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1. Alveolar pentraxin 3 as an early marker of microbiologically confirmed pneumonia: a threshold-finding prospective observational study

Author

Mauri, Tommaso, Coppadoro, Andrea, Bombino, Michela, Bellani, Giacomo, Zambelli, Vanessa, Fornari, Carla, Berra, Lorenzo, Bittner, Edward A, Schmidt, Ulrich, Sironi, Marina, Bottazzi, Barbara, Brambilla, Paolo, Mantovani, Alberto, and Pesenti, Antonio

Abstract

Introduction: Timely diagnosis of pneumonia in intubated critically ill patients is rather challenging. Pentraxin 3 (PTX3) is an acute-phase mediator produced by various cell types in the lungs. Animal studies have shown that, during pneumonia, PTX3 participates in fine-tuning of inflammation (for example, microbial clearance and recruitment of neutrophils). We previously described an association between alveolar PTX3 and lung infection in a small group of intubated patients. The aim of the present study was to determine a threshold level of alveolar PTX3 with elevated sensitivity and specificity for microbiologically confirmed pneumonia. Methods: We recruited 82 intubated patients from two intensive care units (San Gerardo Hospital, Monza, Italy, and Massachusetts General Hospital, Boston, MA, USA) undergoing bronchoalveolar lavage (BAL) as per clinical decision. We collected BAL fluid and plasma samples, together with relevant clinical and microbiological data. We assayed PTX3 and soluble triggering receptor expressed on myeloid cells 1 (sTREM-1) in BAL fluid and PTX3, sTREM-1, C-reactive protein (CRP) and procalcitonin (PCT) in plasma. Two blinded independent physicians reviewed patient data to confirm pneumonia. We determined the PTX3 threshold in BAL fluid for pneumonia and compared it to other biomarkers. Results: Microbiologically confirmed pneumonia of bacterial (n =12), viral (n =4) or fungal (n =8) etiology was diagnosed in 24 patients (29%). PTX3 levels in BAL fluid predicted pneumonia with an area under the receiving operator curve of 0.815 (95% CI =0.710 to 0.921, P <0.0001), whereas none of the other biomarkers were effective. In particular, PTX3 levels ≥1 ng/ml in BAL fluid predicted pneumonia in univariate analysis (β =2.784, SE =0.792, P <0.001) with elevated sensitivity (92%), specificity (60%) and negative predictive value (95%). Net reclassification index PTX3 values ≥1 ng/ml in BAL fluid for pneumonia indicated gain in sensitivity and/or specificity vs. all other mediators. These results did not change when we limited our analyses only to confirmed cases of bacterial pneumonia. Moreover, when we considered only the 70 patients who fulfilled the clinical criteria for the diagnosis of pneumonia at BAL fluid sampling, the diagnostic accuracy of PTX levels was confirmed in univariate and ROC curve analysis. Conclusions: In this hypothesis-generating convenience sample, a PTX3 level ≥1 ng/ml in BAL fluid was discriminative of microbiologically confirmed pneumonia in mechanically ventilated patients. Electronic supplementary material The online version of this article (doi:10.1186/s13054-014-0562-5) contains supplementary material, which is available to authorized users.

Published
2014
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2. Defining the role of common variation in the genomic and biological architecture of adult human height

Author

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, and Frayling, Timothy M

Abstract

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.

Published
2014
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3. Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture

Author

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

Abstract

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

Published
2014
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4. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis

Author

Beecham, Ashley H, Patsopoulos, Nikolaos A, Xifara, Dionysia K, Davis, Mary F, Kemppinen, Anu, Cotsapas, Chris, Shahi, Tejas S, Spencer, Chris, Booth, David, Goris, An, Oturai, Annette, Saarela, Janna, Fontaine, Bertrand, Hemmer, Bernhard, Martin, Claes, Zipp, Frauke, D’alfonso, Sandra, Martinelli-Boneschi, Filippo, Taylor, Bruce, Harbo, Hanne F, Kockum, Ingrid, Hillert, Jan, Olsson, Tomas, Ban, Maria, Oksenberg, Jorge R, Hintzen, Rogier, Barcellos, Lisa F, Agliardi, Cristina, Alfredsson, Lars, Alizadeh, Mehdi, Anderson, Carl, Andrews, Robert, Søndergaard, Helle Bach, Baker, Amie, Band, Gavin, Baranzini, Sergio E, Barizzone, Nadia, Barrett, Jeffrey, Bellenguez, Céline, Bergamaschi, Laura, Bernardinelli, Luisa, Berthele, Achim, Biberacher, Viola, Binder, Thomas M C, Blackburn, Hannah, Bomfim, Izaura L, Brambilla, Paola, Broadley, Simon, Brochet, Bruno, Brundin, Lou, Buck, Dorothea, Butzkueven, Helmut, Caillier, Stacy J, Camu, William, Carpentier, Wassila, Cavalla, Paola, Celius, Elisabeth G, Coman, Irène, Comi, Giancarlo, Corrado, Lucia, Cosemans, Leentje, Cournu-Rebeix, Isabelle, Cree, Bruce A C, Cusi, Daniele, Damotte, Vincent, Defer, Gilles, Delgado, Silvia R, Deloukas, Panos, di Sapio, Alessia, Dilthey, Alexander T, Donnelly, Peter, Dubois, Bénédicte, Duddy, Martin, Edkins, Sarah, Elovaara, Irina, Esposito, Federica, Evangelou, Nikos, Fiddes, Barnaby, Field, Judith, Franke, Andre, Freeman, Colin, Frohlich, Irene Y, Galimberti, Daniela, Gieger, Christian, Gourraud, Pierre-Antoine, Graetz, Christiane, Graham, Andrew, Grummel, Verena, Guaschino, Clara, Hadjixenofontos, Athena, Hakonarson, Hakon, Halfpenny, Christopher, Hall, Gillian, Hall, Per, Hamsten, Anders, Harley, James, Harrower, Timothy, Hawkins, Clive, Hellenthal, Garrett, Hillier, Charles, Hobart, Jeremy, Hoshi, Muni, Hunt, Sarah E, Jagodic, Maja, Jelčić, Ilijas, Jochim, Angela, Kendall, Brian, Kermode, Allan, Kilpatrick, Trevor, Koivisto, Keijo, Konidari, Ioanna, Korn, Thomas, Kronsbein, Helena, Langford, Cordelia, Larsson, Malin, Lathrop, Mark, Lebrun-Frenay, Christine, Lechner-Scott, Jeannette, Lee, Michelle H, Leone, Maurizio A, Leppä, Virpi, Liberatore, Giuseppe, Lie, Benedicte A, Lill, Christina M, Lindén, Magdalena, Link, Jenny, Luessi, Felix, Lycke, Jan, Macciardi, Fabio, Männistö, Satu, Manrique, Clara P, Martin, Roland, Martinelli, Vittorio, Mason, Deborah, Mazibrada, Gordon, McCabe, Cristin, Mero, Inger-Lise, Mescheriakova, Julia, Moutsianas, Loukas, Myhr, Kjell-Morten, Nagels, Guy, Nicholas, Richard, Nilsson, Petra, Piehl, Fredrik, Pirinen, Matti, Price, Siân E, Quach, Hong, Reunanen, Mauri, Robberecht, Wim, Robertson, Neil P, Rodegher, Mariaemma, Rog, David, Salvetti, Marco, Schnetz-Boutaud, Nathalie C, Sellebjerg, Finn, Selter, Rebecca C, Schaefer, Catherine, Shaunak, Sandip, Shen, Ling, Shields, Simon, Siffrin, Volker, Slee, Mark, Sorensen, Per Soelberg, Sorosina, Melissa, Sospedra, Mireia, Spurkland, Anne, Strange, Amy, Sundqvist, Emilie, Thijs, Vincent, Thorpe, John, Ticca, Anna, Tienari, Pentti, van Duijn, Cornelia, Visser, Elizabeth M, Vucic, Steve, Westerlind, Helga, Wiley, James S, Wilkins, Alastair, Wilson, James F, Winkelmann, Juliane, Zajicek, John, Zindler, Eva, Haines, Jonathan L, Pericak-Vance, Margaret A, Ivinson, Adrian J, Stewart, Graeme, Hafler, David, Hauser, Stephen L, Compston, Alastair, McVean, Gil, De Jager, Philip, Sawcer, Stephen, and McCauley, Jacob L

Abstract

Using the ImmunoChip custom genotyping array, we analysed 14,498 multiple sclerosis subjects and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (p-value < 1.0 × 10-4). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 multiple sclerosis subjects and 26,703 healthy controls. In these 80,094 individuals of European ancestry we identified 48 new susceptibility variants (p-value < 5.0 × 10-8); three found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants in 103 discrete loci outside of the Major Histocompatibility Complex. With high resolution Bayesian fine-mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalogue of multiple sclerosis risk variants and illustrates the value of fine-mapping in the resolution of GWAS signals.

Published
2013
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5. Discovery and Refinement of Loci Associated with Lipid Levels

Author

Willer, Cristen J., Schmidt, Ellen M., Sengupta, Sebanti, Peloso, Gina M., Gustafsson, Stefan, Kanoni, Stavroula, Ganna, Andrea, Chen, Jin, Buchkovich, Martin L., Mora, Samia, Beckmann, Jacques S., Bragg-Gresham, Jennifer L., Chang, Hsing-Yi, Demirkan, Ayşe, Den Hertog, Heleen M., Do, Ron, Donnelly, Louise A., Ehret, Georg B., Esko, Tõnu, Feitosa, Mary F., Ferreira, Teresa, Fischer, Krista, Fontanillas, Pierre, Fraser, Ross M., Freitag, Daniel F., Gurdasani, Deepti, Heikkilä, Kauko, Hyppönen, Elina, Isaacs, Aaron, Jackson, Anne U., Johansson, Åsa, Johnson, Toby, Kaakinen, Marika, Kettunen, Johannes, Kleber, Marcus E., Li, Xiaohui, Luan, Jian’an, Lyytikäinen, Leo-Pekka, Magnusson, Patrik K.E., Mangino, Massimo, Mihailov, Evelin, Montasser, May E., Müller-Nurasyid, Martina, Nolte, Ilja M., O’Connell, Jeffrey R., Palmer, Cameron D., Perola, Markus, Petersen, Ann-Kristin, Sanna, Serena, Saxena, Richa, Service, Susan K., Shah, Sonia, Shungin, Dmitry, Sidore, Carlo, Song, Ci, Strawbridge, Rona J., Surakka, Ida, Tanaka, Toshiko, Teslovich, Tanya M., Thorleifsson, Gudmar, Van den Herik, Evita G., Voight, Benjamin F., Volcik, Kelly A., Waite, Lindsay L., Wong, Andrew, Wu, Ying, Zhang, Weihua, Absher, Devin, Asiki, Gershim, Barroso, Inês, Been, Latonya F., Bolton, Jennifer L., Bonnycastle, Lori L, Brambilla, Paolo, Burnett, Mary S., Cesana, Giancarlo, Dimitriou, Maria, Doney, Alex S.F., Döring, Angela, Elliott, Paul, Epstein, Stephen E., Ingi Eyjolfsson, Gudmundur, Gigante, Bruna, Goodarzi, Mark O., Grallert, Harald, Gravito, Martha L., Groves, Christopher J., Hallmans, Göran, Hartikainen, Anna-Liisa, Hayward, Caroline, Hernandez, Dena, Hicks, Andrew A., Holm, Hilma, Hung, Yi-Jen, Illig, Thomas, Jones, Michelle R., Kaleebu, Pontiano, Kastelein, John J.P., Khaw, Kay-Tee, Kim, Eric, Klopp, Norman, Komulainen, Pirjo, Kumari, Meena, Langenberg, Claudia, Lehtimäki, Terho, Lin, Shih-Yi, Lindström, Jaana, Loos, Ruth J.F., Mach, François, McArdle, Wendy L, Meisinger, Christa, Mitchell, Braxton D., Müller, Gabrielle, Nagaraja, Ramaiah, Narisu, Narisu, Nieminen, Tuomo V.M., Nsubuga, Rebecca N., Olafsson, Isleifur, Ong, Ken K., Palotie, Aarno, Papamarkou, Theodore, Pomilla, Cristina, Pouta, Anneli, Rader, Daniel J., Reilly, Muredach P., Ridker, Paul M., Rivadeneira, Fernando, Rudan, Igor, Ruokonen, Aimo, Samani, Nilesh, Scharnagl, Hubert, Seeley, Janet, Silander, Kaisa, Stančáková, Alena, Stirrups, Kathleen, Swift, Amy J., Tiret, Laurence, Uitterlinden, Andre G., van Pelt, L. Joost, Vedantam, Sailaja, Wainwright, Nicholas, Wijmenga, Cisca, Wild, Sarah H., Willemsen, Gonneke, Wilsgaard, Tom, Wilson, James F., Young, Elizabeth H., Zhao, Jing Hua, Adair, Linda S., Arveiler, Dominique, Assimes, Themistocles L., Bandinelli, Stefania, Bennett, Franklyn, Bochud, Murielle, Boehm, Bernhard O., Boomsma, Dorret I., Borecki, Ingrid B., Bornstein, Stefan R., Bovet, Pascal, Burnier, Michel, Campbell, Harry, Chakravarti, Aravinda, Chambers, John C., Chen, Yii-Der Ida, Collins, Francis S., Cooper, Richard S., Danesh, John, Dedoussis, George, de Faire, Ulf, Feranil, Alan B., Ferrières, Jean, Ferrucci, Luigi, Freimer, Nelson B., Gieger, Christian, Groop, Leif C., Gudnason, Vilmundur, Gyllensten, Ulf, Hamsten, Anders, Harris, Tamara B., Hingorani, Aroon, Hirschhorn, Joel N., Hofman, Albert, Hovingh, G. Kees, Hsiung, Chao Agnes, Humphries, Steve E., Hunt, Steven C., Hveem, Kristian, Iribarren, Carlos, Järvelin, Marjo-Riitta, Jula, Antti, Kähönen, Mika, Kaprio, Jaakko, Kesäniemi, Antero, Kivimaki, Mika, Kooner, Jaspal S., Koudstaal, Peter J., Krauss, Ronald M., Kuh, Diana, Kuusisto, Johanna, Kyvik, Kirsten O., Laakso, Markku, Lakka, Timo A., Lind, Lars, Lindgren, Cecilia M., Martin, Nicholas G., März, Winfried, McCarthy, Mark I., McKenzie, Colin A., Meneton, Pierre, Metspalu, Andres, Moilanen, Leena, Morris, Andrew D., Munroe, Patricia B., Njølstad, Inger, Pedersen, Nancy L., Power, Chris, Pramstaller, Peter P., Price, Jackie F., Psaty, Bruce M., Quertermous, Thomas, Rauramaa, Rainer, Saleheen, Danish, Salomaa, Veikko, Sanghera, Dharambir K., Saramies, Jouko, Schwarz, Peter E.H., Sheu, Wayne H-H, Shuldiner, Alan R., Siegbahn, Agneta, Spector, Tim D., Stefansson, Kari, Strachan, David P., Tayo, Bamidele O., Tremoli, Elena, Tuomilehto, Jaakko, Uusitupa, Matti, van Duijn, Cornelia M., Vollenweider, Peter, Wallentin, Lars, Wareham, Nicholas J., Whitfield, John B., Wolffenbuttel, Bruce H.R., Ordovas, Jose M., Boerwinkle, Eric, Palmer, Colin N.A., Thorsteinsdottir, Unnur, Chasman, Daniel I., Rotter, Jerome I., Franks, Paul W., Ripatti, Samuli, Cupples, L. Adrienne, Sandhu, Manjinder S., Rich, Stephen S., Boehnke, Michael, Deloukas, Panos, Kathiresan, Sekar, Mohlke, Karen L., Ingelsson, Erik, and Abecasis, Gonçalo R.

Abstract

Low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, and total cholesterol are heritable, modifiable, risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,578 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5×10−8, including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian, and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipids are often associated with cardiovascular and metabolic traits including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio, and body mass index. Our results illustrate the value of genetic data from individuals of diverse ancestries and provide insights into biological mechanisms regulating blood lipids to guide future genetic, biological, and therapeutic research.

Published
2013
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6. Common variants associated with plasma triglycerides and risk for coronary artery disease

Author

Do, Ron, Willer, Cristen J., Schmidt, Ellen M., Sengupta, Sebanti, Gao, Chi, Peloso, Gina M., Gustafsson, Stefan, Kanoni, Stavroula, Ganna, Andrea, Chen, Jin, Buchkovich, Martin L., Mora, Samia, Beckmann, Jacques S., Bragg-Gresham, Jennifer L., Chang, Hsing-Yi, Demirkan, Ayşe, Den Hertog, Heleen M., Donnelly, Louise A., Ehret, Georg B., Esko, Tõnu, Feitosa, Mary F., Ferreira, Teresa, Fischer, Krista, Fontanillas, Pierre, Fraser, Ross M., Freitag, Daniel F., Gurdasani, Deepti, Heikkilä, Kauko, Hyppönen, Elina, Isaacs, Aaron, Jackson, Anne U., Johansson, Åsa, Johnson, Toby, Kaakinen, Marika, Kettunen, Johannes, Kleber, Marcus E., Li, Xiaohui, Luan, Jian'an, Lyytikäinen, Leo-Pekka, Magnusson, Patrik K.E., Mangino, Massimo, Mihailov, Evelin, Montasser, May E., Müller-Nurasyid, Martina, Nolte, Ilja M., O'Connell, Jeffrey R., Palmer, Cameron D., Perola, Markus, Petersen, Ann-Kristin, Sanna, Serena, Saxena, Richa, Service, Susan K., Shah, Sonia, Shungin, Dmitry, Sidore, Carlo, Song, Ci, Strawbridge, Rona J., Surakka, Ida, Tanaka, Toshiko, Teslovich, Tanya M., Thorleifsson, Gudmar, Van den Herik, Evita G., Voight, Benjamin F., Volcik, Kelly A., Waite, Lindsay L., Wong, Andrew, Wu, Ying, Zhang, Weihua, Absher, Devin, Asiki, Gershim, Barroso, Inês, Been, Latonya F., Bolton, Jennifer L., Bonnycastle, Lori L, Brambilla, Paolo, Burnett, Mary S., Cesana, Giancarlo, Dimitriou, Maria, Doney, Alex S.F., Döring, Angela, Elliott, Paul, Epstein, Stephen E., Eyjolfsson, Gudmundur Ingi, Gigante, Bruna, Goodarzi, Mark O., Grallert, Harald, Gravito, Martha L., Groves, Christopher J., Hallmans, Göran, Hartikainen, Anna-Liisa, Hayward, Caroline, Hernandez, Dena, Hicks, Andrew A., Holm, Hilma, Hung, Yi-Jen, Illig, Thomas, Jones, Michelle R., Kaleebu, Pontiano, Kastelein, John J.P., Khaw, Kay-Tee, Kim, Eric, Klopp, Norman, Komulainen, Pirjo, Kumari, Meena, Langenberg, Claudia, Lehtimäki, Terho, Lin, Shih-Yi, Lindström, Jaana, Loos, Ruth J.F., Mach, François, McArdle, Wendy L, Meisinger, Christa, Mitchell, Braxton D., Müller, Gabrielle, Nagaraja, Ramaiah, Narisu, Narisu, Nieminen, Tuomo V.M., Nsubuga, Rebecca N., Olafsson, Isleifur, Ong, Ken K., Palotie, Aarno, Papamarkou, Theodore, Pomilla, Cristina, Pouta, Anneli, Rader, Daniel J., Reilly, Muredach P., Ridker, Paul M., Rivadeneira, Fernando, Rudan, Igor, Ruokonen, Aimo, Samani, Nilesh, Scharnagl, Hubert, Seeley, Janet, Silander, Kaisa, Stančáková, Alena, Stirrups, Kathleen, Swift, Amy J., Tiret, Laurence, Uitterlinden, Andre G., van Pelt, L. Joost, Vedantam, Sailaja, Wainwright, Nicholas, Wijmenga, Cisca, Wild, Sarah H., Willemsen, Gonneke, Wilsgaard, Tom, Wilson, James F., Young, Elizabeth H., Zhao, Jing Hua, Adair, Linda S., Arveiler, Dominique, Assimes, Themistocles L., Bandinelli, Stefania, Bennett, Franklyn, Bochud, Murielle, Boehm, Bernhard O., Boomsma, Dorret I., Borecki, Ingrid B., Bornstein, Stefan R., Bovet, Pascal, Burnier, Michel, Campbell, Harry, Chakravarti, Aravinda, Chambers, John C., Chen, Yii-Der Ida, Collins, Francis S., Cooper, Richard S., Danesh, John, Dedoussis, George, de Faire, Ulf, Feranil, Alan B., Ferrières, Jean, Ferrucci, Luigi, Freimer, Nelson B., Gieger, Christian, Groop, Leif C., Gudnason, Vilmundur, Gyllensten, Ulf, Hamsten, Anders, Harris, Tamara B., Hingorani, Aroon, Hirschhorn, Joel N., Hofman, Albert, Hovingh, G. Kees, Hsiung, Chao Agnes, Humphries, Steve E., Hunt, Steven C., Hveem, Kristian, Iribarren, Carlos, Järvelin, Marjo-Riitta, Jula, Antti, Kähönen, Mika, Kaprio, Jaakko, Kesäniemi, Antero, Kivimaki, Mika, Kooner, Jaspal S., Koudstaal, Peter J., Krauss, Ronald M., Kuh, Diana, Kuusisto, Johanna, Kyvik, Kirsten O., Laakso, Markku, Lakka, Timo A., Lind, Lars, Lindgren, Cecilia M., Martin, Nicholas G., März, Winfried, McCarthy, Mark I., McKenzie, Colin A., Meneton, Pierre, Metspalu, Andres, Moilanen, Leena, Morris, Andrew D., Munroe, Patricia B., Njølstad, Inger, Pedersen, Nancy L., Power, Chris, Pramstaller, Peter P., Price, Jackie F., Psaty, Bruce M., Quertermous, Thomas, Rauramaa, Rainer, Saleheen, Danish, Salomaa, Veikko, Sanghera, Dharambir K., Saramies, Jouko, Schwarz, Peter E.H., Sheu, Wayne H-H, Shuldiner, Alan R., Siegbahn, Agneta, Spector, Tim D., Stefansson, Kari, Strachan, David P., Tayo, Bamidele O., Tremoli, Elena, Tuomilehto, Jaakko, Uusitupa, Matti, van Duijn, Cornelia M., Vollenweider, Peter, Wallentin, Lars, Wareham, Nicholas J., Whitfield, John B., Wolffenbuttel, Bruce H.R., Altshuler, David, Ordovas, Jose M., Boerwinkle, Eric, Palmer, Colin N.A., Thorsteinsdottir, Unnur, Chasman, Daniel I., Rotter, Jerome I., Franks, Paul W., Ripatti, Samuli, Cupples, L. Adrienne, Sandhu, Manjinder S., Rich, Stephen S., Boehnke, Michael, Deloukas, Panos, Mohlke, Karen L., Ingelsson, Erik, Abecasis, Goncalo R., Daly, Mark J., Neale, Benjamin M., and Kathiresan, Sekar

Abstract

Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiologic studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P<5×10−8 for each) to examine the role of triglycerides on risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglycerides, and show that the direction and magnitude of both are factors in determining CAD risk. Second, we consider loci with only a strong magnitude of association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol, a polymorphism's strength of effect on triglycerides is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.

Published
2013
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7. Persistent Inflammation Alters the Function of the Endogenous Brain Stem Cell Compartment

Author

Pluchino, Stefano, Muzio, Luca, Alfaro-Cervello, Clara, Salani, Giuliana, Porcheri, Cristina, Brambilla, Elena, Cavasinni, Francesca, Bergamaschi, Andrea, Garcia-Verdugo, Jose Manuel, Comi, Giancarlo, Martino, Gianvito, Imitola, Jaime, Deleidi, Michela, and Khoury, Samia Joseph

Subjects
neurogenesis, neural stem cells, inflammation, experimental autoimmune encephalomyelitis, multiple sclerosis
Abstract

Endogenous neural stem/precursor cells (NPCs) are considered a functional reservoir for promoting tissue homeostasis and repair after injury, therefore regenerative strategies that mobilize these cells have recently been proposed. Despite evidence of increased neurogenesis upon acute inflammatory insults (e.g. ischaemic stroke), the plasticity of the endogenous brain stem cell compartment in chronic CNS inflammatory disorders remains poorly characterized. Here we show that persistent brain inflammation, induced by immune cells targeting myelin, extensively alters the proliferative and migratory properties of subventricular zone (SVZ)-resident NPCs in vivo leading to significant accumulation of non-migratory neuroblasts within the SVZ germinal niche. In parallel, we demonstrate a quantitative reduction of the putative brain stem cells proliferation in the SVZ during persistent brain inflammation, which is completely reversed after in vitro culture of the isolated NPCs. Together, these data indicate that the inflamed brain microenvironment sustains a non cell-autonomous dysfunction of the endogenous CNS stem cell compartment and challenge the potential efficacy of proposed therapies aimed at mobilizing endogenous precursors in chronic inflammatory brain disorders.

Published
2008
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