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1.  Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility 
Wessel, Jennifer | Chu, Audrey Y. | Willems, Sara M. | Wang, Shuai | Yaghootkar, Hanieh | Brody, Jennifer A. | Dauriz, Marco | Hivert, Marie-France | Raghavan, Sridharan | Lipovich, Leonard | Hidalgo, Bertha | Fox, Keolu | Huffman, Jennifer E. | An, Ping | Lu, Yingchang | Rasmussen-Torvik, Laura J. | Grarup, Niels | Ehm, Margaret G. | Li, Li | Baldridge, Abigail S. | Stančáková, Alena | Abrol, Ravinder | Besse, Céline | Boland, Anne | Bork-Jensen, Jette | Fornage, Myriam | Freitag, Daniel F. | Garcia, Melissa E. | Guo, Xiuqing | Hara, Kazuo | Isaacs, Aaron | Jakobsdottir, Johanna | Lange, Leslie A. | Layton, Jill C. | Li, Man | Zhao, Jing Hua | Meidtner, Karina | Morrison, Alanna C. | Nalls, Mike A. | Peters, Marjolein J. | Sabater-Lleal, Maria | Schurmann, Claudia | Silveira, Angela | Smith, Albert V. | Southam, Lorraine | Stoiber, Marcus H. | Strawbridge, Rona J. | Taylor, Kent D. | Varga, Tibor V. | Allin, Kristine H. | Amin, Najaf | Aponte, Jennifer L. | Aung, Tin | Barbieri, Caterina | Bihlmeyer, Nathan A. | Boehnke, Michael | Bombieri, Cristina | Bowden, Donald W. | Burns, Sean M. | Chen, Yuning | Chen, Yii-Der I. | Cheng, Ching-Yu | Correa, Adolfo | Czajkowski, Jacek | Dehghan, Abbas | Ehret, Georg B. | Eiriksdottir, Gudny | Escher, Stefan A. | Farmaki, Aliki-Eleni | Frånberg, Mattias | Gambaro, Giovanni | Giulianini, Franco | III, William A. Goddard | Goel, Anuj | Gottesman, Omri | Grove, Megan L. | Gustafsson, Stefan | Hai, Yang | Hallmans, Göran | Heo, Jiyoung | Hoffmann, Per | Ikram, Mohammad K. | Jensen, Richard A. | Jørgensen, Marit E. | Jørgensen, Torben | Karaleftheri, Maria | Khor, Chiea C. | Kirkpatrick, Andrea | Kraja, Aldi T. | Kuusisto, Johanna | Lange, Ethan M. | Lee, I.T. | Lee, Wen-Jane | Leong, Aaron | Liao, Jiemin | Liu, Chunyu | Liu, Yongmei | Lindgren, Cecilia M. | Linneberg, Allan | Malerba, Giovanni | Mamakou, Vasiliki | Marouli, Eirini | Maruthur, Nisa M. | Matchan, Angela | McKean, Roberta | McLeod, Olga | Metcalf, Ginger A. | Mohlke, Karen L. | Muzny, Donna M. | Ntalla, Ioanna | Palmer, Nicholette D. | Pasko, Dorota | Peter, Andreas | Rayner, Nigel W. | Renström, Frida | Rice, Ken | Sala, Cinzia F. | Sennblad, Bengt | Serafetinidis, Ioannis | Smith, Jennifer A. | Soranzo, Nicole | Speliotes, Elizabeth K. | Stahl, Eli A. | Stirrups, Kathleen | Tentolouris, Nikos | Thanopoulou, Anastasia | Torres, Mina | Traglia, Michela | Tsafantakis, Emmanouil | Javad, Sundas | Yanek, Lisa R. | Zengini, Eleni | Becker, Diane M. | Bis, Joshua C. | Brown, James B. | Cupples, L. Adrienne | Hansen, Torben | Ingelsson, Erik | Karter, Andrew J. | Lorenzo, Carlos | Mathias, Rasika A. | Norris, Jill M. | Peloso, Gina M. | Sheu, Wayne H.-H. | Toniolo, Daniela | Vaidya, Dhananjay | Varma, Rohit | Wagenknecht, Lynne E. | Boeing, Heiner | Bottinger, Erwin P. | Dedoussis, George | Deloukas, Panos | Ferrannini, Ele | Franco, Oscar H. | Franks, Paul W. | Gibbs, Richard A. | Gudnason, Vilmundur | Hamsten, Anders | Harris, Tamara B. | Hattersley, Andrew T. | Hayward, Caroline | Hofman, Albert | Jansson, Jan-Håkan | Langenberg, Claudia | Launer, Lenore J. | Levy, Daniel | Oostra, Ben A. | O'Donnell, Christopher J. | O'Rahilly, Stephen | Padmanabhan, Sandosh | Pankow, James S. | Polasek, Ozren | Province, Michael A. | Rich, Stephen S. | Ridker, Paul M | Rudan, Igor | Schulze, Matthias B. | Smith, Blair H. | Uitterlinden, André G. | Walker, Mark | Watkins, Hugh | Wong, Tien Y. | Zeggini, Eleftheria | Scotland, Generation | Laakso, Markku | Borecki, Ingrid B. | Chasman, Daniel I. | Pedersen, Oluf | Psaty, Bruce M. | Tai, E. Shyong | van Duijn, Cornelia M. | Wareham, Nicholas J. | Waterworth, Dawn M. | Boerwinkle, Eric | Kao, WH Linda | Florez, Jose C. | Loos, Ruth J.F. | Wilson, James G. | Frayling, Timothy M. | Siscovick, David S. | Dupuis, Josée | Rotter, Jerome I. | Meigs, James B. | Scott, Robert A. | Goodarzi, Mark O.
Nature communications  2015;6:5897.
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±0.01 mmol L−1, p=3.4×10−12), T2D risk (OR[95%CI]=0.86[0.76-0.96], p=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose−1, p=0.048), but higher 2-h glucose (β=0.16±0.05 mmol L−1, p=4.3×10−4). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8×10−6) 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±0.004 mmol L−1, p=1.3×10−8). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
doi:10.1038/ncomms6897
PMCID: PMC4311266  PMID: 25631608
2.  Genome-Wide Association Study for Circulating Tissue Plasminogen Activator (tPA) Levels and Functional Follow-up Implicates Endothelial STXBP5 and STX2 
Huang, Jie | Huffman, Jennifer E. | Yamkauchi, Munekazu | Trompet, Stella | Asselbergs, Folkert W. | Sabater-Lleal, Maria | Trégouët, David-Alexandre | Chen, Wei-Min | Smith, Nicholas L. | Kleber, Marcus E. | Shin, So-Youn | Becker, Diane M. | Tang, Weihong | Dehghan, Abbas | Johnson, Andrew D. | Truong, Vinh | Folkersen, Lasse | Yang, Qiong | Oudot-Mellakh, Tiphaine | Buckley, Brendan M. | Moore, Jason H. | Williams, Frances M.K. | Campbell, Harry | Silbernagel, Günther | Vitart, Veronique | Rudan, Igor | Tofler, Geoffrey H. | Navis, Gerjan J. | DeStefano, Anita | Wright, Alan F. | Chen, Ming-Huei | de Craen, Anton J.M. | Worrall, Bradford B. | Rudnicka, Alicja R. | Rumley, Ann | Bookman, Ebony B. | Psaty, Bruce M. | Chen, Fang | Keene, Keith L. | Franco, Oscar H. | Böhm, Bernhard O. | Uitterlinden, Andre G. | Carter, Angela M. | Jukema, J. Wouter | Sattar, Naveed | Bis, Joshua C. | Ikram, Mohammad A. | Sale, Michèle M. | McKnight, Barbara | Fornage, Myriam | Ford, Ian | Taylor, Kent | Slagboom, P. Eline | McArdle, Wendy L. | Hsu, Fang-Chi | Franco-Cereceda, Anders | Goodall, Alison H. | Yanek, Lisa R. | Furie, Karen L. | Cushman, Mary | Hofman, Albert | Witteman, Jacqueline CM. | Folsom, Aaron R. | Basu, Saonli | Matijevic, Nena | van Gilst, Wiek H. | Wilson, James F. | Westendorp, Rudi G.J. | Kathiresan, Sekar | Reilly, Muredach P. | Tracy, Russell P. | Polasek, Ozren | Winkelmann, Bernhard R. | Grant, Peter J. | Hillege, Hans L. | Cambien, Francois | Stott, David J. | Lowe, Gordon D. | Spector, Timothy D. | Meigs, James B. | Marz, Winfried | Eriksson, Per | Becker, Lewis C. | Morange, Pierre-Emmanuel | Soranzo, Nicole | Williams, Scott M. | Hayward, Caroline | van der Harst, Pim | Hamsten, Anders | Lowenstein, Charles J. | Strachan, David P. | O'Donnell, Christopher J.
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 (CVD). We conducted a meta-analysis of genome-wide association studies (GWAS) 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 <5.0×10−8). The first locus is on 6q24.3, with the lead SNP (rs9399599, P=2.9×10−14) within STXBP5. The second locus is on 8p11.21. The lead SNP (rs3136739, P=1.3×10−9) is intronic to POLB and less than 200kb away from the tPA encoding gene PLAT. We identified a non-synonymous SNP (rs2020921) in modest LD with rs3136739 (r2 = 0.50) within exon 5 of PLAT (P=2.0×10−8). The third locus is on 12q24.33, with the lead SNP (rs7301826, P=1.0×10−9) within intron 7 of STX2. We further found evidence for association of lead SNPs in STXBP5 and STX2 with expression levels of the respective transcripts. In in vitro cell studies, silencing STXBP5 decreased release of tPA from vascular endothelial cells, while silencing of STX2 increased tPA release. Through an in-silico lookup, we found no associations of the three lead SNPs with coronary artery disease or stroke.
Conclusions
We identified three 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.
doi:10.1161/ATVBAHA.113.302088
PMCID: PMC4009733  PMID: 24578379
tissue plasminogen activator; genome-wide association study; meta-analysis; cardiovascular disease risk; fibrinolysis; hemostasis
3.  Defining the role of common variation in the genomic and biological architecture of adult human height 
Wood, Andrew R | Esko, Tonu | Yang, Jian | Vedantam, Sailaja | Pers, Tune H | Gustafsson, Stefan | Chu, Audrey Y | Estrada, Karol | Luan, Jian’an | Kutalik, Zoltán | Amin, Najaf | Buchkovich, Martin L | Croteau-Chonka, Damien C | Day, Felix R | Duan, Yanan | Fall, Tove | Fehrmann, Rudolf | Ferreira, Teresa | Jackson, Anne U | Karjalainen, Juha | Lo, Ken Sin | Locke, Adam E | Mägi, Reedik | Mihailov, Evelin | Porcu, Eleonora | Randall, Joshua C | Scherag, André | Vinkhuyzen, Anna AE | Westra, Harm-Jan | Winkler, Thomas W | Workalemahu, Tsegaselassie | Zhao, Jing Hua | Absher, Devin | Albrecht, Eva | Anderson, Denise | Baron, Jeffrey | Beekman, Marian | Demirkan, Ayse | Ehret, Georg B | Feenstra, Bjarke | Feitosa, Mary F | Fischer, Krista | Fraser, Ross M | Goel, Anuj | Gong, Jian | Justice, Anne E | Kanoni, Stavroula | Kleber, Marcus E | Kristiansson, Kati | Lim, Unhee | Lotay, Vaneet | Lui, Julian C | Mangino, Massimo | Leach, Irene Mateo | Medina-Gomez, Carolina | Nalls, Michael A | Nyholt, Dale R | Palmer, Cameron D | Pasko, Dorota | Pechlivanis, Sonali | Prokopenko, Inga | Ried, Janina S | Ripke, Stephan | Shungin, Dmitry | Stancáková, Alena | Strawbridge, Rona J | Sung, Yun Ju | Tanaka, Toshiko | Teumer, Alexander | Trompet, Stella | van der Laan, Sander W | van Setten, Jessica | Van Vliet-Ostaptchouk, Jana V | Wang, Zhaoming | Yengo, Loïc | Zhang, Weihua | Afzal, Uzma | Ärnlöv, Johan | Arscott, Gillian M | Bandinelli, Stefania | Barrett, Amy | Bellis, Claire | Bennett, Amanda J | Berne, Christian | Blüher, Matthias | Bolton, Jennifer L | Böttcher, Yvonne | Boyd, Heather A | Bruinenberg, Marcel | Buckley, Brendan M | Buyske, Steven | Caspersen, Ida H | Chines, Peter S | Clarke, Robert | Claudi-Boehm, Simone | Cooper, Matthew | Daw, E Warwick | De Jong, Pim A | Deelen, Joris | Delgado, Graciela | Denny, Josh C | Dhonukshe-Rutten, Rosalie | Dimitriou, Maria | Doney, Alex SF | Dörr, Marcus | Eklund, Niina | Eury, Elodie | Folkersen, Lasse | Garcia, Melissa E | Geller, Frank | Giedraitis, Vilmantas | Go, Alan S | Grallert, Harald | Grammer, Tanja B | Gräßler, Jürgen | Grönberg, Henrik | de Groot, Lisette C.P.G.M. | Groves, Christopher J | Haessler, Jeffrey | Hall, Per | Haller, Toomas | Hallmans, Goran | Hannemann, Anke | Hartman, Catharina A | Hassinen, Maija | Hayward, Caroline | Heard-Costa, Nancy L | Helmer, Quinta | Hemani, Gibran | Henders, Anjali K | Hillege, Hans L | Hlatky, Mark A | Hoffmann, Wolfgang | Hoffmann, Per | Holmen, Oddgeir | Houwing-Duistermaat, Jeanine J | Illig, Thomas | Isaacs, Aaron | James, Alan L | Jeff, Janina | Johansen, Berit | Johansson, Åsa | Jolley, Jennifer | Juliusdottir, Thorhildur | Junttila, Juhani | Kho, Abel N | Kinnunen, Leena | Klopp, Norman | Kocher, Thomas | Kratzer, Wolfgang | Lichtner, Peter | Lind, Lars | Lindström, Jaana | Lobbens, Stéphane | Lorentzon, Mattias | Lu, Yingchang | Lyssenko, Valeriya | Magnusson, Patrik KE | Mahajan, Anubha | Maillard, Marc | McArdle, Wendy L | McKenzie, Colin A | McLachlan, Stela | McLaren, Paul J | Menni, Cristina | Merger, Sigrun | Milani, Lili | Moayyeri, Alireza | Monda, Keri L | Morken, Mario A | Müller, Gabriele | Müller-Nurasyid, Martina | Musk, Arthur W | Narisu, Narisu | Nauck, Matthias | Nolte, Ilja M | Nöthen, Markus M | Oozageer, Laticia | Pilz, Stefan | Rayner, Nigel W | Renstrom, Frida | Robertson, Neil R | Rose, Lynda M | Roussel, Ronan | Sanna, Serena | Scharnagl, Hubert | Scholtens, Salome | Schumacher, Fredrick R | Schunkert, Heribert | Scott, Robert A | Sehmi, Joban | Seufferlein, Thomas | Shi, Jianxin | Silventoinen, Karri | Smit, Johannes H | Smith, Albert Vernon | Smolonska, Joanna | Stanton, Alice V | Stirrups, Kathleen | Stott, David J | Stringham, Heather M | Sundström, Johan | Swertz, Morris A | Syvänen, Ann-Christine | Tayo, Bamidele O | Thorleifsson, Gudmar | Tyrer, Jonathan P | van Dijk, Suzanne | van Schoor, Natasja M | van der Velde, Nathalie | van Heemst, Diana | van Oort, Floor VA | Vermeulen, Sita H | Verweij, Niek | Vonk, Judith M | Waite, Lindsay L | Waldenberger, Melanie | Wennauer, Roman | Wilkens, Lynne R | Willenborg, Christina | Wilsgaard, Tom | Wojczynski, Mary K | Wong, Andrew | Wright, Alan F | Zhang, Qunyuan | Arveiler, Dominique | Bakker, Stephan JL | Beilby, John | Bergman, Richard N | Bergmann, Sven | Biffar, Reiner | Blangero, John | Boomsma, Dorret I | Bornstein, Stefan R | Bovet, Pascal | Brambilla, Paolo | Brown, Morris J | Campbell, Harry | Caulfield, Mark J | Chakravarti, Aravinda | Collins, Rory | Collins, Francis S | Crawford, Dana C | Cupples, L Adrienne | Danesh, John | de Faire, Ulf | den Ruijter, Hester M | Erbel, Raimund | Erdmann, Jeanette | Eriksson, Johan G | Farrall, Martin | Ferrannini, Ele | Ferrières, Jean | Ford, Ian | Forouhi, Nita G | Forrester, Terrence | Gansevoort, Ron T | Gejman, Pablo V | Gieger, Christian | Golay, Alain | Gottesman, Omri | Gudnason, Vilmundur | Gyllensten, Ulf | Haas, David W | Hall, Alistair S | Harris, Tamara B | Hattersley, Andrew T | Heath, Andrew C | Hengstenberg, Christian | Hicks, Andrew A | Hindorff, Lucia A | Hingorani, Aroon D | Hofman, Albert | Hovingh, G Kees | Humphries, Steve E | Hunt, Steven C | Hypponen, Elina | Jacobs, Kevin B | Jarvelin, Marjo-Riitta | Jousilahti, Pekka | Jula, Antti M | Kaprio, Jaakko | Kastelein, John JP | Kayser, Manfred | Kee, Frank | Keinanen-Kiukaanniemi, Sirkka M | Kiemeney, Lambertus A | Kooner, Jaspal S | Kooperberg, Charles | Koskinen, Seppo | Kovacs, Peter | Kraja, Aldi T | Kumari, Meena | Kuusisto, Johanna | Lakka, Timo A | Langenberg, Claudia | Le Marchand, Loic | Lehtimäki, Terho | Lupoli, Sara | Madden, Pamela AF | Männistö, Satu | Manunta, Paolo | Marette, André | Matise, Tara C | McKnight, Barbara | Meitinger, Thomas | Moll, Frans L | Montgomery, Grant W | Morris, Andrew D | Morris, Andrew P | Murray, Jeffrey C | Nelis, Mari | Ohlsson, Claes | Oldehinkel, Albertine J | Ong, Ken K | Ouwehand, Willem H | Pasterkamp, Gerard | Peters, Annette | Pramstaller, Peter P | Price, Jackie F | Qi, Lu | Raitakari, Olli T | Rankinen, Tuomo | Rao, DC | Rice, Treva K | Ritchie, Marylyn | Rudan, Igor | Salomaa, Veikko | Samani, Nilesh J | Saramies, Jouko | Sarzynski, Mark A | Schwarz, Peter EH | Sebert, Sylvain | Sever, Peter | Shuldiner, Alan R | Sinisalo, Juha | Steinthorsdottir, Valgerdur | Stolk, Ronald P | Tardif, Jean-Claude | Tönjes, Anke | Tremblay, Angelo | Tremoli, Elena | Virtamo, Jarmo | Vohl, Marie-Claude | Amouyel, Philippe | Asselbergs, Folkert W | Assimes, Themistocles L | Bochud, Murielle | Boehm, Bernhard O | Boerwinkle, Eric | Bottinger, Erwin P | Bouchard, Claude | Cauchi, Stéphane | Chambers, John C | Chanock, Stephen J | Cooper, Richard S | de Bakker, Paul IW | Dedoussis, George | Ferrucci, Luigi | Franks, Paul W | Froguel, Philippe | Groop, Leif C | Haiman, Christopher A | Hamsten, Anders | Hayes, M Geoffrey | Hui, Jennie | Hunter, David J. | Hveem, Kristian | Jukema, J Wouter | Kaplan, Robert C | Kivimaki, Mika | Kuh, Diana | Laakso, Markku | Liu, Yongmei | Martin, Nicholas G | März, Winfried | Melbye, Mads | Moebus, Susanne | Munroe, Patricia B | Njølstad, Inger | Oostra, Ben A | Palmer, Colin NA | Pedersen, Nancy L | Perola, Markus | Pérusse, Louis | Peters, Ulrike | Powell, Joseph E | Power, Chris | Quertermous, Thomas | Rauramaa, Rainer | Reinmaa, Eva | Ridker, Paul M | Rivadeneira, Fernando | Rotter, Jerome I | Saaristo, Timo E | Saleheen, Danish | Schlessinger, David | Slagboom, P Eline | Snieder, Harold | Spector, Tim D | Strauch, Konstantin | Stumvoll, Michael | Tuomilehto, Jaakko | Uusitupa, Matti | van der Harst, Pim | Völzke, Henry | Walker, Mark | Wareham, Nicholas J | Watkins, Hugh | Wichmann, H-Erich | Wilson, James F | Zanen, Pieter | Deloukas, Panos | Heid, Iris M | Lindgren, Cecilia M | Mohlke, Karen L | Speliotes, Elizabeth K | Thorsteinsdottir, Unnur | Barroso, Inês | Fox, Caroline S | North, Kari E | Strachan, David P | Beckmann, Jacques S. | Berndt, Sonja I | Boehnke, Michael | Borecki, Ingrid B | McCarthy, Mark I | Metspalu, Andres | Stefansson, Kari | Uitterlinden, André G | van Duijn, Cornelia M | Franke, Lude | Willer, Cristen J | Price, Alkes L. | Lettre, Guillaume | Loos, Ruth JF | Weedon, Michael N | Ingelsson, Erik | O’Connell, Jeffrey R | Abecasis, Goncalo R | Chasman, Daniel I | Goddard, Michael E | Visscher, Peter M | Hirschhorn, Joel N | Frayling, Timothy M
Nature genetics  2014;46(11):1173-1186.
Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explain one-fifth of heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ~2,000, ~3,700 and ~9,500 SNPs explained ~21%, ~24% and ~29% of phenotypic variance. Furthermore, all common variants together captured the majority (60%) of heritability. The 697 variants clustered in 423 loci enriched for genes, pathways, and tissue-types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/beta-catenin, and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
doi:10.1038/ng.3097
PMCID: PMC4250049  PMID: 25282103
4.  Defining the role of common variation in the genomic and biological architecture of adult human height 
Wood, Andrew R | Esko, Tonu | Yang, Jian | Vedantam, Sailaja | Pers, Tune H | Gustafsson, Stefan | Chu, Audrey Y | Estrada, Karol | Luan, Jian’an | Kutalik, Zoltán | Amin, Najaf | Buchkovich, Martin L | Croteau-Chonka, Damien C | Day, Felix R | Duan, Yanan | Fall, Tove | Fehrmann, Rudolf | Ferreira, Teresa | Jackson, Anne U | Karjalainen, Juha | Lo, Ken Sin | Locke, Adam E | Mägi, Reedik | Mihailov, Evelin | Porcu, Eleonora | Randall, Joshua C | Scherag, André | Vinkhuyzen, Anna AE | Westra, Harm-Jan | Winkler, Thomas W | Workalemahu, Tsegaselassie | Zhao, Jing Hua | Absher, Devin | Albrecht, Eva | Anderson, Denise | Baron, Jeffrey | Beekman, Marian | Demirkan, Ayse | Ehret, Georg B | Feenstra, Bjarke | Feitosa, Mary F | Fischer, Krista | Fraser, Ross M | Goel, Anuj | Gong, Jian | Justice, Anne E | Kanoni, Stavroula | Kleber, Marcus E | Kristiansson, Kati | Lim, Unhee | Lotay, Vaneet | Lui, Julian C | Mangino, Massimo | Leach, Irene Mateo | Medina-Gomez, Carolina | Nalls, Michael A | Nyholt, Dale R | Palmer, Cameron D | Pasko, Dorota | Pechlivanis, Sonali | Prokopenko, Inga | Ried, Janina S | Ripke, Stephan | Shungin, Dmitry | Stancáková, Alena | Strawbridge, Rona J | Sung, Yun Ju | Tanaka, Toshiko | Teumer, Alexander | Trompet, Stella | van der Laan, Sander W | van Setten, Jessica | Van Vliet-Ostaptchouk, Jana V | Wang, Zhaoming | Yengo, Loïc | Zhang, Weihua | Afzal, Uzma | Ärnlöv, Johan | Arscott, Gillian M | Bandinelli, Stefania | Barrett, Amy | Bellis, Claire | Bennett, Amanda J | Berne, Christian | Blüher, Matthias | Bolton, Jennifer L | Böttcher, Yvonne | Boyd, Heather A | Bruinenberg, Marcel | Buckley, Brendan M | Buyske, Steven | Caspersen, Ida H | Chines, Peter S | Clarke, Robert | Claudi-Boehm, Simone | Cooper, Matthew | Daw, E Warwick | De Jong, Pim A | Deelen, Joris | Delgado, Graciela | Denny, Josh C | Dhonukshe-Rutten, Rosalie | Dimitriou, Maria | Doney, Alex SF | Dörr, Marcus | Eklund, Niina | Eury, Elodie | Folkersen, Lasse | Garcia, Melissa E | Geller, Frank | Giedraitis, Vilmantas | Go, Alan S | Grallert, Harald | Grammer, Tanja B | Gräßler, Jürgen | Grönberg, Henrik | de Groot, Lisette C.P.G.M. | Groves, Christopher J | Haessler, Jeffrey | Hall, Per | Haller, Toomas | Hallmans, Goran | Hannemann, Anke | Hartman, Catharina A | Hassinen, Maija | Hayward, Caroline | Heard-Costa, Nancy L | Helmer, Quinta | Hemani, Gibran | Henders, Anjali K | Hillege, Hans L | Hlatky, Mark A | Hoffmann, Wolfgang | Hoffmann, Per | Holmen, Oddgeir | Houwing-Duistermaat, Jeanine J | Illig, Thomas | Isaacs, Aaron | James, Alan L | Jeff, Janina | Johansen, Berit | Johansson, Åsa | Jolley, Jennifer | Juliusdottir, Thorhildur | Junttila, Juhani | Kho, Abel N | Kinnunen, Leena | Klopp, Norman | Kocher, Thomas | Kratzer, Wolfgang | Lichtner, Peter | Lind, Lars | Lindström, Jaana | Lobbens, Stéphane | Lorentzon, Mattias | Lu, Yingchang | Lyssenko, Valeriya | Magnusson, Patrik KE | Mahajan, Anubha | Maillard, Marc | McArdle, Wendy L | McKenzie, Colin A | McLachlan, Stela | McLaren, Paul J | Menni, Cristina | Merger, Sigrun | Milani, Lili | Moayyeri, Alireza | Monda, Keri L | Morken, Mario A | Müller, Gabriele | Müller-Nurasyid, Martina | Musk, Arthur W | Narisu, Narisu | Nauck, Matthias | Nolte, Ilja M | Nöthen, Markus M | Oozageer, Laticia | Pilz, Stefan | Rayner, Nigel W | Renstrom, Frida | Robertson, Neil R | Rose, Lynda M | Roussel, Ronan | Sanna, Serena | Scharnagl, Hubert | Scholtens, Salome | Schumacher, Fredrick R | Schunkert, Heribert | Scott, Robert A | Sehmi, Joban | Seufferlein, Thomas | Shi, Jianxin | Silventoinen, Karri | Smit, Johannes H | Smith, Albert Vernon | Smolonska, Joanna | Stanton, Alice V | Stirrups, Kathleen | Stott, David J | Stringham, Heather M | Sundström, Johan | Swertz, Morris A | Syvänen, Ann-Christine | Tayo, Bamidele O | Thorleifsson, Gudmar | Tyrer, Jonathan P | van Dijk, Suzanne | van Schoor, Natasja M | van der Velde, Nathalie | van Heemst, Diana | van Oort, Floor VA | Vermeulen, Sita H | Verweij, Niek | Vonk, Judith M | Waite, Lindsay L | Waldenberger, Melanie | Wennauer, Roman | Wilkens, Lynne R | Willenborg, Christina | Wilsgaard, Tom | Wojczynski, Mary K | Wong, Andrew | Wright, Alan F | Zhang, Qunyuan | Arveiler, Dominique | Bakker, Stephan JL | Beilby, John | Bergman, Richard N | Bergmann, Sven | Biffar, Reiner | Blangero, John | Boomsma, Dorret I | Bornstein, Stefan R | Bovet, Pascal | Brambilla, Paolo | Brown, Morris J | Campbell, Harry | Caulfield, Mark J | Chakravarti, Aravinda | Collins, Rory | Collins, Francis S | Crawford, Dana C | Cupples, L Adrienne | Danesh, John | de Faire, Ulf | den Ruijter, Hester M | Erbel, Raimund | Erdmann, Jeanette | Eriksson, Johan G | Farrall, Martin | Ferrannini, Ele | Ferrières, Jean | Ford, Ian | Forouhi, Nita G | Forrester, Terrence | Gansevoort, Ron T | Gejman, Pablo V | Gieger, Christian | Golay, Alain | Gottesman, Omri | Gudnason, Vilmundur | Gyllensten, Ulf | Haas, David W | Hall, Alistair S | Harris, Tamara B | Hattersley, Andrew T | Heath, Andrew C | Hengstenberg, Christian | Hicks, Andrew A | Hindorff, Lucia A | Hingorani, Aroon D | Hofman, Albert | Hovingh, G Kees | Humphries, Steve E | Hunt, Steven C | Hypponen, Elina | Jacobs, Kevin B | Jarvelin, Marjo-Riitta | Jousilahti, Pekka | Jula, Antti M | Kaprio, Jaakko | Kastelein, John JP | Kayser, Manfred | Kee, Frank | Keinanen-Kiukaanniemi, Sirkka M | Kiemeney, Lambertus A | Kooner, Jaspal S | Kooperberg, Charles | Koskinen, Seppo | Kovacs, Peter | Kraja, Aldi T | Kumari, Meena | Kuusisto, Johanna | Lakka, Timo A | Langenberg, Claudia | Le Marchand, Loic | Lehtimäki, Terho | Lupoli, Sara | Madden, Pamela AF | Männistö, Satu | Manunta, Paolo | Marette, André | Matise, Tara C | McKnight, Barbara | Meitinger, Thomas | Moll, Frans L | Montgomery, Grant W | Morris, Andrew D | Morris, Andrew P | Murray, Jeffrey C | Nelis, Mari | Ohlsson, Claes | Oldehinkel, Albertine J | Ong, Ken K | Ouwehand, Willem H | Pasterkamp, Gerard | Peters, Annette | Pramstaller, Peter P | Price, Jackie F | Qi, Lu | Raitakari, Olli T | Rankinen, Tuomo | Rao, DC | Rice, Treva K | Ritchie, Marylyn | Rudan, Igor | Salomaa, Veikko | Samani, Nilesh J | Saramies, Jouko | Sarzynski, Mark A | Schwarz, Peter EH | Sebert, Sylvain | Sever, Peter | Shuldiner, Alan R | Sinisalo, Juha | Steinthorsdottir, Valgerdur | Stolk, Ronald P | Tardif, Jean-Claude | Tönjes, Anke | Tremblay, Angelo | Tremoli, Elena | Virtamo, Jarmo | Vohl, Marie-Claude | Amouyel, Philippe | Asselbergs, Folkert W | Assimes, Themistocles L | Bochud, Murielle | Boehm, Bernhard O | Boerwinkle, Eric | Bottinger, Erwin P | Bouchard, Claude | Cauchi, Stéphane | Chambers, John C | Chanock, Stephen J | Cooper, Richard S | de Bakker, Paul IW | Dedoussis, George | Ferrucci, Luigi | Franks, Paul W | Froguel, Philippe | Groop, Leif C | Haiman, Christopher A | Hamsten, Anders | Hayes, M Geoffrey | Hui, Jennie | Hunter, David J. | Hveem, Kristian | Jukema, J Wouter | Kaplan, Robert C | Kivimaki, Mika | Kuh, Diana | Laakso, Markku | Liu, Yongmei | Martin, Nicholas G | März, Winfried | Melbye, Mads | Moebus, Susanne | Munroe, Patricia B | Njølstad, Inger | Oostra, Ben A | Palmer, Colin NA | Pedersen, Nancy L | Perola, Markus | Pérusse, Louis | Peters, Ulrike | Powell, Joseph E | Power, Chris | Quertermous, Thomas | Rauramaa, Rainer | Reinmaa, Eva | Ridker, Paul M | Rivadeneira, Fernando | Rotter, Jerome I | Saaristo, Timo E | Saleheen, Danish | Schlessinger, David | Slagboom, P Eline | Snieder, Harold | Spector, Tim D | Strauch, Konstantin | Stumvoll, Michael | Tuomilehto, Jaakko | Uusitupa, Matti | van der Harst, Pim | Völzke, Henry | Walker, Mark | Wareham, Nicholas J | Watkins, Hugh | Wichmann, H-Erich | Wilson, James F | Zanen, Pieter | Deloukas, Panos | Heid, Iris M | Lindgren, Cecilia M | Mohlke, Karen L | Speliotes, Elizabeth K | Thorsteinsdottir, Unnur | Barroso, Inês | Fox, Caroline S | North, Kari E | Strachan, David P | Beckmann, Jacques S. | Berndt, Sonja I | Boehnke, Michael | Borecki, Ingrid B | McCarthy, Mark I | Metspalu, Andres | Stefansson, Kari | Uitterlinden, André G | van Duijn, Cornelia M | Franke, Lude | Willer, Cristen J | Price, Alkes L. | Lettre, Guillaume | Loos, Ruth JF | Weedon, Michael N | Ingelsson, Erik | O’Connell, Jeffrey R | Abecasis, Goncalo R | Chasman, Daniel I | Goddard, Michael E | Visscher, Peter M | Hirschhorn, Joel N | Frayling, Timothy M
Nature genetics  2014;46(11):1173-1186.
Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explain one-fifth of heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ~2,000, ~3,700 and ~9,500 SNPs explained ~21%, ~24% and ~29% of phenotypic variance. Furthermore, all common variants together captured the majority (60%) of heritability. The 697 variants clustered in 423 loci enriched for genes, pathways, and tissue-types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/beta-catenin, and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
doi:10.1038/ng.3097
PMCID: PMC4250049  PMID: 25282103
5.  Genomic prediction of complex human traits: relatedness, trait architecture and predictive meta-models 
Human Molecular Genetics  2015;24(14):4167-4182.
We explore the prediction of individuals' phenotypes for complex traits using genomic data. We compare several widely used prediction models, including Ridge Regression, LASSO and Elastic Nets estimated from cohort data, and polygenic risk scores constructed using published summary statistics from genome-wide association meta-analyses (GWAMA). We evaluate the interplay between relatedness, trait architecture and optimal marker density, by predicting height, body mass index (BMI) and high-density lipoprotein level (HDL) in two data cohorts, originating from Croatia and Scotland. We empirically demonstrate that dense models are better when all genetic effects are small (height and BMI) and target individuals are related to the training samples, while sparse models predict better in unrelated individuals and when some effects have moderate size (HDL). For HDL sparse models achieved good across-cohort prediction, performing similarly to the GWAMA risk score and to models trained within the same cohort, which indicates that, for predicting traits with moderately sized effects, large sample sizes and familial structure become less important, though still potentially useful. Finally, we propose a novel ensemble of whole-genome predictors with GWAMA risk scores and demonstrate that the resulting meta-model achieves higher prediction accuracy than either model on its own. We conclude that although current genomic predictors are not accurate enough for diagnostic purposes, performance can be improved without requiring access to large-scale individual-level data. Our methodologically simple meta-model is a means of performing predictive meta-analysis for optimizing genomic predictions and can be easily extended to incorporate multiple population-level summary statistics or other domain knowledge.
doi:10.1093/hmg/ddv145
PMCID: PMC4476450  PMID: 25918167
6.  Prevalence of rheumatoid arthritis in low– and middle–income countries: A systematic review and analysis 
Journal of Global Health  null;5(1):010409.
Background
Rheumatoid arthritis (RA) is an autoimmune disorder that affects the small joints of the body. It is one of the leading causes of chronic morbidity in high–income countries, but little is known about the burden of this disease in low– and middle–income countries (LMIC).
Methods
The aim of this study was to estimate the prevalence of RA in six of the World Health Organization's (WHO) regions that harbour LMIC by identifying all relevant studies in those regions. To accomplish this aim various bibliographic databases were searched: PubMed, EMBASE, Global Health, LILACS and the Chinese databases CNKI and WanFang. Studies were selected based on pre–defined inclusion criteria, including a definition of RA based on the 1987 revision of the American College of Rheumatology (ACR) definition.
Results
Meta–estimates of regional RA prevalence rates for countries of low or middle income were 0.40% (95% CI: 0.23–0.57%) for Southeast Asian, 0.37% (95% CI: 0.23–0.51%) for Eastern Mediterranean, 0.62% (95% CI: 0.47–0.77%) for European, 1.25% (95% CI: 0.64–1.86%) for American and 0.42% (95% CI: 0.30–0.53%) for Western Pacific regions. A formal meta–analysis could not be performed for the sub–Saharan African region due to limited data. Male prevalence of RA in LMIC was 0.16% (95% CI: 0.11–0.20%) while the prevalence in women reached 0.75% (95% CI: 0.60–0.90%). This difference between males and females was statistically significant (P < 0.0001). The prevalence of RA did not differ significantly between urban and rural settings (P = 0.353). These prevalence estimates represent 2.60 (95% CI: 1.85–3.34%) million male sufferers and 12.21 (95% CI: 9.78–14.67%) million female sufferers in LMIC in the year 2000, and 3.16 (95% CI: 2.25–4.05%) million affected males and 14.87 (95% CI: 11.91–17.86%) million affected females in LMIC in the year 2010.
Conclusion
Given that majority of the world’s population resides in LMIC, the number of affected people is substantial, with a projection to increase in the coming years. Therefore, policy makers and health–care providers need to plan to address a significant disease burden both socially and economically.
doi:10.7189/jogh.05.010409
PMCID: PMC4416333  PMID: 25969732
7.  Genetic studies of body mass index yield new insights for obesity biology 
Locke, Adam E. | Kahali, Bratati | Berndt, Sonja I. | Justice, Anne E. | Pers, Tune H. | Day, Felix R. | Powell, Corey | Vedantam, Sailaja | Buchkovich, Martin L. | Yang, Jian | Croteau-Chonka, Damien C. | Esko, Tonu | Fall, Tove | Ferreira, Teresa | Gustafsson, Stefan | Kutalik, Zoltán | Luan, Jian’an | Mägi, Reedik | Randall, Joshua C. | Winkler, Thomas W. | Wood, Andrew R. | Workalemahu, Tsegaselassie | Faul, Jessica D. | Smith, Jennifer A. | Zhao, Jing Hua | Zhao, Wei | Chen, Jin | Fehrmann, Rudolf | Hedman, Åsa K. | Karjalainen, Juha | Schmidt, Ellen M. | Absher, Devin | Amin, Najaf | Anderson, Denise | Beekman, Marian | Bolton, Jennifer L. | Bragg-Gresham, Jennifer L. | Buyske, Steven | Demirkan, Ayse | Deng, Guohong | Ehret, Georg B. | Feenstra, Bjarke | Feitosa, Mary F. | Fischer, Krista | Goel, Anuj | Gong, Jian | Jackson, Anne U. | Kanoni, Stavroula | Kleber, Marcus E. | Kristiansson, Kati | Lim, Unhee | Lotay, Vaneet | Mangino, Massimo | Leach, Irene Mateo | Medina-Gomez, Carolina | Medland, Sarah E. | Nalls, Michael A. | Palmer, Cameron D. | Pasko, Dorota | Pechlivanis, Sonali | Peters, Marjolein J. | Prokopenko, Inga | Shungin, Dmitry | Stančáková, Alena | Strawbridge, Rona J. | Sung, Yun Ju | Tanaka, Toshiko | Teumer, Alexander | Trompet, Stella | van der Laan, Sander W. | van Setten, Jessica | Van Vliet-Ostaptchouk, Jana V. | Wang, Zhaoming | Yengo, Loïc | Zhang, Weihua | Isaacs, Aaron | Albrecht, Eva | Ärnlöv, Johan | Arscott, Gillian M. | Attwood, Antony P. | Bandinelli, Stefania | Barrett, Amy | Bas, Isabelita N. | Bellis, Claire | Bennett, Amanda J. | Berne, Christian | Blagieva, Roza | Blüher, Matthias | Böhringer, Stefan | Bonnycastle, Lori L. | Böttcher, Yvonne | Boyd, Heather A. | Bruinenberg, Marcel | Caspersen, Ida H. | Chen, Yii-Der Ida | Clarke, Robert | Daw, E. Warwick | de Craen, Anton J. M. | Delgado, Graciela | Dimitriou, Maria | Doney, Alex S. F. | Eklund, Niina | Estrada, Karol | Eury, Elodie | Folkersen, Lasse | Fraser, Ross M. | Garcia, Melissa E. | Geller, Frank | Giedraitis, Vilmantas | Gigante, Bruna | Go, Alan S. | Golay, Alain | Goodall, Alison H. | Gordon, Scott D. | Gorski, Mathias | Grabe, Hans-Jörgen | Grallert, Harald | Grammer, Tanja B. | Gräßler, Jürgen | Grönberg, Henrik | Groves, Christopher J. | Gusto, Gaëlle | Haessler, Jeffrey | Hall, Per | Haller, Toomas | Hallmans, Goran | Hartman, Catharina A. | Hassinen, Maija | Hayward, Caroline | Heard-Costa, Nancy L. | Helmer, Quinta | Hengstenberg, Christian | Holmen, Oddgeir | Hottenga, Jouke-Jan | James, Alan L. | Jeff, Janina M. | Johansson, Åsa | Jolley, Jennifer | Juliusdottir, Thorhildur | Kinnunen, Leena | Koenig, Wolfgang | Koskenvuo, Markku | Kratzer, Wolfgang | Laitinen, Jaana | Lamina, Claudia | Leander, Karin | Lee, Nanette R. | Lichtner, Peter | Lind, Lars | Lindström, Jaana | Lo, Ken Sin | Lobbens, Stéphane | Lorbeer, Roberto | Lu, Yingchang | Mach, François | Magnusson, Patrik K. E. | Mahajan, Anubha | McArdle, Wendy L. | McLachlan, Stela | Menni, Cristina | Merger, Sigrun | Mihailov, Evelin | Milani, Lili | Moayyeri, Alireza | Monda, Keri L. | Morken, Mario A. | Mulas, Antonella | Müller, Gabriele | Müller-Nurasyid, Martina | Musk, Arthur W. | Nagaraja, Ramaiah | Nöthen, Markus M. | Nolte, Ilja M. | Pilz, Stefan | Rayner, Nigel W. | Renstrom, Frida | Rettig, Rainer | Ried, Janina S. | Ripke, Stephan | Robertson, Neil R. | Rose, Lynda M. | Sanna, Serena | Scharnagl, Hubert | Scholtens, Salome | Schumacher, Fredrick R. | Scott, William R. | Seufferlein, Thomas | Shi, Jianxin | Smith, Albert Vernon | Smolonska, Joanna | Stanton, Alice V. | Steinthorsdottir, Valgerdur | Stirrups, Kathleen | Stringham, Heather M. | Sundström, Johan | Swertz, Morris A. | Swift, Amy J. | Syvänen, Ann-Christine | Tan, Sian-Tsung | Tayo, Bamidele O. | Thorand, Barbara | Thorleifsson, Gudmar | Tyrer, Jonathan P. | Uh, Hae-Won | Vandenput, Liesbeth | Verhulst, Frank C. | Vermeulen, Sita H. | Verweij, Niek | Vonk, Judith M. | Waite, Lindsay L. | Warren, Helen R. | Waterworth, Dawn | Weedon, Michael N. | Wilkens, Lynne R. | Willenborg, Christina | Wilsgaard, Tom | Wojczynski, Mary K. | Wong, Andrew | Wright, Alan F. | Zhang, Qunyuan | Brennan, Eoin P. | Choi, Murim | Dastani, Zari | Drong, Alexander W. | Eriksson, Per | Franco-Cereceda, Anders | Gådin, Jesper R. | Gharavi, Ali G. | Goddard, Michael E. | Handsaker, Robert E. | Huang, Jinyan | Karpe, Fredrik | Kathiresan, Sekar | Keildson, Sarah | Kiryluk, Krzysztof | Kubo, Michiaki | Lee, Jong-Young | Liang, Liming | Lifton, Richard P. | Ma, Baoshan | McCarroll, Steven A. | McKnight, Amy J. | Min, Josine L. | Moffatt, Miriam F. | Montgomery, Grant W. | Murabito, Joanne M. | Nicholson, George | Nyholt, Dale R. | Okada, Yukinori | Perry, John R. B. | Dorajoo, Rajkumar | Reinmaa, Eva | Salem, Rany M. | Sandholm, Niina | Scott, Robert A. | Stolk, Lisette | Takahashi, Atsushi | Tanaka, Toshihiro | van ’t Hooft, Ferdinand M. | Vinkhuyzen, Anna A. E. | Westra, Harm-Jan | Zheng, Wei | Zondervan, Krina T. | Heath, Andrew C. | Arveiler, Dominique | Bakker, Stephan J. L. | Beilby, John | Bergman, Richard N. | Blangero, John | Bovet, Pascal | Campbell, Harry | Caulfield, Mark J. | Cesana, Giancarlo | Chakravarti, Aravinda | Chasman, Daniel I. | Chines, Peter S. | Collins, Francis S. | Crawford, Dana C. | Cupples, L. Adrienne | Cusi, Daniele | Danesh, John | de Faire, Ulf | den Ruijter, Hester M. | Dominiczak, Anna F. | Erbel, Raimund | Erdmann, Jeanette | Eriksson, Johan G. | Farrall, Martin | Felix, Stephan B. | Ferrannini, Ele | Ferrières, Jean | Ford, Ian | Forouhi, Nita G. | Forrester, Terrence | Franco, Oscar H. | Gansevoort, Ron T. | Gejman, Pablo V. | Gieger, Christian | Gottesman, Omri | Gudnason, Vilmundur | Gyllensten, Ulf | Hall, Alistair S. | Harris, Tamara B. | Hattersley, Andrew T. | Hicks, Andrew A. | Hindorff, Lucia A. | Hingorani, Aroon D. | Hofman, Albert | Homuth, Georg | Hovingh, G. Kees | Humphries, Steve E. | Hunt, Steven C. | Hyppönen, Elina | Illig, Thomas | Jacobs, Kevin B. | Jarvelin, Marjo-Riitta | Jöckel, Karl-Heinz | Johansen, Berit | Jousilahti, Pekka | Jukema, J. Wouter | Jula, Antti M. | Kaprio, Jaakko | Kastelein, John J. P. | Keinanen-Kiukaanniemi, Sirkka M. | Kiemeney, Lambertus A. | Knekt, Paul | Kooner, Jaspal S. | Kooperberg, Charles | Kovacs, Peter | Kraja, Aldi T. | Kumari, Meena | Kuusisto, Johanna | Lakka, Timo A. | Langenberg, Claudia | Marchand, Loic Le | Lehtimäki, Terho | Lyssenko, Valeriya | Männistö, Satu | Marette, André | Matise, Tara C. | McKenzie, Colin A. | McKnight, Barbara | Moll, Frans L. | Morris, Andrew D. | Morris, Andrew P. | Murray, Jeffrey C. | Nelis, Mari | Ohlsson, Claes | Oldehinkel, Albertine J. | Ong, Ken K. | Madden, Pamela A. F. | Pasterkamp, Gerard | Peden, John F. | Peters, Annette | Postma, Dirkje S. | Pramstaller, Peter P. | Price, Jackie F. | Qi, Lu | Raitakari, Olli T. | Rankinen, Tuomo | Rao, D. C. | Rice, Treva K. | Ridker, Paul M. | Rioux, John D. | Ritchie, Marylyn D. | Rudan, Igor | Salomaa, Veikko | Samani, Nilesh J. | Saramies, Jouko | Sarzynski, Mark A. | Schunkert, Heribert | Schwarz, Peter E. H. | Sever, Peter | Shuldiner, Alan R. | Sinisalo, Juha | Stolk, Ronald P. | Strauch, Konstantin | Tönjes, Anke | Trégouët, David-Alexandre | Tremblay, Angelo | Tremoli, Elena | Virtamo, Jarmo | Vohl, Marie-Claude | Völker, Uwe | Waeber, Gérard | Willemsen, Gonneke | Witteman, Jacqueline C. | Zillikens, M. Carola | Adair, Linda S. | Amouyel, Philippe | Asselbergs, Folkert W. | Assimes, Themistocles L. | Bochud, Murielle | Boehm, Bernhard O. | Boerwinkle, Eric | Bornstein, Stefan R. | Bottinger, Erwin P. | Bouchard, Claude | Cauchi, Stéphane | Chambers, John C. | Chanock, Stephen J. | Cooper, Richard S. | de Bakker, Paul I. W. | Dedoussis, George | Ferrucci, Luigi | Franks, Paul W. | Froguel, Philippe | Groop, Leif C. | Haiman, Christopher A. | Hamsten, Anders | Hui, Jennie | Hunter, David J. | Hveem, Kristian | Kaplan, Robert C. | Kivimaki, Mika | Kuh, Diana | Laakso, Markku | Liu, Yongmei | Martin, Nicholas G. | März, Winfried | Melbye, Mads | Metspalu, Andres | Moebus, Susanne | Munroe, Patricia B. | Njølstad, Inger | Oostra, Ben A. | Palmer, Colin N. A. | Pedersen, Nancy L. | Perola, Markus | Pérusse, Louis | Peters, Ulrike | Power, Chris | Quertermous, Thomas | Rauramaa, Rainer | Rivadeneira, Fernando | Saaristo, Timo E. | Saleheen, Danish | Sattar, Naveed | Schadt, Eric E. | Schlessinger, David | Slagboom, P. Eline | Snieder, Harold | Spector, Tim D. | Thorsteinsdottir, Unnur | Stumvoll, Michael | Tuomilehto, Jaakko | Uitterlinden, André G. | Uusitupa, Matti | van der Harst, Pim | Walker, Mark | Wallaschofski, Henri | Wareham, Nicholas J. | Watkins, Hugh | Weir, David R. | Wichmann, H-Erich | Wilson, James F. | Zanen, Pieter | Borecki, Ingrid B. | Deloukas, Panos | Fox, Caroline S. | Heid, Iris M. | O’Connell, Jeffrey R. | Strachan, David P. | Stefansson, Kari | van Duijn, Cornelia M. | Abecasis, Gonçalo R. | Franke, Lude | Frayling, Timothy M. | McCarthy, Mark I. | Visscher, Peter M. | Scherag, André | Willer, Cristen J. | Boehnke, Michael | Mohlke, Karen L. | Lindgren, Cecilia M. | Beckmann, Jacques S. | Barroso, Inês | North, Kari E. | Ingelsson, Erik | Hirschhorn, Joel N. | Loos, Ruth J. F. | Speliotes, Elizabeth K.
Nature  2015;518(7538):197-206.
Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10−8), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ~2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
doi:10.1038/nature14177
PMCID: PMC4382211  PMID: 25673413
8.  Modulation of Genetic Associations with Serum Urate Levels by Body-Mass-Index in Humans 
Huffman, Jennifer E. | Albrecht, Eva | Teumer, Alexander | Mangino, Massimo | Kapur, Karen | Johnson, Toby | Kutalik, Zoltán | Pirastu, Nicola | Pistis, Giorgio | Lopez, Lorna M. | Haller, Toomas | Salo, Perttu | Goel, Anuj | Li, Man | Tanaka, Toshiko | Dehghan, Abbas | Ruggiero, Daniela | Malerba, Giovanni | Smith, Albert V. | Nolte, Ilja M. | Portas, Laura | Phipps-Green, Amanda | Boteva, Lora | Navarro, Pau | Johansson, Asa | Hicks, Andrew A. | Polasek, Ozren | Esko, Tõnu | Peden, John F. | Harris, Sarah E. | Murgia, Federico | Wild, Sarah H. | Tenesa, Albert | Tin, Adrienne | Mihailov, Evelin | Grotevendt, Anne | Gislason, Gauti K. | Coresh, Josef | D'Adamo, Pio | Ulivi, Sheila | Vollenweider, Peter | Waeber, Gerard | Campbell, Susan | Kolcic, Ivana | Fisher, Krista | Viigimaa, Margus | Metter, Jeffrey E. | Masciullo, Corrado | Trabetti, Elisabetta | Bombieri, Cristina | Sorice, Rossella | Döring, Angela | Reischl, Eva | Strauch, Konstantin | Hofman, Albert | Uitterlinden, Andre G. | Waldenberger, Melanie | Wichmann, H-Erich | Davies, Gail | Gow, Alan J. | Dalbeth, Nicola | Stamp, Lisa | Smit, Johannes H. | Kirin, Mirna | Nagaraja, Ramaiah | Nauck, Matthias | Schurmann, Claudia | Budde, Kathrin | Farrington, Susan M. | Theodoratou, Evropi | Jula, Antti | Salomaa, Veikko | Sala, Cinzia | Hengstenberg, Christian | Burnier, Michel | Mägi, Reedik | Klopp, Norman | Kloiber, Stefan | Schipf, Sabine | Ripatti, Samuli | Cabras, Stefano | Soranzo, Nicole | Homuth, Georg | Nutile, Teresa | Munroe, Patricia B. | Hastie, Nicholas | Campbell, Harry | Rudan, Igor | Cabrera, Claudia | Haley, Chris | Franco, Oscar H. | Merriman, Tony R. | Gudnason, Vilmundur | Pirastu, Mario | Penninx, Brenda W. | Snieder, Harold | Metspalu, Andres | Ciullo, Marina | Pramstaller, Peter P. | van Duijn, Cornelia M. | Ferrucci, Luigi | Gambaro, Giovanni | Deary, Ian J. | Dunlop, Malcolm G. | Wilson, James F. | Gasparini, Paolo | Gyllensten, Ulf | Spector, Tim D. | Wright, Alan F. | Hayward, Caroline | Watkins, Hugh | Perola, Markus | Bochud, Murielle | Kao, W. H. Linda | Caulfield, Mark | Toniolo, Daniela | Völzke, Henry | Gieger, Christian | Köttgen, Anna | Vitart, Veronique
PLoS ONE  2015;10(3):e0119752.
We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, Pinter= 2.6 x 10-8). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDARADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10-8), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10-8), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10-4). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.
doi:10.1371/journal.pone.0119752
PMCID: PMC4374966  PMID: 25811787
9.  Genome of the Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels 
van Leeuwen, Elisabeth M. | Karssen, Lennart C. | Deelen, Joris | Isaacs, Aaron | Medina-Gomez, Carolina | Mbarek, Hamdi | Kanterakis, Alexandros | Trompet, Stella | Postmus, Iris | Verweij, Niek | van Enckevort, David J. | Huffman, Jennifer E. | White, Charles C. | Feitosa, Mary F. | Bartz, Traci M. | Manichaikul, Ani | Joshi, Peter K. | Peloso, Gina M. | Deelen, Patrick | van Dijk, Freerk | Willemsen, Gonneke | de Geus, Eco J. | Milaneschi, Yuri | Penninx, Brenda W.J.H. | Francioli, Laurent C. | Menelaou, Androniki | Pulit, Sara L. | Rivadeneira, Fernando | Hofman, Albert | Oostra, Ben A. | Franco, Oscar H. | Leach, Irene Mateo | Beekman, Marian | de Craen, Anton J.M. | Uh, Hae-Won | Trochet, Holly | Hocking, Lynne J. | Porteous, David J. | Sattar, Naveed | Packard, Chris J. | Buckley, Brendan M. | Brody, Jennifer A. | Bis, Joshua C. | Rotter, Jerome I. | Mychaleckyj, Josyf C. | Campbell, Harry | Duan, Qing | Lange, Leslie A. | Wilson, James F. | Hayward, Caroline | Polasek, Ozren | Vitart, Veronique | Rudan, Igor | Wright, Alan F. | Rich, Stephen S. | Psaty, Bruce M. | Borecki, Ingrid B. | Kearney, Patricia M. | Stott, David J. | Adrienne Cupples, L. | Jukema, J. Wouter | van der Harst, Pim | Sijbrands, Eric J. | Hottenga, Jouke-Jan | Uitterlinden, Andre G. | Swertz, Morris A. | van Ommen, Gert-Jan B. | de Bakker, Paul I.W. | Eline Slagboom, P. | Boomsma, Dorret I. | Wijmenga, Cisca | van Duijn, Cornelia M.
Nature Communications  2015;6:6065.
Variants associated with blood lipid levels may be population-specific. To identify low-frequency variants associated with this phenotype, population-specific reference panels may be used. Here we impute nine large Dutch biobanks (~35,000 samples) with the population-specific reference panel created by the Genome of the Netherlands Project and perform association testing with blood lipid levels. We report the discovery of five novel associations at four loci (P value <6.61 × 10−4), including a rare missense variant in ABCA6 (rs77542162, p.Cys1359Arg, frequency 0.034), which is predicted to be deleterious. The frequency of this ABCA6 variant is 3.65-fold increased in the Dutch and its effect (βLDL-C=0.135, βTC=0.140) is estimated to be very similar to those observed for single variants in well-known lipid genes, such as LDLR.
Frequencies of rare variants fluctuate over populations, hampering gene discovery. Here the authors use a population-specific reference panel, the Genome of the Netherlands, to discover four novel loci involved in lipid metabolism, including an exonic variant in ABCA6.
doi:10.1038/ncomms7065
PMCID: PMC4366498  PMID: 25751400
10.  Prevalence of Mobile Phones and Factors Influencing Usage by Caregivers of Young Children in Daily Life and for Health Care in Rural China: A Mixed Methods Study 
PLoS ONE  2015;10(3):e0116216.
Introduction
To capitalise on mHealth, we need to understand the use of mobile phones both in daily life and for health care.
Objective
To assess the prevalence and factors that influence usage of mobile phones by caregivers of young children.
Materials and Methods
A mixed methods approach was used, whereby a survey (N=1854) and semi-structured interviews (N=17) were conducted concurrently. The quantitative and qualitative data obtained were compared and integrated. Participants were caregivers of young children in Zhao County, Hebei Province, China.
Results
Four main themes were found: (i) trends in mobile phone ownership; (ii) usage of mobile phone functions; (iii) factors influencing replying to text messages; and (iv) uses of mobile phones for health care. The majority of 1,854 survey participants (1,620; 87.4%) used mobile phones, but usage was much higher among mothers (1,433; 92.6%) and fathers (41; 100.0%) compared to grandparents (142; 54.6%). Parents were able to send text messages, grandparents often not. Factors influencing the decision to reply to text messages in daily life were checking the mobile phone, trusting the sender, emotion or feeling when receiving a text message, the importance of replying and ease of use of text messages. Of 1,620 survey participants who used a mobile phone, about one in four (432; 26.7%) had used it for health care in the past three months and most (1,110; 93.5%) of 1,187 who had not wished to use their phone to receive health information.
Conclusion
We found that usage of mobile phones is high, several factors influencing usage and an interest of caregivers to use phones for health care in Zhao County, rural China, which can be used to inform studies in settings with similar characteristics. Future work needs to assess factors influencing mobile phone usage in-depth to optimize experiences of users for specific mHealth-based interventions.
doi:10.1371/journal.pone.0116216
PMCID: PMC4366174  PMID: 25789477
11.  Ancient human genomes suggest three ancestral populations for present-day Europeans 
Lazaridis, Iosif | Patterson, Nick | Mittnik, Alissa | Renaud, Gabriel | Mallick, Swapan | Kirsanow, Karola | Sudmant, Peter H. | Schraiber, Joshua G. | Castellano, Sergi | Lipson, Mark | Berger, Bonnie | Economou, Christos | Bollongino, Ruth | Fu, Qiaomei | Bos, Kirsten I. | Nordenfelt, Susanne | Li, Heng | de Filippo, Cesare | Prüfer, Kay | Sawyer, Susanna | Posth, Cosimo | Haak, Wolfgang | Hallgren, Fredrik | Fornander, Elin | Rohland, Nadin | Delsate, Dominique | Francken, Michael | Guinet, Jean-Michel | Wahl, Joachim | Ayodo, George | Babiker, Hamza A. | Bailliet, Graciela | Balanovska, Elena | Balanovsky, Oleg | Barrantes, Ramiro | Bedoya, Gabriel | Ben-Ami, Haim | Bene, Judit | Berrada, Fouad | Bravi, Claudio M. | Brisighelli, Francesca | Busby, George B. J. | Cali, Francesco | Churnosov, Mikhail | Cole, David E. C. | Corach, Daniel | Damba, Larissa | van Driem, George | Dryomov, Stanislav | Dugoujon, Jean-Michel | Fedorova, Sardana A. | Romero, Irene Gallego | Gubina, Marina | Hammer, Michael | Henn, Brenna M. | Hervig, Tor | Hodoglugil, Ugur | Jha, Aashish R. | Karachanak-Yankova, Sena | Khusainova, Rita | Khusnutdinova, Elza | Kittles, Rick | Kivisild, Toomas | Klitz, William | Kučinskas, Vaidutis | Kushniarevich, Alena | Laredj, Leila | Litvinov, Sergey | Loukidis, Theologos | Mahley, Robert W. | Melegh, Béla | Metspalu, Ene | Molina, Julio | Mountain, Joanna | Näkkäläjärvi, Klemetti | Nesheva, Desislava | Nyambo, Thomas | Osipova, Ludmila | Parik, Jüri | Platonov, Fedor | Posukh, Olga | Romano, Valentino | Rothhammer, Francisco | Rudan, Igor | Ruizbakiev, Ruslan | Sahakyan, Hovhannes | Sajantila, Antti | Salas, Antonio | Starikovskaya, Elena B. | Tarekegn, Ayele | Toncheva, Draga | Turdikulova, Shahlo | Uktveryte, Ingrida | Utevska, Olga | Vasquez, René | Villena, Mercedes | Voevoda, Mikhail | Winkler, Cheryl | Yepiskoposyan, Levon | Zalloua, Pierre | Zemunik, Tatijana | Cooper, Alan | Capelli, Cristian | Thomas, Mark G. | Ruiz-Linares, Andres | Tishkoff, Sarah A. | Singh, Lalji | Thangaraj, Kumarasamy | Villems, Richard | Comas, David | Sukernik, Rem | Metspalu, Mait | Meyer, Matthias | Eichler, Evan E. | Burger, Joachim | Slatkin, Montgomery | Pääbo, Svante | Kelso, Janet | Reich, David | Krause, Johannes
Nature  2014;513(7518):409-413.
We sequenced the genomes of a ~7,000 year old farmer from Germany and eight ~8,000 year old hunter-gatherers from Luxembourg and Sweden. We analyzed these and other ancient genomes1–4 with 2,345 contemporary humans to show that most present Europeans derive from at least three highly differentiated populations: West European Hunter-Gatherers (WHG), who contributed ancestry to all Europeans but not to Near Easterners; Ancient North Eurasians (ANE) related to Upper Paleolithic Siberians3, who contributed to both Europeans and Near Easterners; and Early European Farmers (EEF), who were mainly of Near Eastern origin but also harbored WHG-related ancestry. We model these populations’ deep relationships and show that EEF had ~44% ancestry from a “Basal Eurasian” population that split prior to the diversification of other non-African lineages.
doi:10.1038/nature13673
PMCID: PMC4170574  PMID: 25230663
12.  Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility 
Wessel, Jennifer | Chu, Audrey Y | Willems, Sara M | Wang, Shuai | Yaghootkar, Hanieh | Brody, Jennifer A | Dauriz, Marco | Hivert, Marie-France | Raghavan, Sridharan | Lipovich, Leonard | Hidalgo, Bertha | Fox, Keolu | Huffman, Jennifer E | An, Ping | Lu, Yingchang | Rasmussen-Torvik, Laura J | Grarup, Niels | Ehm, Margaret G | Li, Li | Baldridge, Abigail S | Stančáková, Alena | Abrol, Ravinder | Besse, Céline | Boland, Anne | Bork-Jensen, Jette | Fornage, Myriam | Freitag, Daniel F | Garcia, Melissa E | Guo, Xiuqing | Hara, Kazuo | Isaacs, Aaron | Jakobsdottir, Johanna | Lange, Leslie A | Layton, Jill C | Li, Man | Hua Zhao, Jing | Meidtner, Karina | Morrison, Alanna C | Nalls, Mike A | Peters, Marjolein J | Sabater-Lleal, Maria | Schurmann, Claudia | Silveira, Angela | Smith, Albert V | Southam, Lorraine | Stoiber, Marcus H | Strawbridge, Rona J | Taylor, Kent D | Varga, Tibor V | Allin, Kristine H | Amin, Najaf | Aponte, Jennifer L | Aung, Tin | Barbieri, Caterina | Bihlmeyer, Nathan A | Boehnke, Michael | Bombieri, Cristina | Bowden, Donald W | Burns, Sean M | Chen, Yuning | Chen, Yii-DerI | Cheng, Ching-Yu | Correa, Adolfo | Czajkowski, Jacek | Dehghan, Abbas | Ehret, Georg B | Eiriksdottir, Gudny | Escher, Stefan A | Farmaki, Aliki-Eleni | Frånberg, Mattias | Gambaro, Giovanni | Giulianini, Franco | Goddard, William A | Goel, Anuj | Gottesman, Omri | Grove, Megan L | Gustafsson, Stefan | Hai, Yang | Hallmans, Göran | Heo, Jiyoung | Hoffmann, Per | Ikram, Mohammad K | Jensen, Richard A | Jørgensen, Marit E | Jørgensen, Torben | Karaleftheri, Maria | Khor, Chiea C | Kirkpatrick, Andrea | Kraja, Aldi T | Kuusisto, Johanna | Lange, Ethan M | Lee, I T | Lee, Wen-Jane | Leong, Aaron | Liao, Jiemin | Liu, Chunyu | Liu, Yongmei | Lindgren, Cecilia M | Linneberg, Allan | Malerba, Giovanni | Mamakou, Vasiliki | Marouli, Eirini | Maruthur, Nisa M | Matchan, Angela | McKean-Cowdin, Roberta | McLeod, Olga | Metcalf, Ginger A | Mohlke, Karen L | Muzny, Donna M | Ntalla, Ioanna | Palmer, Nicholette D | Pasko, Dorota | Peter, Andreas | Rayner, Nigel W | Renström, Frida | Rice, Ken | Sala, Cinzia F | Sennblad, Bengt | Serafetinidis, Ioannis | Smith, Jennifer A | Soranzo, Nicole | Speliotes, Elizabeth K | Stahl, Eli A | Stirrups, Kathleen | Tentolouris, Nikos | Thanopoulou, Anastasia | Torres, Mina | Traglia, Michela | Tsafantakis, Emmanouil | Javad, Sundas | Yanek, Lisa R | Zengini, Eleni | Becker, Diane M | Bis, Joshua C | Brown, James B | Adrienne Cupples, L | Hansen, Torben | Ingelsson, Erik | Karter, Andrew J | Lorenzo, Carlos | Mathias, Rasika A | Norris, Jill M | Peloso, Gina M | Sheu, Wayne H.-H. | Toniolo, Daniela | Vaidya, Dhananjay | Varma, Rohit | Wagenknecht, Lynne E | Boeing, Heiner | Bottinger, Erwin P | Dedoussis, George | Deloukas, Panos | Ferrannini, Ele | Franco, Oscar H | Franks, Paul W | Gibbs, Richard A | Gudnason, Vilmundur | Hamsten, Anders | Harris, Tamara B | Hattersley, Andrew T | Hayward, Caroline | Hofman, Albert | Jansson, Jan-Håkan | Langenberg, Claudia | Launer, Lenore J | Levy, Daniel | Oostra, Ben A | O'Donnell, Christopher J | O'Rahilly, Stephen | Padmanabhan, Sandosh | Pankow, James S | Polasek, Ozren | Province, Michael A | Rich, Stephen S | Ridker, Paul M | Rudan, Igor | Schulze, Matthias B | Smith, Blair H | Uitterlinden, André G | Walker, Mark | Watkins, Hugh | Wong, Tien Y | Zeggini, Eleftheria | Laakso, Markku | Borecki, Ingrid B | Chasman, Daniel I | Pedersen, Oluf | Psaty, Bruce M | Shyong Tai, E | van Duijn, Cornelia M | Wareham, Nicholas J | Waterworth, Dawn M | Boerwinkle, Eric | Linda Kao, W H | Florez, Jose C | Loos, Ruth J.F. | Wilson, James G | Frayling, Timothy M | Siscovick, David S | Dupuis, Josée | Rotter, Jerome I | Meigs, James B | Scott, Robert A | Goodarzi, Mark O
Nature Communications  2015;6:5897.
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±0.01 mmol l−1, P=3.4 × 10−12), T2D risk (OR[95%CI]=0.86[0.76–0.96], P=0.010), early insulin secretion (β=−0.07±0.035 pmolinsulin mmolglucose−1, P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l−1, P=4.3 × 10−4). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 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±0.004 mmol l−1, P=1.3 × 10−8). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
Both rare and common variants contribute to the aetiology of complex traits such as type 2 diabetes (T2D). Here, the authors examine the effect of coding variation on glycaemic traits and T2D, and identify low-frequency variation in GLP1R significantly associated with these traits.
doi:10.1038/ncomms6897
PMCID: PMC4311266  PMID: 25631608
13.  Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization 
Arking, Dan E. | Pulit, Sara L. | Crotti, Lia | van der Harst, Pim | Munroe, Patricia B. | Koopmann, Tamara T. | Sotoodehnia, Nona | Rossin, Elizabeth J. | Morley, Michael | Wang, Xinchen | Johnson, Andrew D. | Lundby, Alicia | Gudbjartsson, Daníel F. | Noseworthy, Peter A. | Eijgelsheim, Mark | Bradford, Yuki | Tarasov, Kirill V. | Dörr, Marcus | Müller-Nurasyid, Martina | Lahtinen, Annukka M. | Nolte, Ilja M. | Smith, Albert Vernon | Bis, Joshua C. | Isaacs, Aaron | Newhouse, Stephen J. | Evans, Daniel S. | Post, Wendy S. | Waggott, Daryl | Lyytikäinen, Leo-Pekka | Hicks, Andrew A. | Eisele, Lewin | Ellinghaus, David | Hayward, Caroline | Navarro, Pau | Ulivi, Sheila | Tanaka, Toshiko | Tester, David J. | Chatel, Stéphanie | Gustafsson, Stefan | Kumari, Meena | Morris, Richard W. | Naluai, Åsa T. | Padmanabhan, Sandosh | Kluttig, Alexander | Strohmer, Bernhard | Panayiotou, Andrie G. | Torres, Maria | Knoflach, Michael | Hubacek, Jaroslav A. | Slowikowski, Kamil | Raychaudhuri, Soumya | Kumar, Runjun D. | Harris, Tamara B. | Launer, Lenore J. | Shuldiner, Alan R. | Alonso, Alvaro | Bader, Joel S. | Ehret, Georg | Huang, Hailiang | Kao, W.H. Linda | Strait, James B. | Macfarlane, Peter W. | Brown, Morris | Caulfield, Mark J. | Samani, Nilesh J. | Kronenberg, Florian | Willeit, Johann | Smith, J. Gustav | Greiser, Karin H. | zu Schwabedissen, Henriette Meyer | Werdan, Karl | Carella, Massimo | Zelante, Leopoldo | Heckbert, Susan R. | Psaty, Bruce M. | Rotter, Jerome I. | Kolcic, Ivana | Polašek, Ozren | Wright, Alan F. | Griffin, Maura | Daly, Mark J. | Arnar, David O. | Hólm, Hilma | Thorsteinsdottir, Unnur | Denny, Joshua C. | Roden, Dan M. | Zuvich, Rebecca L. | Emilsson, Valur | Plump, Andrew S. | Larson, Martin G. | O'Donnell, Christopher J. | Yin, Xiaoyan | Bobbo, Marco | D'Adamo, Adamo P. | Iorio, Annamaria | Sinagra, Gianfranco | Carracedo, Angel | Cummings, Steven R. | Nalls, Michael A. | Jula, Antti | Kontula, Kimmo K. | Marjamaa, Annukka | Oikarinen, Lasse | Perola, Markus | Porthan, Kimmo | Erbel, Raimund | Hoffmann, Per | Jöckel, Karl-Heinz | Kälsch, Hagen | Nöthen, Markus M. | consortium, HRGEN | den Hoed, Marcel | Loos, Ruth J.F. | Thelle, Dag S. | Gieger, Christian | Meitinger, Thomas | Perz, Siegfried | Peters, Annette | Prucha, Hanna | Sinner, Moritz F. | Waldenberger, Melanie | de Boer, Rudolf A. | Franke, Lude | van der Vleuten, Pieter A. | Beckmann, Britt Maria | Martens, Eimo | Bardai, Abdennasser | Hofman, Nynke | Wilde, Arthur A.M. | Behr, Elijah R. | Dalageorgou, Chrysoula | Giudicessi, John R. | Medeiros-Domingo, Argelia | Barc, Julien | Kyndt, Florence | Probst, Vincent | Ghidoni, Alice | Insolia, Roberto | Hamilton, Robert M. | Scherer, Stephen W. | Brandimarto, Jeffrey | Margulies, Kenneth | Moravec, Christine E. | Fabiola Del, Greco M. | Fuchsberger, Christian | O'Connell, Jeffrey R. | Lee, Wai K. | Watt, Graham C.M. | Campbell, Harry | Wild, Sarah H. | El Mokhtari, Nour E. | Frey, Norbert | Asselbergs, Folkert W. | Leach, Irene Mateo | Navis, Gerjan | van den Berg, Maarten P. | van Veldhuisen, Dirk J. | Kellis, Manolis | Krijthe, Bouwe P. | Franco, Oscar H. | Hofman, Albert | Kors, Jan A. | Uitterlinden, André G. | Witteman, Jacqueline C.M. | Kedenko, Lyudmyla | Lamina, Claudia | Oostra, Ben A. | Abecasis, Gonçalo R. | Lakatta, Edward G. | Mulas, Antonella | Orrú, Marco | Schlessinger, David | Uda, Manuela | Markus, Marcello R.P. | Völker, Uwe | Snieder, Harold | Spector, Timothy D. | Ärnlöv, Johan | Lind, Lars | Sundström, Johan | Syvänen, Ann-Christine | Kivimaki, Mika | Kähönen, Mika | Mononen, Nina | Raitakari, Olli T. | Viikari, Jorma S. | Adamkova, Vera | Kiechl, Stefan | Brion, Maria | Nicolaides, Andrew N. | Paulweber, Bernhard | Haerting, Johannes | Dominiczak, Anna F. | Nyberg, Fredrik | Whincup, Peter H. | Hingorani, Aroon | Schott, Jean-Jacques | Bezzina, Connie R. | Ingelsson, Erik | Ferrucci, Luigi | Gasparini, Paolo | Wilson, James F. | Rudan, Igor | Franke, Andre | Mühleisen, Thomas W. | Pramstaller, Peter P. | Lehtimäki, Terho J. | Paterson, Andrew D. | Parsa, Afshin | Liu, Yongmei | van Duijn, Cornelia | Siscovick, David S. | Gudnason, Vilmundur | Jamshidi, Yalda | Salomaa, Veikko | Felix, Stephan B. | Sanna, Serena | Ritchie, Marylyn D. | Stricker, Bruno H. | Stefansson, Kari | Boyer, Laurie A. | Cappola, Thomas P. | Olsen, Jesper V. | Lage, Kasper | Schwartz, Peter J. | Kääb, Stefan | Chakravarti, Aravinda | Ackerman, Michael J. | Pfeufer, Arne | de Bakker, Paul I.W. | Newton-Cheh, Christopher
Nature genetics  2014;46(8):826-836.
The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal Mendelian Long QT Syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals we identified 35 common variant QT interval loci, that collectively explain ∼8-10% of QT variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 novel QT loci in 298 unrelated LQTS probands identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode for proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies novel candidate genes for ventricular arrhythmias, LQTS,and SCD.
doi:10.1038/ng.3014
PMCID: PMC4124521  PMID: 24952745
genome-wide association study; QT interval; Long QT Syndrome; sudden cardiac death; myocardial repolarization; arrhythmias
14.  Genome-wide association analysis identifies six new loci associated with forced vital capacity 
Loth, Daan W. | Artigas, María Soler | Gharib, Sina A. | Wain, Louise V. | Franceschini, Nora | Koch, Beate | Pottinger, Tess | Smith, Albert Vernon | Duan, Qing | Oldmeadow, Chris | Lee, Mi Kyeong | Strachan, David P. | James, Alan L. | Huffman, Jennifer E. | Vitart, Veronique | Ramasamy, Adaikalavan | Wareham, Nicholas J. | Kaprio, Jaakko | Wang, Xin-Qun | Trochet, Holly | Kähönen, Mika | Flexeder, Claudia | Albrecht, Eva | Lopez, Lorna M. | de Jong, Kim | Thyagarajan, Bharat | Alves, Alexessander Couto | Enroth, Stefan | Omenaas, Ernst | Joshi, Peter K. | Fall, Tove | Viňuela, Ana | Launer, Lenore J. | Loehr, Laura R. | Fornage, Myriam | Li, Guo | Wilk, Jemma B. | Tang, Wenbo | Manichaikul, Ani | Lahousse, Lies | Harris, Tamara B. | North, Kari E. | Rudnicka, Alicja R. | Hui, Jennie | Gu, Xiangjun | Lumley, Thomas | Wright, Alan F. | Hastie, Nicholas D. | Campbell, Susan | Kumar, Rajesh | Pin, Isabelle | Scott, Robert A. | Pietiläinen, Kirsi H. | Surakka, Ida | Liu, Yongmei | Holliday, Elizabeth G. | Schulz, Holger | Heinrich, Joachim | Davies, Gail | Vonk, Judith M. | Wojczynski, Mary | Pouta, Anneli | Johansson, Åsa | Wild, Sarah H. | Ingelsson, Erik | Rivadeneira, Fernando | Völzke, Henry | Hysi, Pirro G. | Eiriksdottir, Gudny | Morrison, Alanna C. | Rotter, Jerome I. | Gao, Wei | Postma, Dirkje S. | White, Wendy B. | Rich, Stephen S. | Hofman, Albert | Aspelund, Thor | Couper, David | Smith, Lewis J. | Psaty, Bruce M. | Lohman, Kurt | Burchard, Esteban G. | Uitterlinden, André G. | Garcia, Melissa | Joubert, Bonnie R. | McArdle, Wendy L. | Musk, A. Bill | Hansel, Nadia | Heckbert, Susan R. | Zgaga, Lina | van Meurs, Joyce B.J. | Navarro, Pau | Rudan, Igor | Oh, Yeon-Mok | Redline, Susan | Jarvis, Deborah | Zhao, Jing Hua | Rantanen, Taina | O’Connor, George T. | Ripatti, Samuli | Scott, Rodney J. | Karrasch, Stefan | Grallert, Harald | Gaddis, Nathan C. | Starr, John M. | Wijmenga, Cisca | Minster, Ryan L. | Lederer, David J. | Pekkanen, Juha | Gyllensten, Ulf | Campbell, Harry | Morris, Andrew P. | Gläser, Sven | Hammond, Christopher J. | Burkart, Kristin M. | Beilby, John | Kritchevsky, Stephen B. | Gudnason, Vilmundur | Hancock, Dana B. | Williams, O. Dale | Polasek, Ozren | Zemunik, Tatijana | Kolcic, Ivana | Petrini, Marcy F. | Wjst, Matthias | Kim, Woo Jin | Porteous, David J. | Scotland, Generation | Smith, Blair H. | Viljanen, Anne | Heliövaara, Markku | Attia, John R. | Sayers, Ian | Hampel, Regina | Gieger, Christian | Deary, Ian J. | Boezen, H. Marike | Newman, Anne | Jarvelin, Marjo-Riitta | Wilson, James F. | Lind, Lars | Stricker, Bruno H. | Teumer, Alexander | Spector, Timothy D. | Melén, Erik | Peters, Marjolein J. | Lange, Leslie A. | Barr, R. Graham | Bracke, Ken R. | Verhamme, Fien M. | Sung, Joohon | Hiemstra, Pieter S. | Cassano, Patricia A. | Sood, Akshay | Hayward, Caroline | Dupuis, Josée | Hall, Ian P. | Brusselle, Guy G. | Tobin, Martin D. | London, Stephanie J.
Nature genetics  2014;46(7):669-677.
Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10−8) with FVC in or near EFEMP1, BMP6, MIR-129-2/HSD17B12, PRDM11, WWOX, and KCNJ2. Two (GSTCD and PTCH1) loci previously associated with spirometric measures were related to FVC. Newly implicated regions were followed-up in samples of African American, Korean, Chinese, and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and pathogenesis of restrictive lung disease.
doi:10.1038/ng.3011
PMCID: PMC4140093  PMID: 24929828
15.  Global, regional, and national estimates of pneumonia burden in HIV-infected children in 2010: a meta-analysis and modelling study 
The Lancet. Infectious Diseases  2014;14(12):1250-1258.
Summary
Background
Globally, pneumonia is a leading cause of mortality and morbidity in children younger than 5 years. Underlying HIV infection is an important risk factor for pneumonia morbidity and mortality in children. There are, however, no global or country level estimates of pneumonia burden in HIV-infected children. We assessed the role of HIV in pneumonia incidence and mortality and estimated the number of pneumonia cases and deaths in HIV-infected children younger than 5 years in 133 high pneumonia-burden countries in 2010.
Methods
We estimated the risk of hospital admission and case fatality rate caused by pneumonia in HIV-infected children compared with HIV-uninfected children from a systematic review of studies published in Medline, Embase, and Global Health between Jan 1, 1980, and Aug 31, 2013. We estimated nationwide pneumonia incidence and mortality with two different models that incorporated several risk factors for paediatric pneumonia hospital admission and mortality (including HIV infection). We then estimated the number of pneumonia episodes and deaths that occurred in HIV-infected children in 2010.
Findings
The odds ratio (OR) for hospital admission for all-cause pneumonia in HIV-infected children compared with HIV-uninfected children was 6·5 (95% CI 5·9–7·2). The risk of death was higher in children with pneumonia and HIV compared with those with pneumonia only (OR 5·9, 95% CI 2·7–12·7). In 2010, 1·4 million pneumonia episodes (uncertainty range [UR] 0·6 million to 3·3 million) and 88 000 pneumonia deaths (UR 47 400–153 000) occurred in HIV-infected children in low-income countries. Of these, 1·2 million pneumonia episodes (UR 0·5 million–2·7 million) and 85 400 deaths (UR 46 000–147 300) were directly attributable to HIV. 1·3 million (90%) pneumonia episodes and 82 400 (93%) pneumonia deaths in HIV-infected children aged younger than 5 years occurred in the WHO African region.
Interpretation
Globally, a small proportion of pneumonia episodes and pneumonia deaths occur in HIV-infected children. However, in the highest HIV-burden countries in sub-Saharan Africa (ie, Swaziland, Lesotho, and Zimbabwe) up to a fifth of all pneumonia cases and 60% of pneumonia deaths occur in HIV-infected children. In these countries, major reductions in child pneumonia mortality can be achieved only if the systemic challenges plaguing the health system (poor coverage of early infant testing for HIV, of antiretroviral drugs in pregnant women and young children, of co-trimoxazole prophylaxis, and of pneumococcal vaccination) can be overcome.
Funding
WHO.
doi:10.1016/S1473-3099(14)70990-9
PMCID: PMC4242006  PMID: 25455992
16.  Treatment of Infections in Young Infants in Low- and Middle-Income Countries: A Systematic Review and Meta-analysis of Frontline Health Worker Diagnosis and Antibiotic Access 
PLoS Medicine  2014;11(10):e1001741.
Anne C. C. Lee and colleagues assess the factors affecting access to treatment for neonatal and infant infections in low- and middle-income countries by conducting a systematic review and meta-analysis of frontline health worker diagnosis and access to antibiotics.
Please see later in the article for the Editors' Summary
Background
Inadequate illness recognition and access to antibiotics contribute to high case fatality from infections in young infants (<2 months) in low- and middle-income countries (LMICs). We aimed to address three questions regarding access to treatment for young infant infections in LMICs: (1) Can frontline health workers accurately diagnose possible bacterial infection (pBI)?; (2) How available and affordable are antibiotics?; (3) How often are antibiotics procured without a prescription?
Methods and Findings
We searched PubMed, Embase, WHO/Health Action International (HAI), databases, service provision assessments (SPAs), Demographic and Health Surveys, Multiple Indicator Cluster Surveys, and grey literature with no date restriction until May 2014. Data were identified from 37 published studies, 46 HAI national surveys, and eight SPAs. For study question 1, meta-analysis showed that clinical sign-based algorithms predicted bacterial infection in young infants with high sensitivity (87%, 95% CI 82%–91%) and lower specificity (62%, 95% CI 48%–75%) (six studies, n = 14,254). Frontline health workers diagnosed pBI in young infants with an average sensitivity of 82% (95% CI 76%–88%) and specificity of 69% (95% CI 54%–83%) (eight studies, n = 11,857) compared to physicians. For question 2, first-line injectable agents (ampicillin, gentamicin, and penicillin) had low variable availability in first-level health facilities in Africa and South Asia. Oral amoxicillin and cotrimoxazole were widely available at low cost in most regions. For question 3, no studies on young infants were identified, however 25% of pediatric antibiotic purchases in LMICs were obtained without a prescription (11 studies, 95% CI 18%–34%), with lower rates among infants <1 year. Study limitations included potential selection bias and lack of neonatal-specific data.
Conclusions
Trained frontline health workers may screen for pBI in young infants with relatively high sensitivity and lower specificity. Availability of first-line injectable antibiotics appears low in many health facilities in Africa and Asia. Improved data and advocacy are needed to increase the availability and appropriate utilization of antibiotics for young infant infections in LMICs.
Review Registration
PROSPERO International prospective register of systematic reviews (CRD42013004586).
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Neonatal mortality—death that occurs during the first 28 days of life—accounts for nearly half of all the deaths that occur in children before they reach their fifth birthday. Worldwide, nearly 3 million neonatal deaths occur every year. Three bacterial infections—sepsis (infection of the bloodstream), pneumonia (infection of the lungs), and meningitis (infection of the brain's protective covering)—are responsible for nearly a quarter of all neonatal deaths. Babies born in low- and middle-income countries (LMICs) are at particularly high risk of developing neonatal bacterial infections because the risk factors for these infections, which include maternal infections and unhygienic delivery care, are more common in LMICs than in high-income countries. Babies born in LMICs are also at a high risk of dying from bacterial infections because access to appropriate medical care and antibiotics is often poor.
Why Was This Study Done?
To reduce neonatal deaths from bacterial infections in LMICs, health care experts need to identify the factors that limit access to medical care and antibiotics in these countries. Are babies dying because health care providers fail to diagnose neonatal bacterial infections, because antibiotics are not available in first-line health facilities, or for some other reason? In this systematic review and meta-analysis, the researchers investigate access to treatment for neonatal bacterial infections in LMICs by first asking whether frontline health workers in LMICs can accurately diagnose bacterial infections in neonates and young infants (babies less than 2 months old). Next, they ask whether antibiotics for treating neonatal infections are available and affordable in LMICs. Finally, they ask how often antibiotics are procured for young children (children up to the age of 5 years) without a prescription. A systematic review uses pre-defined criteria to identify all the research on a given topic; meta-analysis uses statistical methods to combine the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 37 published studies, 46 surveys of drug availability and affordability in LMICs (Health Access International databases), and eight surveys of the capacity of health facilities in LMICs to provide quality health care services (service provision assessments) that met their inclusion criteria. Meta-analysis of six studies indicated that a combination of simple clinical signs for the diagnosis of bacterial infection in children predicted very severe disease in young infants with a sensitivity of 87% and a specificity of 62% (“sensitivity” indicates the percentage of true positives detected by a test; “specificity” indicates the percentage of healthy people that a test correctly identifies as healthy) compared to a physician's diagnosis with laboratory testing. Meta-analysis of eight studies indicated that frontline health workers (for example, community health workers) diagnosed very severe disease (including possible bacterial infection) in young infants with a sensitivity of 82% and a specificity of 69% compared to trained physicians. The national surveys analyzed indicated that first-level (primary) health facilities in Africa and South Asia had low, variable stocks of recommended first-line injectable antibiotics and that the cost of these drugs was high. By contrast, some oral antibiotics were widely available at low cost in most regions. Finally, meta-analysis of 11 studies indicated that, in LMICs, 25% of antibiotic purchases for the treatment of young children were obtained without a prescription.
What Do These Findings Mean?
These findings suggest that trained frontline health workers should be able to identify most young infants who have possible bacterial infections in LMICs but may also diagnose bacterial infections in many young infants who are not infected. This may lead to the inappropriate use of antibiotics and facilitate the emergence of antibiotic resistance. These findings also show that the availability and affordability of first-line injectable antibiotics is low in many health facilities in Africa and Asia. The lack of neonatal-specific data on illness recognition, antibiotic formulations and availability, and other aspects of this systematic review and meta-analysis are likely to limit the accuracy of these findings. Nevertheless, the researchers suggest that, to decrease the neonatal death toll in LMICs, governments, policymakers, and the pharmaceutical industry need to work together to improve the diagnosis of neonatal bacterial infections and to increase the availability, affordability, and appropriate use of antibiotics for the treatment of these infections.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001741.
WHO provides information on global efforts to reduce global child mortality and on ending preventable neonatal deaths (available in several languages)
The United Nations Children's Fund (UNICEF) works for children's rights, survival, development, and protection around the world; it provides information on global efforts to reduce child mortality , and its Childinfo website provides detailed statistics about neonatal survival and health; its “Committing to Child Survival: A Promise Renewed” webpage includes links to its 2013 progress report and to videos about ending preventable child deaths
The WHO has published a report entitled UN Commission on Life Saving Commodities for Women and Children
The Healthy Newborn Network (NHH) is an online community of more than 80 partner organizations that addresses critical knowledge gaps in newborn health; its website includes information on neonatal infections in LMICs
Kidshealth, a resource provided by the not-for-profit Nemours Foundation, has information for parents on neonatal infections (in English and Spanish)
The MedlinePlus Encyclopedia has a page on neonatal sepsis (in English and Spanish)
A personal story about fatal neonatal bacterial meningitis is available on the website of Meningitis UK, a not-for-profit organization; the site also includes a survivor story
doi:10.1371/journal.pmed.1001741
PMCID: PMC4196753  PMID: 25314011
17.  Inference of identity by descent in population isolates and optimal sequencing studies 
European Journal of Human Genetics  2013;21(10):1140-1145.
In an isolated population, individuals are likely to share large genetic regions inherited from common ancestors. Identity by descent (IBD) can be inferred from SNP genotypes, which is useful in a number of applications, including identifying genetic variants influencing complex disease risk, and planning efficient cohort-sequencing strategies. We present ANCHAP – a method for detecting IBD in isolated populations. We compare accuracy of the method against other long-range and local phasing methods, using parent–offspring trios. In our experiments, we show that ANCHAP performs similarly as the other long-range method, but requires an order-of-magnitude less computational resources. A local phasing model is able to achieve similar sensitivity, but only at the cost of higher false discovery rates. In some regions of the genome, the studied individuals share haplotypes particularly often, which hints at the history of the populations studied. We demonstrate the method using SNP genotypes from three isolated island populations, as well as in a cohort of unrelated individuals. In samples from three isolated populations of around 1000 individual each, an average individual shares a haplotype at a genetic locus with 9–12 other individuals, compared with only 1 individual within the non-isolated population. We describe an application of ANCHAP to optimally choose samples in resequencing studies. We find that with sample sizes of 1000 individuals from an isolated population genotyped using a dense SNP array, and with 20% of these individuals sequenced, 65% of sequences of the unsequenced subjects can be partially inferred.
doi:10.1038/ejhg.2012.307
PMCID: PMC3778345  PMID: 23361219
IBD; isolates; resequencing
18.  Genome-Wide Meta-Analysis of Myopia and Hyperopia Provides Evidence for Replication of 11 Loci 
PLoS ONE  2014;9(9):e107110.
Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p = 1.25×10−8), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value = 9.11×10−11) and 8q12 (minimum p value 1.82×10−11) previously reported for MSE and myopia age at onset. We also used an intermarker linkage- disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al.) and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. “Replication-level” association was also seen between hyperopia and 12 of Kiefer et al.'s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of refractive error across the distribution.
doi:10.1371/journal.pone.0107110
PMCID: PMC4169415  PMID: 25233373
19.  A Multi-Ethnic Meta-Analysis of Genome-Wide Association Studies in Over 100,000 Subjects Identifies 23 Fibrinogen-Associated Loci but no Strong Evidence of a Causal Association between Circulating Fibrinogen and Cardiovascular Disease 
Sabater-Lleal, Maria | Huang, Jie | Chasman, Daniel | Naitza, Silvia | Dehghan, Abbas | Johnson, Andrew D | Teumer, Alexander | Reiner, Alex P | Folkersen, Lasse | Basu, Saonli | Rudnicka, Alicja R | Trompet, Stella | Mälarstig, Anders | Baumert, Jens | Bis, Joshua C. | Guo, Xiuqing | Hottenga, Jouke J | Shin, So-Youn | Lopez, Lorna M | Lahti, Jari | Tanaka, Toshiko | Yanek, Lisa R | Oudot-Mellakh, Tiphaine | Wilson, James F | Navarro, Pau | Huffman, Jennifer E | Zemunik, Tatijana | Redline, Susan | Mehra, Reena | Pulanic, Drazen | Rudan, Igor | Wright, Alan F | Kolcic, Ivana | Polasek, Ozren | Wild, Sarah H | Campbell, Harry | Curb, J David | Wallace, Robert | Liu, Simin | Eaton, Charles B. | Becker, Diane M. | Becker, Lewis C. | Bandinelli, Stefania | Räikkönen, Katri | Widen, Elisabeth | Palotie, Aarno | Fornage, Myriam | Green, David | Gross, Myron | Davies, Gail | Harris, Sarah E | Liewald, David C | Starr, John M | Williams, Frances M.K. | Grant, P.J. | Spector, Timothy D. | Strawbridge, Rona J | Silveira, Angela | Sennblad, Bengt | Rivadeneira, Fernando | Uitterlinden, Andre G | Franco, Oscar H | Hofman, Albert | van Dongen, Jenny | Willemsen, G | Boomsma, Dorret I | Yao, Jie | Jenny, Nancy Swords | Haritunians, Talin | McKnight, Barbara | Lumley, Thomas | Taylor, Kent D | Rotter, Jerome I | Psaty, Bruce M | Peters, Annette | Gieger, Christian | Illig, Thomas | Grotevendt, Anne | Homuth, Georg | Völzke, Henry | Kocher, Thomas | Goel, Anuj | Franzosi, Maria Grazia | Seedorf, Udo | Clarke, Robert | Steri, Maristella | Tarasov, Kirill V | Sanna, Serena | Schlessinger, David | Stott, David J | Sattar, Naveed | Buckley, Brendan M | Rumley, Ann | Lowe, Gordon D | McArdle, Wendy L | Chen, Ming-Huei | Tofler, Geoffrey H | Song, Jaejoon | Boerwinkle, Eric | Folsom, Aaron R. | Rose, Lynda M. | Franco-Cereceda, Anders | Teichert, Martina | Ikram, M Arfan | Mosley, Thomas H | Bevan, Steve | Dichgans, Martin | Rothwell, Peter M. | Sudlow, Cathie L M | Hopewell, Jemma C. | Chambers, John C. | Saleheen, Danish | Kooner, Jaspal S. | Danesh, John | Nelson, Christopher P | Erdmann, Jeanette | Reilly, Muredach P. | Kathiresan, Sekar | Schunkert, Heribert | Morange, Pierre-Emmanuel | Ferrucci, Luigi | Eriksson, Johan G | Jacobs, David | Deary, Ian J | Soranzo, Nicole | Witteman, Jacqueline CM | de Geus, Eco JC | Tracy, Russell P. | Hayward, Caroline | Koenig, Wolfgang | Cucca, Francesco | Jukema, J Wouter | Eriksson, Per | Seshadri, Sudha | Markus, Hugh S. | Watkins, Hugh | Samani, Nilesh J | Wallaschofski, Henri | Smith, Nicholas L. | Tregouet, David | Ridker, Paul M. | Tang, Weihong | Strachan, David P. | Hamsten, Anders | O’Donnell, Christopher J.
Circulation  2013;128(12):10.1161/CIRCULATIONAHA.113.002251.
Background
Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease (CVD), range from 34 to 50%. Genetic variants so far identified by genome-wide association (GWA) studies only explain a small proportion (< 2%) of its variation.
Methods and Results
We conducted a meta-analysis of 28 GWA studies, including more than 90,000 subjects of European ancestry, the first GWA meta-analysis of fibrinogen levels in 7 African Americans studies totaling 8,289 samples, and a GWA study in Hispanic-Americans totaling 1,366 samples. Evaluation for association of SNPs with clinical outcomes included a total of 40,695 cases and 85,582 controls for coronary artery disease (CAD), 4,752 cases and 24,030 controls for stroke, and 3,208 cases and 46,167 controls for venous thromboembolism (VTE). Overall, we identified 24 genome-wide significant (P<5×10−8) 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 three structural fibrinogen genes and pathways related to inflammation, adipocytokines and thyrotrophin-releasing hormone signaling. Whereas lead SNPs in a few loci were significantly associated with CAD, the combined effect of all 24 fibrinogen-associated lead SNPs was not significant for CAD, stroke or VTE.
Conclusion
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 CAD, stroke or VTE.
doi:10.1161/CIRCULATIONAHA.113.002251
PMCID: PMC3842025  PMID: 23969696
Fibrinogen; cardiovascular disease; genome-wide association study
20.  High-Performance Mixed Models Based Genome-Wide Association Analysis with omicABEL software 
F1000Research  2014;3:200.
To raise the power of genome-wide association studies (GWAS) and avoid false-positive results in structured populations, one can rely on mixed model based tests. When large samples are used, and when multiple traits are to be studied in the ’omics’ context, this approach becomes computationally challenging. Here we consider the problem of mixed-model based GWAS for arbitrary number of traits, and demonstrate that for the analysis of single-trait and multiple-trait scenarios different computational algorithms are optimal. We implement these optimal algorithms in a high-performance computing framework that uses state-of-the-art linear algebra kernels, incorporates optimizations, and avoids redundant computations,
increasing throughput while reducing memory usage and energy consumption. We show that, compared to existing libraries, our algorithms and software achieve considerable speed-ups. The OmicABEL software described in this manuscript is available under the GNU
GPL v. 3 license as part of the GenABEL project for statistical genomics at http: //www.genabel.org/packages/OmicABEL.
doi:10.12688/f1000research.4867.1
PMCID: PMC4329600  PMID: 25717363
21.  Association of Adiposity Genetic Variants With Menarche Timing in 92,105 Women of European Descent 
Fernández-Rhodes, Lindsay | Demerath, Ellen W. | Cousminer, Diana L. | Tao, Ran | Dreyfus, Jill G. | Esko, Tõnu | Smith, Albert V. | Gudnason, Vilmundur | Harris, Tamara B. | Launer, Lenore | McArdle, Patrick F. | Yerges-Armstrong, Laura M. | Elks, Cathy E. | Strachan, David P. | Kutalik, Zoltán | Vollenweider, Peter | Feenstra, Bjarke | Boyd, Heather A. | Metspalu, Andres | Mihailov, Evelin | Broer, Linda | Zillikens, M. Carola | Oostra, Ben | van Duijn, Cornelia M. | Lunetta, Kathryn L. | Perry, John R. B. | Murray, Anna | Koller, Daniel L. | Lai, Dongbing | Corre, Tanguy | Toniolo, Daniela | Albrecht, Eva | Stöckl, Doris | Grallert, Harald | Gieger, Christian | Hayward, Caroline | Polasek, Ozren | Rudan, Igor | Wilson, James F. | He, Chunyan | Kraft, Peter | Hu, Frank B. | Hunter, David J. | Hottenga, Jouke-Jan | Willemsen, Gonneke | Boomsma, Dorret I. | Byrne, Enda M. | Martin, Nicholas G. | Montgomery, Grant W. | Warrington, Nicole M. | Pennell, Craig E. | Stolk, Lisette | Visser, Jenny A. | Hofman, Albert | Uitterlinden, André G. | Rivadeneira, Fernando | Lin, Peng | Fisher, Sherri L. | Bierut, Laura J. | Crisponi, Laura | Porcu, Eleonora | Mangino, Massimo | Zhai, Guangju | Spector, Tim D. | Buring, Julie E. | Rose, Lynda M. | Ridker, Paul M. | Poole, Charles | Hirschhorn, Joel N. | Murabito, Joanne M. | Chasman, Daniel I. | Widen, Elisabeth | North, Kari E. | Ong, Ken K. | Franceschini, Nora
American Journal of Epidemiology  2013;178(3):451-460.
Obesity is of global health concern. There are well-described inverse relationships between female pubertal timing and obesity. Recent genome-wide association studies of age at menarche identified several obesity-related variants. Using data from the ReproGen Consortium, we employed meta-analytical techniques to estimate the associations of 95 a priori and recently identified obesity-related (body mass index (weight (kg)/height (m)2), waist circumference, and waist:hip ratio) single-nucleotide polymorphisms (SNPs) with age at menarche in 92,116 women of European descent from 38 studies (1970–2010), in order to estimate associations between genetic variants associated with central or overall adiposity and pubertal timing in girls. Investigators in each study performed a separate analysis of associations between the selected SNPs and age at menarche (ages 9–17 years) using linear regression models and adjusting for birth year, site (as appropriate), and population stratification. Heterogeneity of effect-measure estimates was investigated using meta-regression. Six novel associations of body mass index loci with age at menarche were identified, and 11 adiposity loci previously reported to be associated with age at menarche were confirmed, but none of the central adiposity variants individually showed significant associations. These findings suggest complex genetic relationships between menarche and overall obesity, and to a lesser extent central obesity, in normal processes of growth and development.
doi:10.1093/aje/kws473
PMCID: PMC3816344  PMID: 23558354
adiposity; body mass index; genetic association studies; menarche; obesity; waist circumference; waist:hip ratio; women's health
22.  Salt-inducible kinase 3, SIK3, is a new gene associated with hearing 
Human Molecular Genetics  2014;23(23):6407-6418.
Hearing function is known to be heritable, but few significant and reproducible associations of genetic variants have been identified to date in the adult population. In this study, genome-wide association results of hearing function from the G-EAR consortium and TwinsUK were used for meta-analysis. Hearing ability in eight population samples of Northern and Southern European ancestry (n = 4591) and the Silk Road (n = 348) was measured using pure-tone audiometry and summarized using principal component (PC) analysis. Genome-wide association analyses for PC1–3 were conducted separately in each sample assuming an additive model adjusted for age, sex and relatedness of subjects. Meta-analysis was performed using 2.3 million single-nucleotide polymorphisms (SNPs) tested against each of the three PCs of hearing ability in 4939 individuals. A single SNP lying in intron 6 of the salt-inducible kinase 3 (SIK3) gene was found to be associated with hearing PC2 (P = 3.7×10−8) and further supported by whole-genome sequence in a subset. To determine the relevance of this gene in the ear, expression of the Sik3 protein was studied in mouse cochlea of different ages. Sik3 was expressed in murine hair cells during early development and in cells of the spiral ganglion during early development and adulthood. Our results suggest a developmental role of Sik3 in hearing and may be required for the maintenance of adult auditory function.
doi:10.1093/hmg/ddu346
PMCID: PMC4222365  PMID: 25060954
23.  Genome Wide Association Identifies Common Variants at the SERPINA6/SERPINA1 Locus Influencing Plasma Cortisol and Corticosteroid Binding Globulin 
PLoS Genetics  2014;10(7):e1004474.
Variation in plasma levels of cortisol, an essential hormone in the stress response, is associated in population-based studies with cardio-metabolic, inflammatory and neuro-cognitive traits and diseases. Heritability of plasma cortisol is estimated at 30–60% but no common genetic contribution has been identified. The CORtisol NETwork (CORNET) consortium undertook genome wide association meta-analysis for plasma cortisol in 12,597 Caucasian participants, replicated in 2,795 participants. The results indicate that <1% of variance in plasma cortisol is accounted for by genetic variation in a single region of chromosome 14. This locus spans SERPINA6, encoding corticosteroid binding globulin (CBG, the major cortisol-binding protein in plasma), and SERPINA1, encoding α1-antitrypsin (which inhibits cleavage of the reactive centre loop that releases cortisol from CBG). Three partially independent signals were identified within the region, represented by common SNPs; detailed biochemical investigation in a nested sub-cohort showed all these SNPs were associated with variation in total cortisol binding activity in plasma, but some variants influenced total CBG concentrations while the top hit (rs12589136) influenced the immunoreactivity of the reactive centre loop of CBG. Exome chip and 1000 Genomes imputation analysis of this locus in the CROATIA-Korcula cohort identified missense mutations in SERPINA6 and SERPINA1 that did not account for the effects of common variants. These findings reveal a novel common genetic source of variation in binding of cortisol by CBG, and reinforce the key role of CBG in determining plasma cortisol levels. In turn this genetic variation may contribute to cortisol-associated degenerative diseases.
Author Summary
Cortisol is a steroid hormone from the adrenal glands that is essential in the response to stress. Most cortisol in blood is bound to corticosteroid binding globulin (CBG). Diseases causing cortisol deficiency (Addison's disease) or excess (Cushing's syndrome) are life-threatening. Variations in plasma cortisol have been associated with cardiovascular and psychiatric diseases and their risk factors. To dissect the genetic contribution to variation in plasma cortisol, we formed the CORtisol NETwork (CORNET) consortium and recruited collaborators with suitable samples from more than 15,000 people. The results reveal that the major genetic influence on plasma cortisol is mediated by variations in the binding capacity of CBG. This is determined by differences in the circulating concentrations of CBG and also in the immunoreactivity of its ‘reactive centre loop’, potentially influencing not only binding affinity for cortisol but also the stability of CBG and hence the tissue delivery of cortisol. These findings provide the first evidence for a common genetic effect on levels of this clinically important hormone, suggest that differences in CBG between individuals are biologically important, and pave the way for further research to dissect causality in the associations of plasma cortisol with common diseases.
doi:10.1371/journal.pgen.1004474
PMCID: PMC4091794  PMID: 25010111
24.  Meta-analysis of genome-wide association studies in five cohorts reveals common variants in RBFOX1, a regulator of tissue-specific splicing, associated with refractive error 
Human Molecular Genetics  2013;22(13):2754-2764.
Visual refractive errors (REs) are complex genetic traits with a largely unknown etiology. To date, genome-wide association studies (GWASs) of moderate size have identified several novel risk markers for RE, measured here as mean spherical equivalent (MSE). We performed a GWAS using a total of 7280 samples from five cohorts: the Age-Related Eye Disease Study (AREDS); the KORA study (‘Cooperative Health Research in the Region of Augsburg’); the Framingham Eye Study (FES); the Ogliastra Genetic Park-Talana (OGP-Talana) Study and the Multiethnic Study of Atherosclerosis (MESA). Genotyping was performed on Illumina and Affymetrix platforms with additional markers imputed to the HapMap II reference panel. We identified a new genome-wide significant locus on chromosome 16 (rs10500355, P = 3.9 × 10−9) in a combined discovery and replication set (26 953 samples). This single nucleotide polymorphism (SNP) is located within the RBFOX1 gene which is a neuron-specific splicing factor regulating a wide range of alternative splicing events implicated in neuronal development and maturation, including transcription factors, other splicing factors and synaptic proteins.
doi:10.1093/hmg/ddt116
PMCID: PMC3674806  PMID: 23474815
25.  Identification of heart rate–associated loci and their effects on cardiac conduction and rhythm disorders 
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Nature genetics  2013;45(6):621-631.
Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate–increasing and heart rate–decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.
doi:10.1038/ng.2610
PMCID: PMC3696959  PMID: 23583979

Results 1-25 (187)