winkelmann, Bernhard R and Boehm, Bernhard O and Lucae, Susanne and Penninx, Brenda W and Smit, Johannes H and Curhan, Gary and Mudgal, Poorva and Plenge, Robert M and Portas, Laura and Persico, Ivana and Kirin, Mirna and Wilson, James F and Mateo Leach, Irene and van Gilst, Wiek H and Goel, Anuj and Ongen, Halit and Hofman, Albert and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Imboden, Medea and von Eckardstein, Arnold and Cucca, Francesco and Nagaraja, Ramaiah and Piras, Maria Grazia and Nauck, Matthias and Schurmann, Claudia and Budde, Kathrin and Ernst, Florian and Farrington, Susan M and Theodoratou, Evropi and Prokopenko, Inga and Stumvoll, Michael and Jula, Antti and Perola, Markus and Salomaa, Veikko and Shin, So-Youn and Spector, Tim D and Sala, Cinzia and Ridker, Paul M and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and Hengstenberg, Christian and Nelson, Christopher P and Meschia, James F and Nalls, Michael A and Sharma, Pankaj and Singleton, Andrew B and Kamatani, Naoyuki and Zeller, Tanja and Burnier, Michel and Attia, John and Laan, Maris and Klopp, Norman and Hillege, Hans L and Kloiber, Stefan and Choi, Hyon and Pirastu, Mario and Tore, Silvia and Probst-Hensch, Nicole M and V{\"o}lzke, Henry and Gudnason, Vilmundur and Parsa, Afshin and Schmidt, Reinhold and Whitfield, John B and Fornage, Myriam and Gasparini, Paolo and Siscovick, David S and Polasek, Ozren and Campbell, Harry and Rudan, Igor and Bouatia-Naji, Nabila and Metspalu, Andres and Loos, Ruth J F and van Duijn, Cornelia M and Borecki, Ingrid B and Ferrucci, Luigi and Gambaro, Giovanni and Deary, Ian J and Wolffenbuttel, Bruce H R and Chambers, John C and M{\"a}rz, Winfried and Pramstaller, Peter P and Snieder, Harold and Gyllensten, Ulf and Wright, Alan F and Navis, Gerjan and Watkins, Hugh and Witteman, Jacqueline C M and Sanna, Serena and Schipf, Sabine and Dunlop, Malcolm G and T{\"o}njes, Anke and Ripatti, Samuli and Soranzo, Nicole and Toniolo, Daniela and Chasman, Daniel I and Raitakari, Olli and Kao, W H Linda and Ciullo, Marina and Fox, Caroline S and Caulfield, Mark and Bochud, Murielle and Gieger, Christian} } @article {6152, title = {Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture.}, journal = {Nat Genet}, volume = {45}, year = {2013}, month = {2013 May}, pages = {501-12}, abstract = {

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.

}, keywords = {Anthropometry, Body Height, Body Mass Index, Case-Control Studies, European Continental Ancestry Group, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Meta-Analysis as Topic, Obesity, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Waist-Hip Ratio}, issn = {1546-1718}, doi = {10.1038/ng.2606}, author = {Berndt, Sonja I and Gustafsson, Stefan and M{\"a}gi, Reedik and Ganna, Andrea and Wheeler, Eleanor and Feitosa, Mary F and Justice, Anne E and Monda, Keri L and Croteau-Chonka, Damien C and Day, Felix R and Esko, T{\~o}nu and Fall, Tove and Ferreira, Teresa and Gentilini, Davide and Jackson, Anne U and Luan, Jian{\textquoteright}an and Randall, Joshua C and Vedantam, Sailaja and Willer, Cristen J and Winkler, Thomas W and Wood, Andrew R and Workalemahu, Tsegaselassie and Hu, Yi-Juan and Lee, Sang Hong and Liang, Liming and Lin, Dan-Yu and Min, Josine L and Neale, Benjamin M and Thorleifsson, Gudmar and Yang, Jian and Albrecht, Eva and Amin, Najaf and Bragg-Gresham, Jennifer L and Cadby, Gemma and den Heijer, Martin and Eklund, Niina and Fischer, Krista and Goel, Anuj and Hottenga, Jouke-Jan and Huffman, Jennifer E and Jarick, Ivonne and Johansson, Asa and Johnson, Toby and Kanoni, Stavroula and Kleber, Marcus E and K{\"o}nig, Inke R and Kristiansson, Kati and Kutalik, Zolt{\'a}n and Lamina, Claudia and Lecoeur, C{\'e}cile and Li, Guo and Mangino, Massimo and McArdle, Wendy L and Medina-G{\'o}mez, Carolina and M{\"u}ller-Nurasyid, Martina and Ngwa, Julius S and Nolte, Ilja M and Paternoster, Lavinia and Pechlivanis, Sonali and Perola, Markus and Peters, Marjolein J and Preuss, Michael and Rose, Lynda M and Shi, Jianxin and Shungin, Dmitry and Smith, Albert Vernon and Strawbridge, Rona J and Surakka, Ida and Teumer, Alexander and Trip, Mieke D and Tyrer, Jonathan and van Vliet-Ostaptchouk, Jana V and Vandenput, Liesbeth and Waite, Lindsay L and Zhao, Jing Hua and Absher, Devin and Asselbergs, Folkert W and Atalay, Mustafa and Attwood, Antony P and Balmforth, Anthony J and Basart, Hanneke and Beilby, John and Bonnycastle, Lori L and Brambilla, Paolo and Bruinenberg, Marcel and Campbell, Harry and Chasman, Daniel I and Chines, Peter S and Collins, Francis S and Connell, John M and Cookson, William O and de Faire, Ulf and de Vegt, Femmie and Dei, Mariano and Dimitriou, Maria and Edkins, Sarah and Estrada, Karol and Evans, David M and Farrall, Martin and Ferrario, Marco M and Ferrieres, Jean and Franke, Lude and Frau, Francesca and Gejman, Pablo V and Grallert, Harald and Gr{\"o}nberg, Henrik and Gudnason, Vilmundur and Hall, Alistair S and Hall, Per and Hartikainen, Anna-Liisa and Hayward, Caroline and Heard-Costa, Nancy L and Heath, Andrew C and Hebebrand, Johannes and Homuth, Georg and Hu, Frank B and Hunt, Sarah E and Hypp{\"o}nen, Elina and Iribarren, Carlos and Jacobs, Kevin B and Jansson, John-Olov and Jula, Antti and K{\"a}h{\"o}nen, Mika and Kathiresan, Sekar and Kee, Frank and Khaw, Kay-Tee and Kivimaki, Mika and Koenig, Wolfgang and Kraja, Aldi T and Kumari, Meena and Kuulasmaa, Kari and Kuusisto, Johanna and Laitinen, Jaana H and Lakka, Timo A and Langenberg, Claudia and Launer, Lenore J and Lind, Lars and Lindstr{\"o}m, Jaana and Liu, Jianjun and Liuzzi, Antonio and Lokki, Marja-Liisa and Lorentzon, Mattias and Madden, Pamela A and Magnusson, Patrik K and Manunta, Paolo and Marek, Diana and M{\"a}rz, Winfried and Mateo Leach, Irene and McKnight, Barbara and Medland, Sarah E and Mihailov, Evelin and Milani, Lili and Montgomery, Grant W and Mooser, Vincent and M{\"u}hleisen, Thomas W and Munroe, Patricia B and Musk, Arthur W and Narisu, Narisu and Navis, Gerjan and Nicholson, George and Nohr, Ellen A and Ong, Ken K and Oostra, Ben A and Palmer, Colin N A and Palotie, Aarno and Peden, John F and Pedersen, Nancy and Peters, Annette and Polasek, Ozren and Pouta, Anneli and Pramstaller, Peter P and Prokopenko, Inga and P{\"u}tter, Carolin and Radhakrishnan, Aparna and Raitakari, Olli and Rendon, Augusto and Rivadeneira, Fernando and Rudan, Igor and Saaristo, Timo E and Sambrook, Jennifer G and Sanders, Alan R and Sanna, Serena and Saramies, Jouko and Schipf, Sabine and Schreiber, Stefan and Schunkert, Heribert and Shin, So-Youn and Signorini, Stefano and Sinisalo, Juha and Skrobek, Boris and Soranzo, Nicole and Stan{\v c}{\'a}kov{\'a}, Alena and Stark, Klaus and Stephens, Jonathan C and Stirrups, Kathleen and Stolk, Ronald P and Stumvoll, Michael and Swift, Amy J and Theodoraki, Eirini V and Thorand, Barbara and Tr{\'e}gou{\"e}t, David-Alexandre and Tremoli, Elena and van der Klauw, Melanie M and van Meurs, Joyce B J and Vermeulen, Sita H and Viikari, Jorma and Virtamo, Jarmo and Vitart, Veronique and Waeber, G{\'e}rard and Wang, Zhaoming and Widen, Elisabeth and Wild, Sarah H and Willemsen, Gonneke and Winkelmann, Bernhard R and Witteman, Jacqueline C M and Wolffenbuttel, Bruce H R and Wong, Andrew and Wright, Alan F and Zillikens, M Carola and Amouyel, Philippe and Boehm, Bernhard O and Boerwinkle, Eric and Boomsma, Dorret I and Caulfield, Mark J and Chanock, Stephen J and Cupples, L Adrienne and Cusi, Daniele and Dedoussis, George V and Erdmann, Jeanette and Eriksson, Johan G and Franks, Paul W and Froguel, Philippe and Gieger, Christian and Gyllensten, Ulf and Hamsten, Anders and Harris, Tamara B and Hengstenberg, Christian and Hicks, Andrew A and Hingorani, Aroon and Hinney, Anke and Hofman, Albert and Hovingh, Kees G and Hveem, Kristian and Illig, Thomas and Jarvelin, Marjo-Riitta and J{\"o}ckel, Karl-Heinz and Keinanen-Kiukaanniemi, Sirkka M and Kiemeney, Lambertus A and Kuh, Diana and Laakso, Markku and Lehtim{\"a}ki, Terho and Levinson, Douglas F and Martin, Nicholas G and Metspalu, Andres and Morris, Andrew D and Nieminen, Markku S and Nj{\o}lstad, Inger and Ohlsson, Claes and Oldehinkel, Albertine J and Ouwehand, Willem H and Palmer, Lyle J and Penninx, Brenda and Power, Chris and Province, Michael A and Psaty, Bruce M and Qi, Lu and Rauramaa, Rainer and Ridker, Paul M and Ripatti, Samuli and Salomaa, Veikko and Samani, Nilesh J and Snieder, Harold and S{\o}rensen, Thorkild I A and Spector, Timothy D and Stefansson, Kari and T{\"o}njes, Anke and Tuomilehto, Jaakko and Uitterlinden, Andr{\'e} G and Uusitupa, Matti and van der Harst, Pim and Vollenweider, Peter and Wallaschofski, Henri and Wareham, Nicholas J and Watkins, Hugh and Wichmann, H-Erich and Wilson, James F and Abecasis, Goncalo R and Assimes, Themistocles L and Barroso, In{\^e}s and Boehnke, Michael and Borecki, Ingrid B and Deloukas, Panos and Fox, Caroline S and Frayling, Timothy and Groop, Leif C and Haritunian, Talin and Heid, Iris M and Hunter, David and Kaplan, Robert C and Karpe, Fredrik and Moffatt, Miriam F and Mohlke, Karen L and O{\textquoteright}Connell, Jeffrey R and Pawitan, Yudi and Schadt, Eric E and Schlessinger, David and Steinthorsdottir, Valgerdur and Strachan, David P and Thorsteinsdottir, Unnur and van Duijn, Cornelia M and Visscher, Peter M and Di Blasio, Anna Maria and Hirschhorn, Joel N and Lindgren, Cecilia M and Morris, Andrew P and Meyre, David and Scherag, Andre and McCarthy, Mark I and Speliotes, Elizabeth K and North, Kari E and Loos, Ruth J F and Ingelsson, Erik} } @article {8015, title = {Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders.}, journal = {Nat Genet}, volume = {45}, year = {2013}, month = {2013 Jun}, pages = {621-31}, abstract = {

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.

}, keywords = {Animals, Arrhythmias, Cardiac, Gene Frequency, Genetic Loci, Genome-Wide Association Study, Heart Conduction System, Heart Rate, Humans, Metabolic Networks and Pathways, Polymorphism, Single Nucleotide, Quantitative Trait Loci}, issn = {1546-1718}, doi = {10.1038/ng.2610}, author = {den Hoed, Marcel and Eijgelsheim, Mark and Esko, T{\~o}nu and Brundel, Bianca J J M and Peal, David S and Evans, David M and Nolte, Ilja M and Segr{\`e}, Ayellet V and Holm, Hilma and Handsaker, Robert E and Westra, Harm-Jan and Johnson, Toby and Isaacs, Aaron and Yang, Jian and Lundby, Alicia and Zhao, Jing Hua and Kim, Young Jin and Go, Min Jin and Almgren, Peter and Bochud, Murielle and Boucher, Gabrielle and Cornelis, Marilyn C and Gudbjartsson, Daniel and Hadley, David and van der Harst, Pim and Hayward, Caroline and den Heijer, Martin and Igl, Wilmar and Jackson, Anne U and Kutalik, Zolt{\'a}n and Luan, Jian{\textquoteright}an and Kemp, John P and Kristiansson, Kati and Ladenvall, Claes and Lorentzon, Mattias and Montasser, May E and Njajou, Omer T and O{\textquoteright}Reilly, Paul F and Padmanabhan, Sandosh and St Pourcain, Beate and Rankinen, Tuomo and Salo, Perttu and Tanaka, Toshiko and Timpson, Nicholas J and Vitart, Veronique and Waite, Lindsay and Wheeler, William and Zhang, Weihua and Draisma, Harmen H M and Feitosa, Mary F and Kerr, Kathleen F and Lind, Penelope A and Mihailov, Evelin and Onland-Moret, N Charlotte and Song, Ci and Weedon, Michael N and Xie, Weijia and Yengo, Loic and Absher, Devin and Albert, Christine M and Alonso, Alvaro and Arking, Dan E and de Bakker, Paul I W and Balkau, Beverley and Barlassina, Cristina and Benaglio, Paola and Bis, Joshua C and Bouatia-Naji, Nabila and Brage, S{\o}ren and Chanock, Stephen J and Chines, Peter S and Chung, Mina and Darbar, Dawood and Dina, Christian and D{\"o}rr, Marcus and Elliott, Paul and Felix, Stephan B and Fischer, Krista and Fuchsberger, Christian and de Geus, Eco J C and Goyette, Philippe and Gudnason, Vilmundur and Harris, Tamara B and Hartikainen, Anna-Liisa and Havulinna, Aki S and Heckbert, Susan R and Hicks, Andrew A and Hofman, Albert and Holewijn, Suzanne and Hoogstra-Berends, Femke and Hottenga, Jouke-Jan and Jensen, Majken K and Johansson, Asa and Junttila, Juhani and K{\"a}{\"a}b, Stefan and Kanon, Bart and Ketkar, Shamika and Khaw, Kay-Tee and Knowles, Joshua W and Kooner, Angrad S and Kors, Jan A and Kumari, Meena and Milani, Lili and Laiho, P{\"a}ivi and Lakatta, Edward G and Langenberg, Claudia and Leusink, Maarten and Liu, Yongmei and Luben, Robert N and Lunetta, Kathryn L and Lynch, Stacey N and Markus, Marcello R P and Marques-Vidal, Pedro and Mateo Leach, Irene and McArdle, Wendy L and McCarroll, Steven A and Medland, Sarah E and Miller, Kathryn A and Montgomery, Grant W and Morrison, Alanna C and M{\"u}ller-Nurasyid, Martina and Navarro, Pau and Nelis, Mari and O{\textquoteright}Connell, Jeffrey R and O{\textquoteright}Donnell, Christopher J and Ong, Ken K and Newman, Anne B and Peters, Annette and Polasek, Ozren and Pouta, Anneli and Pramstaller, Peter P and Psaty, Bruce M and Rao, Dabeeru C and Ring, Susan M and Rossin, Elizabeth J and Rudan, Diana and Sanna, Serena and Scott, Robert A and Sehmi, Jaban S and Sharp, Stephen and Shin, Jordan T and Singleton, Andrew B and Smith, Albert V and Soranzo, Nicole and Spector, Tim D and Stewart, Chip and Stringham, Heather M and Tarasov, Kirill V and Uitterlinden, Andr{\'e} G and Vandenput, Liesbeth and Hwang, Shih-Jen and Whitfield, John B and Wijmenga, Cisca and Wild, Sarah H and Willemsen, Gonneke and Wilson, James F and Witteman, Jacqueline C M and Wong, Andrew and Wong, Quenna and Jamshidi, Yalda and Zitting, Paavo and Boer, Jolanda M A and Boomsma, Dorret I and Borecki, Ingrid B and van Duijn, Cornelia M and Ekelund, Ulf and Forouhi, Nita G and Froguel, Philippe and Hingorani, Aroon and Ingelsson, Erik and Kivimaki, Mika and Kronmal, Richard A and Kuh, Diana and Lind, Lars and Martin, Nicholas G and Oostra, Ben A and Pedersen, Nancy L and Quertermous, Thomas and Rotter, Jerome I and van der Schouw, Yvonne T and Verschuren, W M Monique and Walker, Mark and Albanes, Demetrius and Arnar, David O and Assimes, Themistocles L and Bandinelli, Stefania and Boehnke, Michael and de Boer, Rudolf A and Bouchard, Claude and Caulfield, W L Mark and Chambers, John C and Curhan, Gary and Cusi, Daniele and Eriksson, Johan and Ferrucci, Luigi and van Gilst, Wiek H and Glorioso, Nicola and de Graaf, Jacqueline and Groop, Leif and Gyllensten, Ulf and Hsueh, Wen-Chi and Hu, Frank B and Huikuri, Heikki V and Hunter, David J and Iribarren, Carlos and Isomaa, Bo and Jarvelin, Marjo-Riitta and Jula, Antti and K{\"a}h{\"o}nen, Mika and Kiemeney, Lambertus A and van der Klauw, Melanie M and Kooner, Jaspal S and Kraft, Peter and Iacoviello, Licia and Lehtim{\"a}ki, Terho and Lokki, Marja-Liisa L and Mitchell, Braxton D and Navis, Gerjan and Nieminen, Markku S and Ohlsson, Claes and Poulter, Neil R and Qi, Lu and Raitakari, Olli T and Rimm, Eric B and Rioux, John D and Rizzi, Federica and Rudan, Igor and Salomaa, Veikko and Sever, Peter S and Shields, Denis C and Shuldiner, Alan R and Sinisalo, Juha and Stanton, Alice V and Stolk, Ronald P and Strachan, David P and Tardif, Jean-Claude and Thorsteinsdottir, Unnur and Tuomilehto, Jaako and van Veldhuisen, Dirk J and Virtamo, Jarmo and Viikari, Jorma and Vollenweider, Peter and Waeber, G{\'e}rard and Widen, Elisabeth and Cho, Yoon Shin and Olsen, Jesper V and Visscher, Peter M and Willer, Cristen and Franke, Lude and Erdmann, Jeanette and Thompson, John R and Pfeufer, Arne and Sotoodehnia, Nona and Newton-Cheh, Christopher and Ellinor, Patrick T and Stricker, Bruno H Ch and Metspalu, Andres and Perola, Markus and Beckmann, Jacques S and Smith, George Davey and Stefansson, Kari and Wareham, Nicholas J and Munroe, Patricia B and Sibon, Ody C M and Milan, David J and Snieder, Harold and Samani, Nilesh J and Loos, Ruth J F} } @article {6108, title = {Ischemic stroke is associated with the ABO locus: the EuroCLOT study.}, journal = {Ann Neurol}, volume = {73}, year = {2013}, month = {2013 Jan}, pages = {16-31}, abstract = {

OBJECTIVE: End-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischemic stroke. We explored whether genetic variants associated with end-stage coagulation in healthy volunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype.

METHODS: Common genetic variants identified through genome-wide association studies of coagulation factors and fibrin structure/function in healthy twins (n = 2,100, Stage 1) were examined in ischemic stroke (n = 4,200 cases) using 2 independent samples of European ancestry (Stage 2). A third clinical collection having stroke subtyping (total 8,900 cases, 55,000 controls) was used for replication (Stage 3).

RESULTS: Stage 1 identified 524 single nucleotide polymorphisms (SNPs) from 23 linkage disequilibrium blocks having significant association (p < 5 {\texttimes} 10(-8)) with 1 or more coagulation/fibrin phenotypes. The most striking associations included SNP rs5985 with factor XIII activity (p = 2.6 {\texttimes} 10(-186)), rs10665 with FVII (p = 2.4 {\texttimes} 10(-47)), and rs505922 in the ABO gene with both von Willebrand factor (p = 4.7 {\texttimes} 10(-57)) and factor VIII (p = 1.2 {\texttimes} 10(-36)). In Stage 2, the 23 independent SNPs were examined in stroke cases/noncases using MOnica Risk, Genetics, Archiving and Monograph (MORGAM) and Wellcome Trust Case Control Consortium 2 collections. SNP rs505922 was nominally associated with ischemic stroke (odds ratio = 0.94, 95\% confidence interval = 0.88-0.99, p = 0.023). Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta (standard error, SE) = 0.066 (0.02), p = 0.001, a finding specific to large-vessel and cardioembolic stroke (p = 0.001 and p = < 0.001, respectively) but not seen with small-vessel stroke (p = 0.811).

INTERPRETATION: ABO gene variants are associated with large-vessel and cardioembolic stroke but not small-vessel disease. This work sheds light on the different pathogenic mechanisms underpinning stroke subtype.

}, keywords = {ABO Blood-Group System, Adolescent, Adult, Aged, Aged, 80 and over, Blood Coagulation, Brain Ischemia, Cohort Studies, Europe, Female, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Stroke, Young Adult}, issn = {1531-8249}, doi = {10.1002/ana.23838}, author = {Williams, Frances M K and Carter, Angela M and Hysi, Pirro G and Surdulescu, Gabriela and Hodgkiss, Dylan and Soranzo, Nicole and Traylor, Matthew and Bevan, Steve and Dichgans, Martin and Rothwell, Peter M W and Sudlow, Cathie and Farrall, Martin and Silander, Kaisa and Kaunisto, Mari and Wagner, Peter and Saarela, Olli and Kuulasmaa, Kari and Virtamo, Jarmo and Salomaa, Veikko and Amouyel, Philippe and Arveiler, Dominique and Ferrieres, Jean and Wiklund, Per-Gunnar and Ikram, M Arfan and Hofman, Albert and Boncoraglio, Giorgio B and Parati, Eugenio A and Helgadottir, Anna and Gretarsdottir, Solveig and Thorsteinsdottir, Unnur and Thorleifsson, Gudmar and Stefansson, Kari and Seshadri, Sudha and DeStefano, Anita and Gschwendtner, Andreas and Psaty, Bruce and Longstreth, Will and Mitchell, Braxton D and Cheng, Yu-Ching and Clarke, Robert and Ferrario, Marco and Bis, Joshua C and Levi, Christopher and Attia, John and Holliday, Elizabeth G and Scott, Rodney J and Fornage, Myriam and Sharma, Pankaj and Furie, Karen L and Rosand, Jonathan and Nalls, Mike and Meschia, James and Mosely, Thomas H and Evans, Alun and Palotie, Aarno and Markus, Hugh S and Grant, Peter J and Spector, Tim D} } @article {5877, title = {A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function.}, journal = {PLoS Genet}, volume = {9}, year = {2013}, month = {2013}, pages = {e1003266}, abstract = {

Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10\% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64\% and 2.30\% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.

}, keywords = {Female, Genome-Wide Association Study, Humans, Hyperthyroidism, Hypothyroidism, Male, Phenotype, Polymorphism, Genetic, Polymorphism, Single Nucleotide, Sex Characteristics, Signal Transduction, Thyroid Gland, Thyrotropin, Thyroxine}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1003266}, author = {Porcu, Eleonora and Medici, Marco and Pistis, Giorgio and Volpato, Claudia B and Wilson, Scott G and Cappola, Anne R and Bos, Steffan D and Deelen, Joris and den Heijer, Martin and Freathy, Rachel M and Lahti, Jari and Liu, Chunyu and Lopez, Lorna M and Nolte, Ilja M and O{\textquoteright}Connell, Jeffrey R and Tanaka, Toshiko and Trompet, Stella and Arnold, Alice and Bandinelli, Stefania and Beekman, Marian and B{\"o}hringer, Stefan and Brown, Suzanne J and Buckley, Brendan M and Camaschella, Clara and de Craen, Anton J M and Davies, Gail and de Visser, Marieke C H and Ford, Ian and Forsen, Tom and Frayling, Timothy M and Fugazzola, Laura and G{\"o}gele, Martin and Hattersley, Andrew T and Hermus, Ad R and Hofman, Albert and Houwing-Duistermaat, Jeanine J and Jensen, Richard A and Kajantie, Eero and Kloppenburg, Margreet and Lim, Ee M and Masciullo, Corrado and Mariotti, Stefano and Minelli, Cosetta and Mitchell, Braxton D and Nagaraja, Ramaiah and Netea-Maier, Romana T and Palotie, Aarno and Persani, Luca and Piras, Maria G and Psaty, Bruce M and R{\"a}ikk{\"o}nen, Katri and Richards, J Brent and Rivadeneira, Fernando and Sala, Cinzia and Sabra, Mona M and Sattar, Naveed and Shields, Beverley M and Soranzo, Nicole and Starr, John M and Stott, David J and Sweep, Fred C G J and Usala, Gianluca and van der Klauw, Melanie M and van Heemst, Diana and van Mullem, Alies and Vermeulen, Sita H and Visser, W Edward and Walsh, John P and Westendorp, Rudi G J and Widen, Elisabeth and Zhai, Guangju and Cucca, Francesco and Deary, Ian J and Eriksson, Johan G and Ferrucci, Luigi and Fox, Caroline S and Jukema, J Wouter and Kiemeney, Lambertus A and Pramstaller, Peter P and Schlessinger, David and Shuldiner, Alan R and Slagboom, Eline P and Uitterlinden, Andr{\'e} G and Vaidya, Bijay and Visser, Theo J and Wolffenbuttel, Bruce H R and Meulenbelt, Ingrid and Rotter, Jerome I and Spector, Tim D and Hicks, Andrew A and Toniolo, Daniela and Sanna, Serena and Peeters, Robin P and Naitza, Silvia} } @article {6155, title = {Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease.}, journal = {Circulation}, volume = {128}, year = {2013}, month = {2013 Sep 17}, pages = {1310-24}, abstract = {

BACKGROUND: Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34\% to 50\%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2\%) of its variation.

METHODS AND RESULTS: We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant (P<5{\texttimes}10(-8)) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7\% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism.

CONCLUSIONS: We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.

}, keywords = {Adolescent, Adult, African Continental Ancestry Group, Aged, Aged, 80 and over, Cardiovascular Diseases, Coronary Artery Disease, European Continental Ancestry Group, Female, Fibrinogen, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Hispanic Americans, Humans, Male, Middle Aged, Myocardial Infarction, Polymorphism, Single Nucleotide, Risk Factors, Stroke, Venous Thromboembolism, Young Adult}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.113.002251}, author = {Sabater-Lleal, Maria and Huang, Jie and Chasman, Daniel and Naitza, Silvia and Dehghan, Abbas and Johnson, Andrew D and Teumer, Alexander and Reiner, Alex P and Folkersen, Lasse and Basu, Saonli and Rudnicka, Alicja R and Trompet, Stella and M{\"a}larstig, Anders and Baumert, Jens and Bis, Joshua C and Guo, Xiuqing and Hottenga, Jouke J and Shin, So-Youn and Lopez, Lorna M and Lahti, Jari and Tanaka, Toshiko and Yanek, Lisa R and Oudot-Mellakh, Tiphaine and Wilson, James F and Navarro, Pau and Huffman, Jennifer E and Zemunik, Tatijana and Redline, Susan and Mehra, Reena and Pulanic, Drazen and Rudan, Igor and Wright, Alan F and Kolcic, Ivana and Polasek, Ozren and Wild, Sarah H and Campbell, Harry and Curb, J David and Wallace, Robert and Liu, Simin and Eaton, Charles B and Becker, Diane M and Becker, Lewis C and Bandinelli, Stefania and R{\"a}ikk{\"o}nen, Katri and Widen, Elisabeth and Palotie, Aarno and Fornage, Myriam and Green, David and Gross, Myron and Davies, Gail and Harris, Sarah E and Liewald, David C and Starr, John M and Williams, Frances M K and Grant, Peter J and Spector, Timothy D and Strawbridge, Rona J and Silveira, Angela and Sennblad, Bengt and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Franco, Oscar H and Hofman, Albert and van Dongen, Jenny and Willemsen, Gonneke and Boomsma, Dorret I and Yao, Jie and Swords Jenny, Nancy and Haritunians, Talin and McKnight, Barbara and Lumley, Thomas and Taylor, Kent D and Rotter, Jerome I and Psaty, Bruce M and Peters, Annette and Gieger, Christian and Illig, Thomas and Grotevendt, Anne and Homuth, Georg and V{\"o}lzke, Henry and Kocher, Thomas and Goel, Anuj and Franzosi, Maria Grazia and Seedorf, Udo and Clarke, Robert and Steri, Maristella and Tarasov, Kirill V and Sanna, Serena and Schlessinger, David and Stott, David J and Sattar, Naveed and Buckley, Brendan M and Rumley, Ann and Lowe, Gordon D and McArdle, Wendy L and Chen, Ming-Huei and Tofler, Geoffrey H and Song, Jaejoon and Boerwinkle, Eric and Folsom, Aaron R and Rose, Lynda M and Franco-Cereceda, Anders and Teichert, Martina and Ikram, M Arfan and Mosley, Thomas H and Bevan, Steve and Dichgans, Martin and Rothwell, Peter M and Sudlow, Cathie L M and Hopewell, Jemma C and Chambers, John C and Saleheen, Danish and Kooner, Jaspal S and Danesh, John and Nelson, Christopher P and Erdmann, Jeanette and Reilly, Muredach P and Kathiresan, Sekar and Schunkert, Heribert and Morange, Pierre-Emmanuel and Ferrucci, Luigi and Eriksson, Johan G and Jacobs, David and Deary, Ian J and Soranzo, Nicole and Witteman, Jacqueline C M and de Geus, Eco J C and Tracy, Russell P and Hayward, Caroline and Koenig, Wolfgang and Cucca, Francesco and Jukema, J Wouter and Eriksson, Per and Seshadri, Sudha and Markus, Hugh S and Watkins, Hugh and Samani, Nilesh J and Wallaschofski, Henri and Smith, Nicholas L and Tregouet, David and Ridker, Paul M and Tang, Weihong and Strachan, David P and Hamsten, Anders and O{\textquoteright}Donnell, Christopher J} } @article {6367, title = {Genome-wide association study for circulating tissue plasminogen activator levels and functional follow-up implicates endothelial STXBP5 and STX2.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {34}, year = {2014}, month = {2014 May}, pages = {1093-101}, abstract = {

OBJECTIVE: Tissue plasminogen activator (tPA), a serine protease, catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for endogenous fibrinolysis. In some populations, elevated plasma levels of tPA have been associated with myocardial infarction and other cardiovascular diseases. We conducted a meta-analysis of genome-wide association studies to identify novel correlates of circulating levels of tPA.

APPROACH AND RESULTS: Fourteen cohort studies with tPA measures (N=26 929) contributed to the meta-analysis. Three loci were significantly associated with circulating tPA levels (P<5.0{\texttimes}10(-8)). The first locus is on 6q24.3, with the lead single nucleotide polymorphism (SNP; rs9399599; P=2.9{\texttimes}10(-14)) within STXBP5. The second locus is on 8p11.21. The lead SNP (rs3136739; P=1.3{\texttimes}10(-9)) is intronic to POLB and <200 kb away from the tPA encoding the gene PLAT. We identified a nonsynonymous SNP (rs2020921) in modest linkage disequilibrium with rs3136739 (r(2)=0.50) within exon 5 of PLAT (P=2.0{\texttimes}10(-8)). The third locus is on 12q24.33, with the lead SNP (rs7301826; P=1.0{\texttimes}10(-9)) within intron 7 of STX2. We further found evidence for the association of lead SNPs in STXBP5 and STX2 with expression levels of the respective transcripts. In in vitro cell studies, silencing STXBP5 decreased the release of tPA from vascular endothelial cells, whereas silencing STX2 increased the tPA release. Through an in silico lookup, we found no associations of the 3 lead SNPs with coronary artery disease or stroke.

CONCLUSIONS: We identified 3 loci associated with circulating tPA levels, the PLAT region, STXBP5, and STX2. Our functional studies implicate a novel role for STXBP5 and STX2 in regulating tPA release.

}, keywords = {Aged, Cells, Cultured, Coronary Artery Disease, Endothelial Cells, Europe, Female, Gene Expression Regulation, Gene Silencing, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Nerve Tissue Proteins, Phenotype, Polymorphism, Single Nucleotide, R-SNARE Proteins, Risk Factors, Stroke, Syntaxin 1, Tissue Plasminogen Activator, Transfection, United States, Up-Regulation}, issn = {1524-4636}, doi = {10.1161/ATVBAHA.113.302088}, author = {Huang, Jie and Huffman, Jennifer E and Yamakuchi, Munekazu and Yamkauchi, Munekazu and Trompet, Stella and Asselbergs, Folkert W and Sabater-Lleal, Maria and Tr{\'e}gou{\"e}t, David-Alexandre and Chen, Wei-Min and Smith, Nicholas L and Kleber, Marcus E and Shin, So-Youn and Becker, Diane M and Tang, Weihong and Dehghan, Abbas and Johnson, Andrew D and Truong, Vinh and Folkersen, Lasse and Yang, Qiong and Oudot-Mellkah, Tiphaine and Buckley, Brendan M and Moore, Jason H and Williams, Frances M K and Campbell, Harry and Silbernagel, G{\"u}nther and Vitart, Veronique and Rudan, Igor and Tofler, Geoffrey H and Navis, Gerjan J and DeStefano, Anita and Wright, Alan F and Chen, Ming-Huei and de Craen, Anton J M and Worrall, Bradford B and Rudnicka, Alicja R and Rumley, Ann and Bookman, Ebony B and Psaty, Bruce M and Chen, Fang and Keene, Keith L and Franco, Oscar H and B{\"o}hm, Bernhard O and Uitterlinden, Andr{\'e} G and Carter, Angela M and Jukema, J Wouter and Sattar, Naveed and Bis, Joshua C and Ikram, Mohammad A and Sale, Mich{\`e}le M and McKnight, Barbara and Fornage, Myriam and Ford, Ian and Taylor, Kent and Slagboom, P Eline and McArdle, Wendy L and Hsu, Fang-Chi and Franco-Cereceda, Anders and Goodall, Alison H and Yanek, Lisa R and Furie, Karen L and Cushman, Mary and Hofman, Albert and Witteman, Jacqueline C M and Folsom, Aaron R and Basu, Saonli and Matijevic, Nena and van Gilst, Wiek H and Wilson, James F and Westendorp, Rudi G J and Kathiresan, Sekar and Reilly, Muredach P and Tracy, Russell P and Polasek, Ozren and Winkelmann, Bernhard R and Grant, Peter J and Hillege, Hans L and Cambien, Francois and Stott, David J and Lowe, Gordon D and Spector, Timothy D and Meigs, James B and M{\"a}rz, Winfried and Eriksson, Per and Becker, Lewis C and Morange, Pierre-Emmanuel and Soranzo, Nicole and Williams, Scott M and Hayward, Caroline and van der Harst, Pim and Hamsten, Anders and Lowenstein, Charles J and Strachan, David P and O{\textquoteright}Donnell, Christopher J} } @article {6294, title = {Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease.}, journal = {PLoS Genet}, volume = {10}, year = {2014}, month = {2014 Feb}, pages = {e1004123}, abstract = {

Autoimmune thyroid diseases (AITD) are common, affecting 2-5\% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto{\textquoteright}s thyroiditis), as well as autoimmune hyperthyroidism (Graves{\textquoteright} disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5{\texttimes}10(-8)) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95\% CI 1.68-2.81, P = 8.1{\texttimes}10(-8)), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95\% CI 1.26-1.82, P = 2.9{\texttimes}10(-6)), as well as a decreased risk of goiter (OR: 0.77, 95\% CI 0.66-0.89, P = 6.5{\texttimes}10(-4)). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves{\textquoteright} disease (OR: 1.37, 95\% CI 1.22-1.54, P = 1.2{\texttimes}10(-7) and OR: 1.25, 95\% CI 1.12-1.39, P = 6.2{\texttimes}10(-5)). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95\% CI 1.18-2.10, P = 1.9{\texttimes}10(-3)). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.

}, keywords = {Autoantibodies, Genetic Loci, Genome-Wide Association Study, Graves Disease, Hashimoto Disease, Humans, Iodide Peroxidase, Risk Factors, Thyroiditis, Autoimmune, Thyrotropin}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1004123}, author = {Medici, Marco and Porcu, Eleonora and Pistis, Giorgio and Teumer, Alexander and Brown, Suzanne J and Jensen, Richard A and Rawal, Rajesh and Roef, Greet L and Plantinga, Theo S and Vermeulen, Sita H and Lahti, Jari and Simmonds, Matthew J and Husemoen, Lise Lotte N and Freathy, Rachel M and Shields, Beverley M and Pietzner, Diana and Nagy, Rebecca and Broer, Linda and Chaker, Layal and Korevaar, Tim I M and Plia, Maria Grazia and Sala, Cinzia and V{\"o}lker, Uwe and Richards, J Brent and Sweep, Fred C and Gieger, Christian and Corre, Tanguy and Kajantie, Eero and Thuesen, Betina and Taes, Youri E and Visser, W Edward and Hattersley, Andrew T and Kratzsch, J{\"u}rgen and Hamilton, Alexander and Li, Wei and Homuth, Georg and Lobina, Monia and Mariotti, Stefano and Soranzo, Nicole and Cocca, Massimiliano and Nauck, Matthias and Spielhagen, Christin and Ross, Alec and Arnold, Alice and van de Bunt, Martijn and Liyanarachchi, Sandya and Heier, Margit and Grabe, Hans J{\"o}rgen and Masciullo, Corrado and Galesloot, Tessel E and Lim, Ee M and Reischl, Eva and Leedman, Peter J and Lai, Sandra and Delitala, Alessandro and Bremner, Alexandra P and Philips, David I W and Beilby, John P and Mulas, Antonella and Vocale, Matteo and Abecasis, Goncalo and Forsen, Tom and James, Alan and Widen, Elisabeth and Hui, Jennie and Prokisch, Holger and Rietzschel, Ernst E and Palotie, Aarno and Feddema, Peter and Fletcher, Stephen J and Schramm, Katharina and Rotter, Jerome I and Kluttig, Alexander and Radke, D{\"o}rte and Traglia, Michela and Surdulescu, Gabriela L and He, Huiling and Franklyn, Jayne A and Tiller, Daniel and Vaidya, Bijay and De Meyer, Tim and J{\o}rgensen, Torben and Eriksson, Johan G and O{\textquoteright}Leary, Peter C and Wichmann, Eric and Hermus, Ad R and Psaty, Bruce M and Ittermann, Till and Hofman, Albert and Bosi, Emanuele and Schlessinger, David and Wallaschofski, Henri and Pirastu, Nicola and Aulchenko, Yurii S and de la Chapelle, Albert and Netea-Maier, Romana T and Gough, Stephen C L and Meyer Zu Schwabedissen, Henriette and Frayling, Timothy M and Kaufman, Jean-Marc and Linneberg, Allan and R{\"a}ikk{\"o}nen, Katri and Smit, Johannes W A and Kiemeney, Lambertus A and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Walsh, John P and Meisinger, Christa and den Heijer, Martin and Visser, Theo J and Spector, Timothy D and Wilson, Scott G and V{\"o}lzke, Henry and Cappola, Anne and Toniolo, Daniela and Sanna, Serena and Naitza, Silvia and Peeters, Robin P} } @article {6686, title = {Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility.}, journal = {Nat Commun}, volume = {6}, year = {2015}, month = {2015}, pages = {5897}, abstract = {

Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4\%) with lower FG (β=-0.09{\textpm}0.01 mmol l(-1), P=3.4 {\texttimes} 10(-12)), T2D risk (OR[95\%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (β=-0.07{\textpm}0.035 pmolinsulin mmolglucose(-1), P=0.048), but higher 2-h glucose (β=0.16{\textpm}0.05 mmol l(-1), P=4.3 {\texttimes} 10(-4)). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 {\texttimes} 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20\%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02{\textpm}0.004 mmol l(-1), P=1.3 {\texttimes} 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.

}, keywords = {African Continental Ancestry Group, Blood Glucose, Diabetes Mellitus, Type 2, European Continental Ancestry Group, Exome, Fasting, Genetic Association Studies, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Glucagon-Like Peptide-1 Receptor, Glucose-6-Phosphatase, Humans, Insulin, Mutation Rate, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide}, issn = {2041-1723}, doi = {10.1038/ncomms6897}, author = {Wessel, Jennifer and Chu, Audrey Y and Willems, Sara M and Wang, Shuai and Yaghootkar, Hanieh and Brody, Jennifer A and Dauriz, Marco and Hivert, Marie-France and Raghavan, Sridharan and Lipovich, Leonard and Hidalgo, Bertha and Fox, Keolu and Huffman, Jennifer E and An, Ping and Lu, Yingchang and Rasmussen-Torvik, Laura J and Grarup, Niels and Ehm, Margaret G and Li, Li and Baldridge, Abigail S and Stan{\v c}{\'a}kov{\'a}, Alena and Abrol, Ravinder and Besse, C{\'e}line and Boland, Anne and Bork-Jensen, Jette and Fornage, Myriam and Freitag, Daniel F and Garcia, Melissa E and Guo, Xiuqing and Hara, Kazuo and Isaacs, Aaron and Jakobsdottir, Johanna and Lange, Leslie A and Layton, Jill C and Li, Man and Hua Zhao, Jing and Meidtner, Karina and Morrison, Alanna C and Nalls, Mike A and Peters, Marjolein J and Sabater-Lleal, Maria and Schurmann, Claudia and Silveira, Angela and Smith, Albert V and Southam, Lorraine and Stoiber, Marcus H and Strawbridge, Rona J and Taylor, Kent D and Varga, Tibor V and Allin, Kristine H and Amin, Najaf and Aponte, Jennifer L and Aung, Tin and Barbieri, Caterina and Bihlmeyer, Nathan A and Boehnke, Michael and Bombieri, Cristina and Bowden, Donald W and Burns, Sean M and Chen, Yuning and Chen, Yii-DerI and Cheng, Ching-Yu and Correa, Adolfo and Czajkowski, Jacek and Dehghan, Abbas and Ehret, Georg B and Eiriksdottir, Gudny and Escher, Stefan A and Farmaki, Aliki-Eleni and Fr{\r a}nberg, Mattias and Gambaro, Giovanni and Giulianini, Franco and Goddard, William A and Goel, Anuj and Gottesman, Omri and Grove, Megan L and Gustafsson, Stefan and Hai, Yang and Hallmans, G{\"o}ran and Heo, Jiyoung and Hoffmann, Per and Ikram, Mohammad K and Jensen, Richard A and J{\o}rgensen, Marit E and J{\o}rgensen, Torben and Karaleftheri, Maria and Khor, Chiea C and Kirkpatrick, Andrea and Kraja, Aldi T and Kuusisto, Johanna and Lange, Ethan M and Lee, I T and Lee, Wen-Jane and Leong, Aaron and Liao, Jiemin and Liu, Chunyu and Liu, Yongmei and Lindgren, Cecilia M and Linneberg, Allan and Malerba, Giovanni and Mamakou, Vasiliki and Marouli, Eirini and Maruthur, Nisa M and Matchan, Angela and McKean-Cowdin, Roberta and McLeod, Olga and Metcalf, Ginger A and Mohlke, Karen L and Muzny, Donna M and Ntalla, Ioanna and Palmer, Nicholette D and Pasko, Dorota and Peter, Andreas and Rayner, Nigel W and Renstrom, Frida and Rice, Ken and Sala, Cinzia F and Sennblad, Bengt and Serafetinidis, Ioannis and Smith, Jennifer A and Soranzo, Nicole and Speliotes, Elizabeth K and Stahl, Eli A and Stirrups, Kathleen and Tentolouris, Nikos and Thanopoulou, Anastasia and Torres, Mina and Traglia, Michela and Tsafantakis, Emmanouil and Javad, Sundas and Yanek, Lisa R and Zengini, Eleni and Becker, Diane M and Bis, Joshua C and Brown, James B and Cupples, L Adrienne and Hansen, Torben and Ingelsson, Erik and Karter, Andrew J and Lorenzo, Carlos and Mathias, Rasika A and Norris, Jill M and Peloso, Gina M and Sheu, Wayne H-H and Toniolo, Daniela and Vaidya, Dhananjay and Varma, Rohit and Wagenknecht, Lynne E and Boeing, Heiner and Bottinger, Erwin P and Dedoussis, George and Deloukas, Panos and Ferrannini, Ele and Franco, Oscar H and Franks, Paul W and Gibbs, Richard A and Gudnason, Vilmundur and Hamsten, Anders and Harris, Tamara B and Hattersley, Andrew T and Hayward, Caroline and Hofman, Albert and Jansson, Jan-H{\r a}kan and Langenberg, Claudia and Launer, Lenore J and Levy, Daniel and Oostra, Ben A and O{\textquoteright}Donnell, Christopher J and O{\textquoteright}Rahilly, Stephen and Padmanabhan, Sandosh and Pankow, James S and Polasek, Ozren and Province, Michael A and Rich, Stephen S and Ridker, Paul M and Rudan, Igor and Schulze, Matthias B and Smith, Blair H and Uitterlinden, Andr{\'e} G and Walker, Mark and Watkins, Hugh and Wong, Tien Y and Zeggini, Eleftheria and Laakso, Markku and Borecki, Ingrid B and Chasman, Daniel I and Pedersen, Oluf and Psaty, Bruce M and Tai, E Shyong and van Duijn, Cornelia M and Wareham, Nicholas J and Waterworth, Dawn M and Boerwinkle, Eric and Kao, W H Linda and Florez, Jose C and Loos, Ruth J F and Wilson, James G and Frayling, Timothy M and Siscovick, David S and Dupuis, Jos{\'e}e and Rotter, Jerome I and Meigs, James B and Scott, Robert A and Goodarzi, Mark O} } @article {7255, title = {SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function.}, journal = {J Am Soc Nephrol}, year = {2016}, month = {2016 Dec 05}, abstract = {

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1<3.7{\texttimes}10(-7)), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4{\texttimes}10(-8) by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.

}, issn = {1533-3450}, doi = {10.1681/ASN.2016020131}, author = {Li, Man and Li, Yong and Weeks, Olivia and Mijatovic, Vladan and Teumer, Alexander and Huffman, Jennifer E and Tromp, Gerard and Fuchsberger, Christian and Gorski, Mathias and Lyytik{\"a}inen, Leo-Pekka and Nutile, Teresa and Sedaghat, Sanaz and Sorice, Rossella and Tin, Adrienne and Yang, Qiong and Ahluwalia, Tarunveer S and Arking, Dan E and Bihlmeyer, Nathan A and B{\"o}ger, Carsten A and Carroll, Robert J and Chasman, Daniel I and Cornelis, Marilyn C and Dehghan, Abbas and Faul, Jessica D and Feitosa, Mary F and Gambaro, Giovanni and Gasparini, Paolo and Giulianini, Franco and Heid, Iris and Huang, Jinyan and Imboden, Medea and Jackson, Anne U and Jeff, Janina and Jhun, Min A and Katz, Ronit and Kifley, Annette and Kilpel{\"a}inen, Tuomas O and Kumar, Ashish and Laakso, Markku and Li-Gao, Ruifang and Lohman, Kurt and Lu, Yingchang and M{\"a}gi, Reedik and Malerba, Giovanni and Mihailov, Evelin and Mohlke, Karen L and Mook-Kanamori, Dennis O and Robino, Antonietta and Ruderfer, Douglas and Salvi, Erika and Schick, Ursula M and Schulz, Christina-Alexandra and Smith, Albert V and Smith, Jennifer A and Traglia, Michela and Yerges-Armstrong, Laura M and Zhao, Wei and Goodarzi, Mark O and Kraja, Aldi T and Liu, Chunyu and Wessel, Jennifer and Boerwinkle, Eric and Borecki, Ingrid B and Bork-Jensen, Jette and Bottinger, Erwin P and Braga, Daniele and Brandslund, Ivan and Brody, Jennifer A and Campbell, Archie and Carey, David J and Christensen, Cramer and Coresh, Josef and Crook, Errol and Curhan, Gary C and Cusi, Daniele and de Boer, Ian H and de Vries, Aiko P J and Denny, Joshua C and Devuyst, Olivier and Dreisbach, Albert W and Endlich, Karlhans and Esko, T{\~o}nu and Franco, Oscar H and Fulop, Tibor and Gerhard, Glenn S and Gl{\"u}mer, Charlotte and Gottesman, Omri and Grarup, Niels and Gudnason, Vilmundur and Harris, Tamara B and Hayward, Caroline and Hocking, Lynne and Hofman, Albert and Hu, Frank B and Husemoen, Lise Lotte N and Jackson, Rebecca D and J{\o}rgensen, Torben and J{\o}rgensen, Marit E and K{\"a}h{\"o}nen, Mika and Kardia, Sharon L R and K{\"o}nig, Wolfgang and Kooperberg, Charles and Kriebel, Jennifer and Launer, Lenore J and Lauritzen, Torsten and Lehtim{\"a}ki, Terho and Levy, Daniel and Linksted, Pamela and Linneberg, Allan and Liu, Yongmei and Loos, Ruth J F and Lupo, Antonio and Meisinger, Christine and Melander, Olle and Metspalu, Andres and Mitchell, Paul and Nauck, Matthias and N{\"u}rnberg, Peter and Orho-Melander, Marju and Parsa, Afshin and Pedersen, Oluf and Peters, Annette and Peters, Ulrike and Polasek, Ozren and Porteous, David and Probst-Hensch, Nicole M and Psaty, Bruce M and Qi, Lu and Raitakari, Olli T and Reiner, Alex P and Rettig, Rainer and Ridker, Paul M and Rivadeneira, Fernando and Rossouw, Jacques E and Schmidt, Frank and Siscovick, David and Soranzo, Nicole and Strauch, Konstantin and Toniolo, Daniela and Turner, Stephen T and Uitterlinden, Andr{\'e} G and Ulivi, Sheila and Velayutham, Dinesh and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Waldenberger, Melanie and Wang, Jie Jin and Weir, David R and Witte, Daniel and Kuivaniemi, Helena and Fox, Caroline S and Franceschini, Nora and Goessling, Wolfram and K{\"o}ttgen, Anna and Chu, Audrey Y} } @article {7263, title = {Whole-Exome Sequencing Identifies Loci Associated with Blood Cell Traits and Reveals a Role for Alternative GFI1B Splice Variants in Human Hematopoiesis.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Sep 01}, pages = {785}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.08.002}, author = {Polfus, Linda M and Khajuria, Rajiv K and Schick, Ursula M and Pankratz, Nathan and Pazoki, Raha and Brody, Jennifer A and Chen, Ming-Huei and Auer, Paul L and Floyd, James S and Huang, Jie and Lange, Leslie and van Rooij, Frank J A and Gibbs, Richard A and Metcalf, Ginger and Muzny, Donna and Veeraraghavan, Narayanan and Walter, Klaudia and Chen, Lu and Yanek, Lisa and Becker, Lewis C and Peloso, Gina M and Wakabayashi, Aoi and Kals, Mart and Metspalu, Andres and Esko, T{\~o}nu and Fox, Keolu and Wallace, Robert and Franceschini, Nora and Matijevic, Nena and Rice, Kenneth M and Bartz, Traci M and Lyytik{\"a}inen, Leo-Pekka and K{\"a}h{\"o}nen, Mika and Lehtim{\"a}ki, Terho and Raitakari, Olli T and Li-Gao, Ruifang and Mook-Kanamori, Dennis O and Lettre, Guillaume and van Duijn, Cornelia M and Franco, Oscar H and Rich, Stephen S and Rivadeneira, Fernando and Hofman, Albert and Uitterlinden, Andr{\'e} G and Wilson, James G and Psaty, Bruce M and Soranzo, Nicole and Dehghan, Abbas and Boerwinkle, Eric and Zhang, Xiaoling and Johnson, Andrew D and O{\textquoteright}Donnell, Christopher J and Johnsen, Jill M and Reiner, Alexander P and Ganesh, Santhi K and Sankaran, Vijay G} } @article {7594, title = {Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study.}, journal = {JAMA Oncol}, volume = {3}, year = {2017}, month = {2017 May 01}, pages = {636-651}, abstract = {

Importance: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation.

Objective: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases.

Data Sources: Genomewide association studies (GWAS) published up to January 15, 2015.

Study Selection: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available.

Data Extraction and Synthesis: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population.

Main Outcomes and Measures: Odds ratios (ORs) and 95\% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation.

Results: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95\% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95\% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95\% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95\% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95\% CI, 0.05-0.15]).

Conclusions and Relevance: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

}, keywords = {Adult, Aged, Aged, 80 and over, Cardiovascular Diseases, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Germ-Line Mutation, Humans, Male, Mendelian Randomization Analysis, Middle Aged, Neoplasms, Polymorphism, Single Nucleotide, Risk Assessment, Telomere, Telomere Homeostasis}, issn = {2374-2445}, doi = {10.1001/jamaoncol.2016.5945}, author = {Haycock, Philip C and Burgess, Stephen and Nounu, Aayah and Zheng, Jie and Okoli, George N and Bowden, Jack and Wade, Kaitlin Hazel and Timpson, Nicholas J and Evans, David M and Willeit, Peter and Aviv, Abraham and Gaunt, Tom R and Hemani, Gibran and Mangino, Massimo and Ellis, Hayley Patricia and Kurian, Kathreena M and Pooley, Karen A and Eeles, Rosalind A and Lee, Jeffrey E and Fang, Shenying and Chen, Wei V and Law, Matthew H and Bowdler, Lisa M and Iles, Mark M and Yang, Qiong and Worrall, Bradford B and Markus, Hugh Stephen and Hung, Rayjean J and Amos, Chris I and Spurdle, Amanda B and Thompson, Deborah J and O{\textquoteright}Mara, Tracy A and Wolpin, Brian and Amundadottir, Laufey and Stolzenberg-Solomon, Rachael and Trichopoulou, Antonia and Onland-Moret, N Charlotte and Lund, Eiliv and Duell, Eric J and Canzian, Federico and Severi, Gianluca and Overvad, Kim and Gunter, Marc J and Tumino, Rosario and Svenson, Ulrika and van Rij, Andre and Baas, Annette F and Bown, Matthew J and Samani, Nilesh J and van t{\textquoteright}Hof, Femke N G and Tromp, Gerard and Jones, Gregory T and Kuivaniemi, Helena and Elmore, James R and Johansson, Mattias and Mckay, James and Scelo, Ghislaine and Carreras-Torres, Robert and Gaborieau, Valerie and Brennan, Paul and Bracci, Paige M and Neale, Rachel E and Olson, Sara H and Gallinger, Steven and Li, Donghui and Petersen, Gloria M and Risch, Harvey A and Klein, Alison P and Han, Jiali and Abnet, Christian C and Freedman, Neal D and Taylor, Philip R and Maris, John M and Aben, Katja K and Kiemeney, Lambertus A and Vermeulen, Sita H and Wiencke, John K and Walsh, Kyle M and Wrensch, Margaret and Rice, Terri and Turnbull, Clare and Litchfield, Kevin and Paternoster, Lavinia and Standl, Marie and Abecasis, Goncalo R and SanGiovanni, John Paul and Li, Yong and Mijatovic, Vladan and Sapkota, Yadav and Low, Siew-Kee and Zondervan, Krina T and Montgomery, Grant W and Nyholt, Dale R and van Heel, David A and Hunt, Karen and Arking, Dan E and Ashar, Foram N and Sotoodehnia, Nona and Woo, Daniel and Rosand, Jonathan and Comeau, Mary E and Brown, W Mark and Silverman, Edwin K and Hokanson, John E and Cho, Michael H and Hui, Jennie and Ferreira, Manuel A and Thompson, Philip J and Morrison, Alanna C and Felix, Janine F and Smith, Nicholas L and Christiano, Angela M and Petukhova, Lynn and Betz, Regina C and Fan, Xing and Zhang, Xuejun and Zhu, Caihong and Langefeld, Carl D and Thompson, Susan D and Wang, Feijie and Lin, Xu and Schwartz, David A and Fingerlin, Tasha and Rotter, Jerome I and Cotch, Mary Frances and Jensen, Richard A and Munz, Matthias and Dommisch, Henrik and Schaefer, Arne S and Han, Fang and Ollila, Hanna M and Hillary, Ryan P and Albagha, Omar and Ralston, Stuart H and Zeng, Chenjie and Zheng, Wei and Shu, Xiao-Ou and Reis, Andre and Uebe, Steffen and H{\"u}ffmeier, Ulrike and Kawamura, Yoshiya and Otowa, Takeshi and Sasaki, Tsukasa and Hibberd, Martin Lloyd and Davila, Sonia and Xie, Gang and Siminovitch, Katherine and Bei, Jin-Xin and Zeng, Yi-Xin and F{\"o}rsti, Asta and Chen, Bowang and Landi, Stefano and Franke, Andre and Fischer, Annegret and Ellinghaus, David and Flores, Carlos and Noth, Imre and Ma, Shwu-Fan and Foo, Jia Nee and Liu, Jianjun and Kim, Jong-Won and Cox, David G and Delattre, Olivier and Mirabeau, Olivier and Skibola, Christine F and Tang, Clara S and Garcia-Barcelo, Merce and Chang, Kai-Ping and Su, Wen-Hui and Chang, Yu-Sun and Martin, Nicholas G and Gordon, Scott and Wade, Tracey D and Lee, Chaeyoung and Kubo, Michiaki and Cha, Pei-Chieng and Nakamura, Yusuke and Levy, Daniel and Kimura, Masayuki and Hwang, Shih-Jen and Hunt, Steven and Spector, Tim and Soranzo, Nicole and Manichaikul, Ani W and Barr, R Graham and Kahali, Bratati and Speliotes, Elizabeth and Yerges-Armstrong, Laura M and Cheng, Ching-Yu and Jonas, Jost B and Wong, Tien Yin and Fogh, Isabella and Lin, Kuang and Powell, John F and Rice, Kenneth and Relton, Caroline L and Martin, Richard M and Davey Smith, George} } @article {7596, title = {Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis.}, journal = {PLoS Med}, volume = {14}, year = {2017}, month = {2017 Sep}, pages = {e1002383}, abstract = {

BACKGROUND: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.

METHODS \& FINDINGS: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95\% CI 1.04-1.06, per HbA1c-raising allele, p = 3 {\texttimes} 10-29); whereas GS-E was not (OR = 1.00, 95\% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11\%) was associated with an absolute decrease in HbA1c of 0.81\%-units (95\% CI 0.66-0.96) per allele in hemizygous men, and 0.68\%-units (95\% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2\% (N = 0.65 million, 95\% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.

CONCLUSIONS: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.

}, keywords = {Diabetes Mellitus, Type 2, Genetic Variation, Genome-Wide Association Study, Glycated Hemoglobin A, Humans, Phenotype, Risk}, issn = {1549-1676}, doi = {10.1371/journal.pmed.1002383}, author = {Wheeler, Eleanor and Leong, Aaron and Liu, Ching-Ti and Hivert, Marie-France and Strawbridge, Rona J and Podmore, Clara and Li, Man and Yao, Jie and Sim, Xueling and Hong, Jaeyoung and Chu, Audrey Y and Zhang, Weihua and Wang, Xu and Chen, Peng and Maruthur, Nisa M and Porneala, Bianca C and Sharp, Stephen J and Jia, Yucheng and Kabagambe, Edmond K and Chang, Li-Ching and Chen, Wei-Min and Elks, Cathy E and Evans, Daniel S and Fan, Qiao and Giulianini, Franco and Go, Min Jin and Hottenga, Jouke-Jan and Hu, Yao and Jackson, Anne U and Kanoni, Stavroula and Kim, Young Jin and Kleber, Marcus E and Ladenvall, Claes and Lecoeur, C{\'e}cile and Lim, Sing-Hui and Lu, Yingchang and Mahajan, Anubha and Marzi, Carola and Nalls, Mike A and Navarro, Pau and Nolte, Ilja M and Rose, Lynda M and Rybin, Denis V and Sanna, Serena and Shi, Yuan and Stram, Daniel O and Takeuchi, Fumihiko and Tan, Shu Pei and van der Most, Peter J and van Vliet-Ostaptchouk, Jana V and Wong, Andrew and Yengo, Loic and Zhao, Wanting and Goel, Anuj and Martinez Larrad, Maria Teresa and Radke, D{\"o}rte and Salo, Perttu and Tanaka, Toshiko and van Iperen, Erik P A and Abecasis, Goncalo and Afaq, Saima and Alizadeh, Behrooz Z and Bertoni, Alain G and Bonnefond, Am{\'e}lie and B{\"o}ttcher, Yvonne and Bottinger, Erwin P and Campbell, Harry and Carlson, Olga D and Chen, Chien-Hsiun and Cho, Yoon Shin and Garvey, W Timothy and Gieger, Christian and Goodarzi, Mark O and Grallert, Harald and Hamsten, Anders and Hartman, Catharina A and Herder, Christian and Hsiung, Chao Agnes and Huang, Jie and Igase, Michiya and Isono, Masato and Katsuya, Tomohiro and Khor, Chiea-Chuen and Kiess, Wieland and Kohara, Katsuhiko and Kovacs, Peter and Lee, Juyoung and Lee, Wen-Jane and Lehne, Benjamin and Li, Huaixing and Liu, Jianjun and Lobbens, Stephane and Luan, Jian{\textquoteright}an and Lyssenko, Valeriya and Meitinger, Thomas and Miki, Tetsuro and Miljkovic, Iva and Moon, Sanghoon and Mulas, Antonella and M{\"u}ller, Gabriele and M{\"u}ller-Nurasyid, Martina and Nagaraja, Ramaiah and Nauck, Matthias and Pankow, James S and Polasek, Ozren and Prokopenko, Inga and Ramos, Paula S and Rasmussen-Torvik, Laura and Rathmann, Wolfgang and Rich, Stephen S and Robertson, Neil R and Roden, Michael and Roussel, Ronan and Rudan, Igor and Scott, Robert A and Scott, William R and Sennblad, Bengt and Siscovick, David S and Strauch, Konstantin and Sun, Liang and Swertz, Morris and Tajuddin, Salman M and Taylor, Kent D and Teo, Yik-Ying and Tham, Yih Chung and T{\"o}njes, Anke and Wareham, Nicholas J and Willemsen, Gonneke and Wilsgaard, Tom and Hingorani, Aroon D and Egan, Josephine and Ferrucci, Luigi and Hovingh, G Kees and Jula, Antti and Kivimaki, Mika and Kumari, Meena and Nj{\o}lstad, Inger and Palmer, Colin N A and Serrano R{\'\i}os, Manuel and Stumvoll, Michael and Watkins, Hugh and Aung, Tin and Bl{\"u}her, Matthias and Boehnke, Michael and Boomsma, Dorret I and Bornstein, Stefan R and Chambers, John C and Chasman, Daniel I and Chen, Yii-Der Ida and Chen, Yduan-Tsong and Cheng, Ching-Yu and Cucca, Francesco and de Geus, Eco J C and Deloukas, Panos and Evans, Michele K and Fornage, Myriam and Friedlander, Yechiel and Froguel, Philippe and Groop, Leif and Gross, Myron D and Harris, Tamara B and Hayward, Caroline and Heng, Chew-Kiat and Ingelsson, Erik and Kato, Norihiro and Kim, Bong-Jo and Koh, Woon-Puay and Kooner, Jaspal S and K{\"o}rner, Antje and Kuh, Diana and Kuusisto, Johanna and Laakso, Markku and Lin, Xu and Liu, Yongmei and Loos, Ruth J F and Magnusson, Patrik K E and M{\"a}rz, Winfried and McCarthy, Mark I and Oldehinkel, Albertine J and Ong, Ken K and Pedersen, Nancy L and Pereira, Mark A and Peters, Annette and Ridker, Paul M and Sabanayagam, Charumathi and Sale, Michele and Saleheen, Danish and Saltevo, Juha and Schwarz, Peter Eh and Sheu, Wayne H H and Snieder, Harold and Spector, Timothy D and Tabara, Yasuharu and Tuomilehto, Jaakko and van Dam, Rob M and Wilson, James G and Wilson, James F and Wolffenbuttel, Bruce H R and Wong, Tien Yin and Wu, Jer-Yuarn and Yuan, Jian-Min and Zonderman, Alan B and Soranzo, Nicole and Guo, Xiuqing and Roberts, David J and Florez, Jose C and Sladek, Robert and Dupuis, Jos{\'e}e and Morris, Andrew P and Tai, E-Shyong and Selvin, Elizabeth and Rotter, Jerome I and Langenberg, Claudia and Barroso, In{\^e}s and Meigs, James B} } @article {7600, title = {Large meta-analysis of genome-wide association studies identifies five loci for lean body mass.}, journal = {Nat Commun}, volume = {8}, year = {2017}, month = {2017 Jul 19}, pages = {80}, abstract = {

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 {\texttimes} 10-8) or suggestively genome wide (p < 2.3 {\texttimes} 10-6). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.Lean body mass is a highly heritable trait and is associated with various health conditions. Here, Kiel and colleagues perform a meta-analysis of genome-wide association studies for whole body lean body mass and find five novel genetic loci to be significantly associated.

}, issn = {2041-1723}, doi = {10.1038/s41467-017-00031-7}, author = {Zillikens, M Carola and Demissie, Serkalem and Hsu, Yi-Hsiang and Yerges-Armstrong, Laura M and Chou, Wen-Chi and Stolk, Lisette and Livshits, Gregory and Broer, Linda and Johnson, Toby and Koller, Daniel L and Kutalik, Zolt{\'a}n and Luan, Jian{\textquoteright}an and Malkin, Ida and Ried, Janina S and Smith, Albert V and Thorleifsson, Gudmar and Vandenput, Liesbeth and Hua Zhao, Jing and Zhang, Weihua and Aghdassi, Ali and {\r A}kesson, Kristina and Amin, Najaf and Baier, Leslie J and Barroso, In{\^e}s and Bennett, David A and Bertram, Lars and Biffar, Rainer and Bochud, Murielle and Boehnke, Michael and Borecki, Ingrid B and Buchman, Aron S and Byberg, Liisa and Campbell, Harry and Campos Obanda, Natalia and Cauley, Jane A and Cawthon, Peggy M and Cederberg, Henna and Chen, Zhao and Cho, Nam H and Jin Choi, Hyung and Claussnitzer, Melina and Collins, Francis and Cummings, Steven R and De Jager, Philip L and Demuth, Ilja and Dhonukshe-Rutten, Rosalie A M and Diatchenko, Luda and Eiriksdottir, Gudny and Enneman, Anke W and Erdos, Mike and Eriksson, Johan G and Eriksson, Joel and Estrada, Karol and Evans, Daniel S and Feitosa, Mary F and Fu, Mao and Garcia, Melissa and Gieger, Christian and Girke, Thomas and Glazer, Nicole L and Grallert, Harald and Grewal, Jagvir and Han, Bok-Ghee and Hanson, Robert L and Hayward, Caroline and Hofman, Albert and Hoffman, Eric P and Homuth, Georg and Hsueh, Wen-Chi and Hubal, Monica J and Hubbard, Alan and Huffman, Kim M and Husted, Lise B and Illig, Thomas and Ingelsson, Erik and Ittermann, Till and Jansson, John-Olov and Jordan, Joanne M and Jula, Antti and Karlsson, Magnus and Khaw, Kay-Tee and Kilpel{\"a}inen, Tuomas O and Klopp, Norman and Kloth, Jacqueline S L and Koistinen, Heikki A and Kraus, William E and Kritchevsky, Stephen and Kuulasmaa, Teemu and Kuusisto, Johanna and Laakso, Markku and Lahti, Jari and Lang, Thomas and Langdahl, Bente L and Launer, Lenore J and Lee, Jong-Young and Lerch, Markus M and Lewis, Joshua R and Lind, Lars and Lindgren, Cecilia and Liu, Yongmei and Liu, Tian and Liu, Youfang and Ljunggren, Osten and Lorentzon, Mattias and Luben, Robert N and Maixner, William and McGuigan, Fiona E and Medina-G{\'o}mez, Carolina and Meitinger, Thomas and Melhus, H{\r a}kan and Mellstr{\"o}m, Dan and Melov, Simon and Micha{\"e}lsson, Karl and Mitchell, Braxton D and Morris, Andrew P and Mosekilde, Leif and Newman, Anne and Nielson, Carrie M and O{\textquoteright}Connell, Jeffrey R and Oostra, Ben A and Orwoll, Eric S and Palotie, Aarno and Parker, Stephen C J and Peacock, Munro and Perola, Markus and Peters, Annette and Polasek, Ozren and Prince, Richard L and R{\"a}ikk{\"o}nen, Katri and Ralston, Stuart H and Ripatti, Samuli and Robbins, John A and Rotter, Jerome I and Rudan, Igor and Salomaa, Veikko and Satterfield, Suzanne and Schadt, Eric E and Schipf, Sabine and Scott, Laura and Sehmi, Joban and Shen, Jian and Soo Shin, Chan and Sigurdsson, Gunnar and Smith, Shad and Soranzo, Nicole and Stan{\v c}{\'a}kov{\'a}, Alena and Steinhagen-Thiessen, Elisabeth and Streeten, Elizabeth A and Styrkarsdottir, Unnur and Swart, Karin M A and Tan, Sian-Tsung and Tarnopolsky, Mark A and Thompson, Patricia and Thomson, Cynthia A and Thorsteinsdottir, Unnur and Tikkanen, Emmi and Tranah, Gregory J and Tuomilehto, Jaakko and van Schoor, Natasja M and Verma, Arjun and Vollenweider, Peter and V{\"o}lzke, Henry and Wactawski-Wende, Jean and Walker, Mark and Weedon, Michael N and Welch, Ryan and Wichmann, H-Erich and Widen, Elisabeth and Williams, Frances M K and Wilson, James F and Wright, Nicole C and Xie, Weijia and Yu, Lei and Zhou, Yanhua and Chambers, John C and D{\"o}ring, Angela and van Duijn, Cornelia M and Econs, Michael J and Gudnason, Vilmundur and Kooner, Jaspal S and Psaty, Bruce M and Spector, Timothy D and Stefansson, Kari and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Wareham, Nicholas J and Ossowski, Vicky and Waterworth, Dawn and Loos, Ruth J F and Karasik, David and Harris, Tamara B and Ohlsson, Claes and Kiel, Douglas P} } @article {7920, title = {Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders.}, journal = {Am J Hum Genet}, volume = {103}, year = {2018}, month = {2018 Nov 01}, pages = {691-706}, abstract = {

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5~{\texttimes} 10). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0\% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.09.009}, author = {Ligthart, Symen and Vaez, Ahmad and V{\~o}sa, Urmo and Stathopoulou, Maria G and de Vries, Paul S and Prins, Bram P and van der Most, Peter J and Tanaka, Toshiko and Naderi, Elnaz and Rose, Lynda M and Wu, Ying and Karlsson, Robert and Barbalic, Maja and Lin, Honghuang and Pool, Rene and Zhu, Gu and Mace, Aurelien and Sidore, Carlo and Trompet, Stella and Mangino, Massimo and Sabater-Lleal, Maria and Kemp, John P and Abbasi, Ali and Kacprowski, Tim and Verweij, Niek and Smith, Albert V and Huang, Tao and Marzi, Carola and Feitosa, Mary F and Lohman, Kurt K and Kleber, Marcus E and Milaneschi, Yuri and Mueller, Christian and Huq, Mahmudul and Vlachopoulou, Efthymia and Lyytik{\"a}inen, Leo-Pekka and Oldmeadow, Christopher and Deelen, Joris and Perola, Markus and Zhao, Jing Hua and Feenstra, Bjarke and Amini, Marzyeh and Lahti, Jari and Schraut, Katharina E and Fornage, Myriam and Suktitipat, Bhoom and Chen, Wei-Min and Li, Xiaohui and Nutile, Teresa and Malerba, Giovanni and Luan, Jian{\textquoteright}an and Bak, Tom and Schork, Nicholas and del Greco M, Fabiola and Thiering, Elisabeth and Mahajan, Anubha and Marioni, Riccardo E and Mihailov, Evelin and Eriksson, Joel and Ozel, Ayse Bilge and Zhang, Weihua and Nethander, Maria and Cheng, Yu-Ching and Aslibekyan, Stella and Ang, Wei and Gandin, Ilaria and Yengo, Loic and Portas, Laura and Kooperberg, Charles and Hofer, Edith and Rajan, Kumar B and Schurmann, Claudia and den Hollander, Wouter and Ahluwalia, Tarunveer S and Zhao, Jing and Draisma, Harmen H M and Ford, Ian and Timpson, Nicholas and Teumer, Alexander and Huang, Hongyan and Wahl, Simone and Liu, Yongmei and Huang, Jie and Uh, Hae-Won and Geller, Frank and Joshi, Peter K and Yanek, Lisa R and Trabetti, Elisabetta and Lehne, Benjamin and Vozzi, Diego and Verbanck, Marie and Biino, Ginevra and Saba, Yasaman and Meulenbelt, Ingrid and O{\textquoteright}Connell, Jeff R and Laakso, Markku and Giulianini, Franco and Magnusson, Patrik K E and Ballantyne, Christie M and Hottenga, Jouke Jan and Montgomery, Grant W and Rivadineira, Fernando and Rueedi, Rico and Steri, Maristella and Herzig, Karl-Heinz and Stott, David J and Menni, Cristina and Fr{\r a}nberg, Mattias and St Pourcain, Beate and Felix, Stephan B and Pers, Tune H and Bakker, Stephan J L and Kraft, Peter and Peters, Annette and Vaidya, Dhananjay and Delgado, Graciela and Smit, Johannes H and Gro{\ss}mann, Vera and Sinisalo, Juha and Sepp{\"a}l{\"a}, Ilkka and Williams, Stephen R and Holliday, Elizabeth G and Moed, Matthijs and Langenberg, Claudia and R{\"a}ikk{\"o}nen, Katri and Ding, Jingzhong and Campbell, Harry and Sale, Mich{\`e}le M and Chen, Yii-der I and James, Alan L and Ruggiero, Daniela and Soranzo, Nicole and Hartman, Catharina A and Smith, Erin N and Berenson, Gerald S and Fuchsberger, Christian and Hernandez, Dena and Tiesler, Carla M T and Giedraitis, Vilmantas and Liewald, David and Fischer, Krista and Mellstr{\"o}m, Dan and Larsson, Anders and Wang, Yunmei and Scott, William R and Lorentzon, Matthias and Beilby, John and Ryan, Kathleen A and Pennell, Craig E and Vuckovic, Dragana and Balkau, Beverly and Concas, Maria Pina and Schmidt, Reinhold and Mendes de Leon, Carlos F and Bottinger, Erwin P and Kloppenburg, Margreet and Paternoster, Lavinia and Boehnke, Michael and Musk, A W and Willemsen, Gonneke and Evans, David M and Madden, Pamela A F and K{\"a}h{\"o}nen, Mika and Kutalik, Zolt{\'a}n and Zoledziewska, Magdalena and Karhunen, Ville and Kritchevsky, Stephen B and Sattar, Naveed and Lachance, Genevieve and Clarke, Robert and Harris, Tamara B and Raitakari, Olli T and Attia, John R and van Heemst, Diana and Kajantie, Eero and Sorice, Rossella and Gambaro, Giovanni and Scott, Robert A and Hicks, Andrew A and Ferrucci, Luigi and Standl, Marie and Lindgren, Cecilia M and Starr, John M and Karlsson, Magnus and Lind, Lars and Li, Jun Z and Chambers, John C and Mori, Trevor A and de Geus, Eco J C N and Heath, Andrew C and Martin, Nicholas G and Auvinen, Juha and Buckley, Brendan M and de Craen, Anton J M and Waldenberger, Melanie and Strauch, Konstantin and Meitinger, Thomas and Scott, Rodney J and McEvoy, Mark and Beekman, Marian and Bombieri, Cristina and Ridker, Paul M and Mohlke, Karen L and Pedersen, Nancy L and Morrison, Alanna C and Boomsma, Dorret I and Whitfield, John B and Strachan, David P and Hofman, Albert and Vollenweider, Peter and Cucca, Francesco and Jarvelin, Marjo-Riitta and Jukema, J Wouter and Spector, Tim D and Hamsten, Anders and Zeller, Tanja and Uitterlinden, Andr{\'e} G and Nauck, Matthias and Gudnason, Vilmundur and Qi, Lu and Grallert, Harald and Borecki, Ingrid B and Rotter, Jerome I and M{\"a}rz, Winfried and Wild, Philipp S and Lokki, Marja-Liisa and Boyle, Michael and Salomaa, Veikko and Melbye, Mads and Eriksson, Johan G and Wilson, James F and Penninx, Brenda W J H and Becker, Diane M and Worrall, Bradford B and Gibson, Greg and Krauss, Ronald M and Ciullo, Marina and Zaza, Gianluigi and Wareham, Nicholas J and Oldehinkel, Albertine J and Palmer, Lyle J and Murray, Sarah S and Pramstaller, Peter P and Bandinelli, Stefania and Heinrich, Joachim and Ingelsson, Erik and Deary, Ian J and M{\"a}gi, Reedik and Vandenput, Liesbeth and van der Harst, Pim and Desch, Karl C and Kooner, Jaspal S and Ohlsson, Claes and Hayward, Caroline and Lehtim{\"a}ki, Terho and Shuldiner, Alan R and Arnett, Donna K and Beilin, Lawrence J and Robino, Antonietta and Froguel, Philippe and Pirastu, Mario and Jess, Tine and Koenig, Wolfgang and Loos, Ruth J F and Evans, Denis A and Schmidt, Helena and Smith, George Davey and Slagboom, P Eline and Eiriksdottir, Gudny and Morris, Andrew P and Psaty, Bruce M and Tracy, Russell P and Nolte, Ilja M and Boerwinkle, Eric and Visvikis-Siest, Sophie and Reiner, Alex P and Gross, Myron and Bis, Joshua C and Franke, Lude and Franco, Oscar H and Benjamin, Emelia J and Chasman, Daniel I and Dupuis, Jos{\'e}e and Snieder, Harold and Dehghan, Abbas and Alizadeh, Behrooz Z} } @article {7927, title = {Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 10 26}, pages = {4455}, abstract = {

Thyroid dysfunction is an important public health problem, which affects 10\% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves{\textquoteright} disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.

}, issn = {2041-1723}, doi = {10.1038/s41467-018-06356-1}, author = {Teumer, Alexander and Chaker, Layal and Groeneweg, Stefan and Li, Yong and Di Munno, Celia and Barbieri, Caterina and Schultheiss, Ulla T and Traglia, Michela and Ahluwalia, Tarunveer S and Akiyama, Masato and Appel, Emil Vincent R and Arking, Dan E and Arnold, Alice and Astrup, Arne and Beekman, Marian and Beilby, John P and Bekaert, Sofie and Boerwinkle, Eric and Brown, Suzanne J and De Buyzere, Marc and Campbell, Purdey J and Ceresini, Graziano and Cerqueira, Charlotte and Cucca, Francesco and Deary, Ian J and Deelen, Joris and Eckardt, Kai-Uwe and Ekici, Arif B and Eriksson, Johan G and Ferrrucci, Luigi and Fiers, Tom and Fiorillo, Edoardo and Ford, Ian and Fox, Caroline S and Fuchsberger, Christian and Galesloot, Tessel E and Gieger, Christian and G{\"o}gele, Martin and De Grandi, Alessandro and Grarup, Niels and Greiser, Karin Halina and Haljas, Kadri and Hansen, Torben and Harris, Sarah E and van Heemst, Diana and den Heijer, Martin and Hicks, Andrew A and den Hollander, Wouter and Homuth, Georg and Hui, Jennie and Ikram, M Arfan and Ittermann, Till and Jensen, Richard A and Jing, Jiaojiao and Jukema, J Wouter and Kajantie, Eero and Kamatani, Yoichiro and Kasbohm, Elisa and Kaufman, Jean-Marc and Kiemeney, Lambertus A and Kloppenburg, Margreet and Kronenberg, Florian and Kubo, Michiaki and Lahti, Jari and Lapauw, Bruno and Li, Shuo and Liewald, David C M and Lim, Ee Mun and Linneberg, Allan and Marina, Michela and Mascalzoni, Deborah and Matsuda, Koichi and Medenwald, Daniel and Meisinger, Christa and Meulenbelt, Ingrid and De Meyer, Tim and Meyer zu Schwabedissen, Henriette E and Mikolajczyk, Rafael and Moed, Matthijs and Netea-Maier, Romana T and Nolte, Ilja M and Okada, Yukinori and Pala, Mauro and Pattaro, Cristian and Pedersen, Oluf and Petersmann, Astrid and Porcu, Eleonora and Postmus, Iris and Pramstaller, Peter P and Psaty, Bruce M and Ramos, Yolande F M and Rawal, Rajesh and Redmond, Paul and Richards, J Brent and Rietzschel, Ernst R and Rivadeneira, Fernando and Roef, Greet and Rotter, Jerome I and Sala, Cinzia F and Schlessinger, David and Selvin, Elizabeth and Slagboom, P Eline and Soranzo, Nicole and S{\o}rensen, Thorkild I A and Spector, Timothy D and Starr, John M and Stott, David J and Taes, Youri and Taliun, Daniel and Tanaka, Toshiko and Thuesen, Betina and Tiller, Daniel and Toniolo, Daniela and Uitterlinden, Andr{\'e} G and Visser, W Edward and Walsh, John P and Wilson, Scott G and Wolffenbuttel, Bruce H R and Yang, Qiong and Zheng, Hou-Feng and Cappola, Anne and Peeters, Robin P and Naitza, Silvia and V{\"o}lzke, Henry and Sanna, Serena and K{\"o}ttgen, Anna and Visser, Theo J and Medici, Marco} } @article {7668, title = {Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Apr}, pages = {559-571}, abstract = {

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 {\texttimes} 10); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio <=1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent {\textquoteright}false leads{\textquoteright} with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0084-1}, author = {Mahajan, Anubha and Wessel, Jennifer and Willems, Sara M and Zhao, Wei and Robertson, Neil R and Chu, Audrey Y and Gan, Wei and Kitajima, Hidetoshi and Taliun, Daniel and Rayner, N William and Guo, Xiuqing and Lu, Yingchang and Li, Man and Jensen, Richard A and Hu, Yao and Huo, Shaofeng and Lohman, Kurt K and Zhang, Weihua and Cook, James P and Prins, Bram Peter and Flannick, Jason and Grarup, Niels and Trubetskoy, Vassily Vladimirovich and Kravic, Jasmina and Kim, Young Jin and Rybin, Denis V and Yaghootkar, Hanieh and M{\"u}ller-Nurasyid, Martina and Meidtner, Karina and Li-Gao, Ruifang and Varga, Tibor V and Marten, Jonathan and Li, Jin and Smith, Albert Vernon and An, Ping and Ligthart, Symen and Gustafsson, Stefan and Malerba, Giovanni and Demirkan, Ayse and Tajes, Juan Fernandez and Steinthorsdottir, Valgerdur and Wuttke, Matthias and Lecoeur, C{\'e}cile and Preuss, Michael and Bielak, Lawrence F and Graff, Marielisa and Highland, Heather M and Justice, Anne E and Liu, Dajiang J and Marouli, Eirini and Peloso, Gina Marie and Warren, Helen R and Afaq, Saima and Afzal, Shoaib and Ahlqvist, Emma and Almgren, Peter and Amin, Najaf and Bang, Lia B and Bertoni, Alain G and Bombieri, Cristina and Bork-Jensen, Jette and Brandslund, Ivan and Brody, Jennifer A and Burtt, Noel P and Canouil, Micka{\"e}l and Chen, Yii-Der Ida and Cho, Yoon Shin and Christensen, Cramer and Eastwood, Sophie V and Eckardt, Kai-Uwe and Fischer, Krista and Gambaro, Giovanni and Giedraitis, Vilmantas and Grove, Megan L and de Haan, Hugoline G and Hackinger, Sophie and Hai, Yang and Han, Sohee and Tybj{\ae}rg-Hansen, Anne and Hivert, Marie-France and Isomaa, Bo and J{\"a}ger, Susanne and J{\o}rgensen, Marit E and J{\o}rgensen, Torben and K{\"a}r{\"a}j{\"a}m{\"a}ki, AnneMari and Kim, Bong-Jo and Kim, Sung Soo and Koistinen, Heikki A and Kovacs, Peter and Kriebel, Jennifer and Kronenberg, Florian and L{\"a}ll, Kristi and Lange, Leslie A and Lee, Jung-Jin and Lehne, Benjamin and Li, Huaixing and Lin, Keng-Hung and Linneberg, Allan and Liu, Ching-Ti and Liu, Jun and Loh, Marie and M{\"a}gi, Reedik and Mamakou, Vasiliki and McKean-Cowdin, Roberta and Nadkarni, Girish and Neville, Matt and Nielsen, Sune F and Ntalla, Ioanna and Peyser, Patricia A and Rathmann, Wolfgang and Rice, Kenneth and Rich, Stephen S and Rode, Line and Rolandsson, Olov and Sch{\"o}nherr, Sebastian and Selvin, Elizabeth and Small, Kerrin S and Stan{\v c}{\'a}kov{\'a}, Alena and Surendran, Praveen and Taylor, Kent D and Teslovich, Tanya M and Thorand, Barbara and Thorleifsson, Gudmar and Tin, Adrienne and T{\"o}njes, Anke and Varbo, Anette and Witte, Daniel R and Wood, Andrew R and Yajnik, Pranav and Yao, Jie and Yengo, Loic and Young, Robin and Amouyel, Philippe and Boeing, Heiner and Boerwinkle, Eric and Bottinger, Erwin P and Chowdhury, Rajiv and Collins, Francis S and Dedoussis, George and Dehghan, Abbas and Deloukas, Panos and Ferrario, Marco M and Ferrieres, Jean and Florez, Jose C and Frossard, Philippe and Gudnason, Vilmundur and Harris, Tamara B and Heckbert, Susan R and Howson, Joanna M M and Ingelsson, Martin and Kathiresan, Sekar and Kee, Frank and Kuusisto, Johanna and Langenberg, Claudia and Launer, Lenore J and Lindgren, Cecilia M and M{\"a}nnist{\"o}, Satu and Meitinger, Thomas and Melander, Olle and Mohlke, Karen L and Moitry, Marie and Morris, Andrew D and Murray, Alison D and de Mutsert, Ren{\'e}e and Orho-Melander, Marju and Owen, Katharine R and Perola, Markus and Peters, Annette and Province, Michael A and Rasheed, Asif and Ridker, Paul M and Rivadineira, Fernando and Rosendaal, Frits R and Rosengren, Anders H and Salomaa, Veikko and Sheu, Wayne H-H and Sladek, Rob and Smith, Blair H and Strauch, Konstantin and Uitterlinden, Andr{\'e} G and Varma, Rohit and Willer, Cristen J and Bl{\"u}her, Matthias and Butterworth, Adam S and Chambers, John Campbell and Chasman, Daniel I and Danesh, John and van Duijn, Cornelia and Dupuis, Jos{\'e}e and Franco, Oscar H and Franks, Paul W and Froguel, Philippe and Grallert, Harald and Groop, Leif and Han, Bok-Ghee and Hansen, Torben and Hattersley, Andrew T and Hayward, Caroline and Ingelsson, Erik and Kardia, Sharon L R and Karpe, Fredrik and Kooner, Jaspal Singh and K{\"o}ttgen, Anna and Kuulasmaa, Kari and Laakso, Markku and Lin, Xu and Lind, Lars and Liu, Yongmei and Loos, Ruth J F and Marchini, Jonathan and Metspalu, Andres and Mook-Kanamori, Dennis and Nordestgaard, B{\o}rge G and Palmer, Colin N A and Pankow, James S and Pedersen, Oluf and Psaty, Bruce M and Rauramaa, Rainer and Sattar, Naveed and Schulze, Matthias B and Soranzo, Nicole and Spector, Timothy D and Stefansson, Kari and Stumvoll, Michael and Thorsteinsdottir, Unnur and Tuomi, Tiinamaija and Tuomilehto, Jaakko and Wareham, Nicholas J and Wilson, James G and Zeggini, Eleftheria and Scott, Robert A and Barroso, In{\^e}s and Frayling, Timothy M and Goodarzi, Mark O and Meigs, James B and Boehnke, Michael and Saleheen, Danish and Morris, Andrew P and Rotter, Jerome I and McCarthy, Mark I} } @article {8109, title = {A catalog of genetic loci associated with kidney function from analyses of a million individuals.}, journal = {Nat Genet}, volume = {51}, year = {2019}, month = {2019 06}, pages = {957-972}, abstract = {

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.

}, keywords = {Chromosome Mapping, European Continental Ancestry Group, Genetic Association Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Inheritance Patterns, Kidney Function Tests, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Quantitative Trait, Heritable, Renal Insufficiency, Chronic, Uromodulin}, issn = {1546-1718}, doi = {10.1038/s41588-019-0407-x}, author = {Wuttke, Matthias and Li, Yong and Li, Man and Sieber, Karsten B and Feitosa, Mary F and Gorski, Mathias and Tin, Adrienne and Wang, Lihua and Chu, Audrey Y and Hoppmann, Anselm and Kirsten, Holger and Giri, Ayush and Chai, Jin-Fang and Sveinbjornsson, Gardar and Tayo, Bamidele O and Nutile, Teresa and Fuchsberger, Christian and Marten, Jonathan and Cocca, Massimiliano and Ghasemi, Sahar and Xu, Yizhe and Horn, Katrin and Noce, Damia and van der Most, Peter J and Sedaghat, Sanaz and Yu, Zhi and Akiyama, Masato and Afaq, Saima and Ahluwalia, Tarunveer S and Almgren, Peter and Amin, Najaf and Arnl{\"o}v, Johan and Bakker, Stephan J L and Bansal, Nisha and Baptista, Daniela and Bergmann, Sven and Biggs, Mary L and Biino, Ginevra and Boehnke, Michael and Boerwinkle, Eric and Boissel, Mathilde and Bottinger, Erwin P and Boutin, Thibaud S and Brenner, Hermann and Brumat, Marco and Burkhardt, Ralph and Butterworth, Adam S and Campana, Eric and Campbell, Archie and Campbell, Harry and Canouil, Micka{\"e}l and Carroll, Robert J and Catamo, Eulalia and Chambers, John C and Chee, Miao-Ling and Chee, Miao-Li and Chen, Xu and Cheng, Ching-Yu and Cheng, Yurong and Christensen, Kaare and Cifkova, Renata and Ciullo, Marina and Concas, Maria Pina and Cook, James P and Coresh, Josef and Corre, Tanguy and Sala, Cinzia Felicita and Cusi, Daniele and Danesh, John and Daw, E Warwick and de Borst, Martin H and De Grandi, Alessandro and de Mutsert, Ren{\'e}e and de Vries, Aiko P J and Degenhardt, Frauke and Delgado, Graciela and Demirkan, Ayse and Di Angelantonio, Emanuele and Dittrich, Katalin and Divers, Jasmin and Dorajoo, Rajkumar and Eckardt, Kai-Uwe and Ehret, Georg and Elliott, Paul and Endlich, Karlhans and Evans, Michele K and Felix, Janine F and Foo, Valencia Hui Xian and Franco, Oscar H and Franke, Andre and Freedman, Barry I and Freitag-Wolf, Sandra and Friedlander, Yechiel and Froguel, Philippe and Gansevoort, Ron T and Gao, He and Gasparini, Paolo and Gaziano, J Michael and Giedraitis, Vilmantas and Gieger, Christian and Girotto, Giorgia and Giulianini, Franco and G{\"o}gele, Martin and Gordon, Scott D and Gudbjartsson, Daniel F and Gudnason, Vilmundur and Haller, Toomas and Hamet, Pavel and Harris, Tamara B and Hartman, Catharina A and Hayward, Caroline and Hellwege, Jacklyn N and Heng, Chew-Kiat and Hicks, Andrew A and Hofer, Edith and Huang, Wei and Hutri-K{\"a}h{\"o}nen, Nina and Hwang, Shih-Jen and Ikram, M Arfan and Indridason, Olafur S and Ingelsson, Erik and Ising, Marcus and Jaddoe, Vincent W V and Jakobsdottir, Johanna and Jonas, Jost B and Joshi, Peter K and Josyula, Navya Shilpa and Jung, Bettina and K{\"a}h{\"o}nen, Mika and Kamatani, Yoichiro and Kammerer, Candace M and Kanai, Masahiro and Kastarinen, Mika and Kerr, Shona M and Khor, Chiea-Chuen and Kiess, Wieland and Kleber, Marcus E and Koenig, Wolfgang and Kooner, Jaspal S and K{\"o}rner, Antje and Kovacs, Peter and Kraja, Aldi T and Krajcoviechova, Alena and Kramer, Holly and Kr{\"a}mer, Bernhard K and Kronenberg, Florian and Kubo, Michiaki and Kuhnel, Brigitte and Kuokkanen, Mikko and Kuusisto, Johanna and La Bianca, Martina and Laakso, Markku and Lange, Leslie A and Langefeld, Carl D and Lee, Jeannette Jen-Mai and Lehne, Benjamin and Lehtim{\"a}ki, Terho and Lieb, Wolfgang and Lim, Su-Chi and Lind, Lars and Lindgren, Cecilia M and Liu, Jun and Liu, Jianjun and Loeffler, Markus and Loos, Ruth J F and Lucae, Susanne and Lukas, Mary Ann and Lyytik{\"a}inen, Leo-Pekka and M{\"a}gi, Reedik and Magnusson, Patrik K E and Mahajan, Anubha and Martin, Nicholas G and Martins, Jade and M{\"a}rz, Winfried and Mascalzoni, Deborah and Matsuda, Koichi and Meisinger, Christa and Meitinger, Thomas and Melander, Olle and Metspalu, Andres and Mikaelsdottir, Evgenia K and Milaneschi, Yuri and Miliku, Kozeta and Mishra, Pashupati P and Mohlke, Karen L and Mononen, Nina and Montgomery, Grant W and Mook-Kanamori, Dennis O and Mychaleckyj, Josyf C and Nadkarni, Girish N and Nalls, Mike A and Nauck, Matthias and Nikus, Kjell and Ning, Boting and Nolte, Ilja M and Noordam, Raymond and O{\textquoteright}Connell, Jeffrey and O{\textquoteright}Donoghue, Michelle L and Olafsson, Isleifur and Oldehinkel, Albertine J and Orho-Melander, Marju and Ouwehand, Willem H and Padmanabhan, Sandosh and Palmer, Nicholette D and Palsson, Runolfur and Penninx, Brenda W J H and Perls, Thomas and Perola, Markus and Pirastu, Mario and Pirastu, Nicola and Pistis, Giorgio and Podgornaia, Anna I and Polasek, Ozren and Ponte, Belen and Porteous, David J and Poulain, Tanja and Pramstaller, Peter P and Preuss, Michael H and Prins, Bram P and Province, Michael A and Rabelink, Ton J and Raffield, Laura M and Raitakari, Olli T and Reilly, Dermot F and Rettig, Rainer and Rheinberger, Myriam and Rice, Kenneth M and Ridker, Paul M and Rivadeneira, Fernando and Rizzi, Federica and Roberts, David J and Robino, Antonietta and Rossing, Peter and Rudan, Igor and Rueedi, Rico and Ruggiero, Daniela and Ryan, Kathleen A and Saba, Yasaman and Sabanayagam, Charumathi and Salomaa, Veikko and Salvi, Erika and Saum, Kai-Uwe and Schmidt, Helena and Schmidt, Reinhold and Sch{\"o}ttker, Ben and Schulz, Christina-Alexandra and Schupf, Nicole and Shaffer, Christian M and Shi, Yuan and Smith, Albert V and Smith, Blair H and Soranzo, Nicole and Spracklen, Cassandra N and Strauch, Konstantin and Stringham, Heather M and Stumvoll, Michael and Svensson, Per O and Szymczak, Silke and Tai, E-Shyong and Tajuddin, Salman M and Tan, Nicholas Y Q and Taylor, Kent D and Teren, Andrej and Tham, Yih-Chung and Thiery, Joachim and Thio, Chris H L and Thomsen, Hauke and Thorleifsson, Gudmar and Toniolo, Daniela and T{\"o}njes, Anke and Tremblay, Johanne and Tzoulaki, Ioanna and Uitterlinden, Andr{\'e} G and Vaccargiu, Simona and van Dam, Rob M and van der Harst, Pim and van Duijn, Cornelia M and Velez Edward, Digna R and Verweij, Niek and Vogelezang, Suzanne and V{\"o}lker, Uwe and Vollenweider, Peter and Waeber, G{\'e}rard and Waldenberger, Melanie and Wallentin, Lars and Wang, Ya Xing and Wang, Chaolong and Waterworth, Dawn M and Bin Wei, Wen and White, Harvey and Whitfield, John B and Wild, Sarah H and Wilson, James F and Wojczynski, Mary K and Wong, Charlene and Wong, Tien-Yin and Xu, Liang and Yang, Qiong and Yasuda, Masayuki and Yerges-Armstrong, Laura M and Zhang, Weihua and Zonderman, Alan B and Rotter, Jerome I and Bochud, Murielle and Psaty, Bruce M and Vitart, Veronique and Wilson, James G and Dehghan, Abbas and Parsa, Afshin and Chasman, Daniel I and Ho, Kevin and Morris, Andrew P and Devuyst, Olivier and Akilesh, Shreeram and Pendergrass, Sarah A and Sim, Xueling and B{\"o}ger, Carsten A and Okada, Yukinori and Edwards, Todd L and Snieder, Harold and Stefansson, Kari and Hung, Adriana M and Heid, Iris M and Scholz, Markus and Teumer, Alexander and K{\"o}ttgen, Anna and Pattaro, Cristian} } @article {7974, title = {Disentangling the genetics of lean mass.}, journal = {Am J Clin Nutr}, volume = {109}, year = {2019}, month = {2019 Feb 01}, pages = {276-287}, abstract = {

Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass.

Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci.

Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n~=~38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms).

Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection.

Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.

}, issn = {1938-3207}, doi = {10.1093/ajcn/nqy272}, author = {Karasik, David and Zillikens, M Carola and Hsu, Yi-Hsiang and Aghdassi, Ali and {\r A}kesson, Kristina and Amin, Najaf and Barroso, In{\^e}s and Bennett, David A and Bertram, Lars and Bochud, Murielle and Borecki, Ingrid B and Broer, Linda and Buchman, Aron S and Byberg, Liisa and Campbell, Harry and Campos-Obando, Natalia and Cauley, Jane A and Cawthon, Peggy M and Chambers, John C and Chen, Zhao and Cho, Nam H and Choi, Hyung Jin and Chou, Wen-Chi and Cummings, Steven R and de Groot, Lisette C P G M and De Jager, Phillip L and Demuth, Ilja and Diatchenko, Luda and Econs, Michael J and Eiriksdottir, Gudny and Enneman, Anke W and Eriksson, Joel and Eriksson, Johan G and Estrada, Karol and Evans, Daniel S and Feitosa, Mary F and Fu, Mao and Gieger, Christian and Grallert, Harald and Gudnason, Vilmundur and Lenore, Launer J and Hayward, Caroline and Hofman, Albert and Homuth, Georg and Huffman, Kim M and Husted, Lise B and Illig, Thomas and Ingelsson, Erik and Ittermann, Till and Jansson, John-Olov and Johnson, Toby and Biffar, Reiner and Jordan, Joanne M and Jula, Antti and Karlsson, Magnus and Khaw, Kay-Tee and Kilpel{\"a}inen, Tuomas O and Klopp, Norman and Kloth, Jacqueline S L and Koller, Daniel L and Kooner, Jaspal S and Kraus, William E and Kritchevsky, Stephen and Kutalik, Zolt{\'a}n and Kuulasmaa, Teemu and Kuusisto, Johanna and Laakso, Markku and Lahti, Jari and Lang, Thomas and Langdahl, Bente L and Lerch, Markus M and Lewis, Joshua R and Lill, Christina and Lind, Lars and Lindgren, Cecilia and Liu, Yongmei and Livshits, Gregory and Ljunggren, Osten and Loos, Ruth J F and Lorentzon, Mattias and Luan, Jian{\textquoteright}an and Luben, Robert N and Malkin, Ida and McGuigan, Fiona E and Medina-G{\'o}mez, Carolina and Meitinger, Thomas and Melhus, H{\r a}kan and Mellstr{\"o}m, Dan and Micha{\"e}lsson, Karl and Mitchell, Braxton D and Morris, Andrew P and Mosekilde, Leif and Nethander, Maria and Newman, Anne B and O{\textquoteright}Connell, Jeffery R and Oostra, Ben A and Orwoll, Eric S and Palotie, Aarno and Peacock, Munro and Perola, Markus and Peters, Annette and Prince, Richard L and Psaty, Bruce M and R{\"a}ikk{\"o}nen, Katri and Ralston, Stuart H and Ripatti, Samuli and Rivadeneira, Fernando and Robbins, John A and Rotter, Jerome I and Rudan, Igor and Salomaa, Veikko and Satterfield, Suzanne and Schipf, Sabine and Shin, Chan Soo and Smith, Albert V and Smith, Shad B and Soranzo, Nicole and Spector, Timothy D and Stan{\v c}{\'a}kov{\'a}, Alena and Stefansson, Kari and Steinhagen-Thiessen, Elisabeth and Stolk, Lisette and Streeten, Elizabeth A and Styrkarsdottir, Unnur and Swart, Karin M A and Thompson, Patricia and Thomson, Cynthia A and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Tikkanen, Emmi and Tranah, Gregory J and Uitterlinden, Andr{\'e} G and van Duijn, Cornelia M and van Schoor, Natasja M and Vandenput, Liesbeth and Vollenweider, Peter and V{\"o}lzke, Henry and Wactawski-Wende, Jean and Walker, Mark and J Wareham, Nicholas and Waterworth, Dawn and Weedon, Michael N and Wichmann, H-Erich and Widen, Elisabeth and Williams, Frances M K and Wilson, James F and Wright, Nicole C and Yerges-Armstrong, Laura M and Yu, Lei and Zhang, Weihua and Zhao, Jing Hua and Zhou, Yanhua and Nielson, Carrie M and Harris, Tamara B and Demissie, Serkalem and Kiel, Douglas P and Ohlsson, Claes} } @article {8490, title = {The Polygenic and Monogenic Basis of Blood Traits and Diseases.}, journal = {Cell}, volume = {182}, year = {2020}, month = {2020 Sep 03}, pages = {1214-1231.e11}, abstract = {

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.

}, issn = {1097-4172}, doi = {10.1016/j.cell.2020.08.008}, author = {Vuckovic, Dragana and Bao, Erik L and Akbari, Parsa and Lareau, Caleb A and Mousas, Abdou and Jiang, Tao and Chen, Ming-Huei and Raffield, Laura M and Tardaguila, Manuel and Huffman, Jennifer E and Ritchie, Scott C and Megy, Karyn and Ponstingl, Hannes and Penkett, Christopher J and Albers, Patrick K and Wigdor, Emilie M and Sakaue, Saori and Moscati, Arden and Manansala, Regina and Lo, Ken Sin and Qian, Huijun and Akiyama, Masato and Bartz, Traci M and Ben-Shlomo, Yoav and Beswick, Andrew and Bork-Jensen, Jette and Bottinger, Erwin P and Brody, Jennifer A and van Rooij, Frank J A and Chitrala, Kumaraswamy N and Wilson, Peter W F and Choquet, Helene and Danesh, John and Di Angelantonio, Emanuele and Dimou, Niki and Ding, Jingzhong and Elliott, Paul and Esko, T{\~o}nu and Evans, Michele K and Felix, Stephan B and Floyd, James S and Broer, Linda and Grarup, Niels and Guo, Michael H and Guo, Qi and Greinacher, Andreas and Haessler, Jeff and Hansen, Torben and Howson, Joanna M M and Huang, Wei and Jorgenson, Eric and Kacprowski, Tim and K{\"a}h{\"o}nen, Mika and Kamatani, Yoichiro and Kanai, Masahiro and Karthikeyan, Savita and Koskeridis, Fotios and Lange, Leslie A and Lehtim{\"a}ki, Terho and Linneberg, Allan and Liu, Yongmei and Lyytik{\"a}inen, Leo-Pekka and Manichaikul, Ani and Matsuda, Koichi and Mohlke, Karen L and Mononen, Nina and Murakami, Yoshinori and Nadkarni, Girish N and Nikus, Kjell and Pankratz, Nathan and Pedersen, Oluf and Preuss, Michael and Psaty, Bruce M and Raitakari, Olli T and Rich, Stephen S and Rodriguez, Benjamin A T and Rosen, Jonathan D and Rotter, Jerome I and Schubert, Petra and Spracklen, Cassandra N and Surendran, Praveen and Tang, Hua and Tardif, Jean-Claude and Ghanbari, Mohsen and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Watkins, Nicholas A and Weiss, Stefan and Cai, Na and Kundu, Kousik and Watt, Stephen B and Walter, Klaudia and Zonderman, Alan B and Cho, Kelly and Li, Yun and Loos, Ruth J F and Knight, Julian C and Georges, Michel and Stegle, Oliver and Evangelou, Evangelos and Okada, Yukinori and Roberts, David J and Inouye, Michael and Johnson, Andrew D and Auer, Paul L and Astle, William J and Reiner, Alexander P and Butterworth, Adam S and Ouwehand, Willem H and Lettre, Guillaume and Sankaran, Vijay G and Soranzo, Nicole} } @article {8481, title = {Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations.}, journal = {Cell}, volume = {182}, year = {2020}, month = {2020 Sep 03}, pages = {1198-1213.e14}, abstract = {

Most loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p~< 5~{\texttimes} 10, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in~vivo and IL-7 secretion levels in~vitro. Fine-mapping prioritized variants annotated as functional and generated 95\% credible sets that were 30\% smaller when using the trans-ethnic as opposed to the EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies.

}, issn = {1097-4172}, doi = {10.1016/j.cell.2020.06.045}, author = {Chen, Ming-Huei and Raffield, Laura M and Mousas, Abdou and Sakaue, Saori and Huffman, Jennifer E and Moscati, Arden and Trivedi, Bhavi and Jiang, Tao and Akbari, Parsa and Vuckovic, Dragana and Bao, Erik L and Zhong, Xue and Manansala, Regina and Laplante, V{\'e}ronique and Chen, Minhui and Lo, Ken Sin and Qian, Huijun and Lareau, Caleb A and Beaudoin, M{\'e}lissa and Hunt, Karen A and Akiyama, Masato and Bartz, Traci M and Ben-Shlomo, Yoav and Beswick, Andrew and Bork-Jensen, Jette and Bottinger, Erwin P and Brody, Jennifer A and van Rooij, Frank J A and Chitrala, Kumaraswamynaidu and Cho, Kelly and Choquet, Helene and Correa, Adolfo and Danesh, John and Di Angelantonio, Emanuele and Dimou, Niki and Ding, Jingzhong and Elliott, Paul and Esko, T{\~o}nu and Evans, Michele K and Floyd, James S and Broer, Linda and Grarup, Niels and Guo, Michael H and Greinacher, Andreas and Haessler, Jeff and Hansen, Torben and Howson, Joanna M M and Huang, Qin Qin and Huang, Wei and Jorgenson, Eric and Kacprowski, Tim and K{\"a}h{\"o}nen, Mika and Kamatani, Yoichiro and Kanai, Masahiro and Karthikeyan, Savita and Koskeridis, Fotis and Lange, Leslie A and Lehtim{\"a}ki, Terho and Lerch, Markus M and Linneberg, Allan and Liu, Yongmei and Lyytik{\"a}inen, Leo-Pekka and Manichaikul, Ani and Martin, Hilary C and Matsuda, Koichi and Mohlke, Karen L and Mononen, Nina and Murakami, Yoshinori and Nadkarni, Girish N and Nauck, Matthias and Nikus, Kjell and Ouwehand, Willem H and Pankratz, Nathan and Pedersen, Oluf and Preuss, Michael and Psaty, Bruce M and Raitakari, Olli T and Roberts, David J and Rich, Stephen S and Rodriguez, Benjamin A T and Rosen, Jonathan D and Rotter, Jerome I and Schubert, Petra and Spracklen, Cassandra N and Surendran, Praveen and Tang, Hua and Tardif, Jean-Claude and Trembath, Richard C and Ghanbari, Mohsen and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Watkins, Nicholas A and Zonderman, Alan B and Wilson, Peter W F and Li, Yun and Butterworth, Adam S and Gauchat, Jean-Fran{\c c}ois and Chiang, Charleston W K and Li, Bingshan and Loos, Ruth J F and Astle, William J and Evangelou, Evangelos and van Heel, David A and Sankaran, Vijay G and Okada, Yukinori and Soranzo, Nicole and Johnson, Andrew D and Reiner, Alexander P and Auer, Paul L and Lettre, Guillaume} } @article {8779, title = {Whole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program.}, journal = {Am J Hum Genet}, volume = {108}, year = {2021}, month = {2021 05 06}, pages = {874-893}, abstract = {

Whole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3~bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.

}, keywords = {Adult, Aged, Chromosomes, Human, Pair 16, Datasets as Topic, Erythrocytes, Female, Gene Editing, Genetic Variation, Genome-Wide Association Study, HEK293 Cells, Humans, Male, Middle Aged, National Heart, Lung, and Blood Institute (U.S.), Phenotype, Quality Control, Reproducibility of Results, United States}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.04.003}, author = {Hu, Yao and Stilp, Adrienne M and McHugh, Caitlin P and Rao, Shuquan and Jain, Deepti and Zheng, Xiuwen and Lane, John and M{\'e}ric de Bellefon, S{\'e}bastian and Raffield, Laura M and Chen, Ming-Huei and Yanek, Lisa R and Wheeler, Marsha and Yao, Yao and Ren, Chunyan and Broome, Jai and Moon, Jee-Young and de Vries, Paul S and Hobbs, Brian D and Sun, Quan and Surendran, Praveen and Brody, Jennifer A and Blackwell, Thomas W and Choquet, Helene and Ryan, Kathleen and Duggirala, Ravindranath and Heard-Costa, Nancy and Wang, Zhe and Chami, Nathalie and Preuss, Michael H and Min, Nancy and Ekunwe, Lynette and Lange, Leslie A and Cushman, Mary and Faraday, Nauder and Curran, Joanne E and Almasy, Laura and Kundu, Kousik and Smith, Albert V and Gabriel, Stacey and Rotter, Jerome I and Fornage, Myriam and Lloyd-Jones, Donald M and Vasan, Ramachandran S and Smith, Nicholas L and North, Kari E and Boerwinkle, Eric and Becker, Lewis C and Lewis, Joshua P and Abecasis, Goncalo R and Hou, Lifang and O{\textquoteright}Connell, Jeffrey R and Morrison, Alanna C and Beaty, Terri H and Kaplan, Robert and Correa, Adolfo and Blangero, John and Jorgenson, Eric and Psaty, Bruce M and Kooperberg, Charles and Walton, Russell T and Kleinstiver, Benjamin P and Tang, Hua and Loos, Ruth J F and Soranzo, Nicole and Butterworth, Adam S and Nickerson, Debbie and Rich, Stephen S and Mitchell, Braxton D and Johnson, Andrew D and Auer, Paul L and Li, Yun and Mathias, Rasika A and Lettre, Guillaume and Pankratz, Nathan and Laurie, Cathy C and Laurie, Cecelia A and Bauer, Daniel E and Conomos, Matthew P and Reiner, Alexander P} } @article {8914, title = {Whole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program.}, journal = {Am J Hum Genet}, volume = {108}, year = {2021}, month = {2021 10 07}, pages = {1836-1851}, abstract = {

Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs.

}, keywords = {Asthma, Biomarkers, Dermatitis, Atopic, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Leukocytes, National Heart, Lung, and Blood Institute (U.S.), Phenotype, Polymorphism, Single Nucleotide, Prognosis, Proteome, Pulmonary Disease, Chronic Obstructive, Quantitative Trait Loci, United Kingdom, United States, Whole Genome Sequencing}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.08.007}, author = {Mikhaylova, Anna V and McHugh, Caitlin P and Polfus, Linda M and Raffield, Laura M and Boorgula, Meher Preethi and Blackwell, Thomas W and Brody, Jennifer A and Broome, Jai and Chami, Nathalie and Chen, Ming-Huei and Conomos, Matthew P and Cox, Corey and Curran, Joanne E and Daya, Michelle and Ekunwe, Lynette and Glahn, David C and Heard-Costa, Nancy and Highland, Heather M and Hobbs, Brian D and Ilboudo, Yann and Jain, Deepti and Lange, Leslie A and Miller-Fleming, Tyne W and Min, Nancy and Moon, Jee-Young and Preuss, Michael H and Rosen, Jonathon and Ryan, Kathleen and Smith, Albert V and Sun, Quan and Surendran, Praveen and de Vries, Paul S and Walter, Klaudia and Wang, Zhe and Wheeler, Marsha and Yanek, Lisa R and Zhong, Xue and Abecasis, Goncalo R and Almasy, Laura and Barnes, Kathleen C and Beaty, Terri H and Becker, Lewis C and Blangero, John and Boerwinkle, Eric and Butterworth, Adam S and Chavan, Sameer and Cho, Michael H and Choquet, Helene and Correa, Adolfo and Cox, Nancy and DeMeo, Dawn L and Faraday, Nauder and Fornage, Myriam and Gerszten, Robert E and Hou, Lifang and Johnson, Andrew D and Jorgenson, Eric and Kaplan, Robert and Kooperberg, Charles and Kundu, Kousik and Laurie, Cecelia A and Lettre, Guillaume and Lewis, Joshua P and Li, Bingshan and Li, Yun and Lloyd-Jones, Donald M and Loos, Ruth J F and Manichaikul, Ani and Meyers, Deborah A and Mitchell, Braxton D and Morrison, Alanna C and Ngo, Debby and Nickerson, Deborah A and Nongmaithem, Suraj and North, Kari E and O{\textquoteright}Connell, Jeffrey R and Ortega, Victor E and Pankratz, Nathan and Perry, James A and Psaty, Bruce M and Rich, Stephen S and Soranzo, Nicole and Rotter, Jerome I and Silverman, Edwin K and Smith, Nicholas L and Tang, Hua and Tracy, Russell P and Thornton, Timothy A and Vasan, Ramachandran S and Zein, Joe and Mathias, Rasika A and Reiner, Alexander P and Auer, Paul L} }