Nature Genetics

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Genome-wide association study identifies two susceptibility loci for osteosarcoma.

Publication Date: 2013 Jun 2 PMID: 23727862
Authors: Savage, S. A. - Mirabello, L. - Wang, Z. - Gastier-Foster, J. M. - Gorlick, R. - Khanna, C. - Flanagan, A. M. - Tirabosco, R. - Andrulis, I. L. - Wunder, J. S. - Gokgoz, N. - Patino-Garcia, A. - Sierrasesumaga, L. - Lecanda, F. - Kurucu, N. - Ilhan, I. E. - Sari, N. - Serra, M. - Hattinger, C. - Picci, P. - Spector, L. G. - Barkauskas, D. A. - Marina, N. - de Toledo, S. R. - Petrilli, A. S. - Amary, M. F. - Halai, D. - Thomas, D. M. - Douglass, C. - Meltzer, P. S. - Jacobs, K. - Chung, C. C. - Berndt, S. I. - Purdue, M. P. - Caporaso, N. E. - Tucker, M. - Rothman, N. - Landi, M. T. - Silverman, D. T. - Kraft, P. - Hunter, D. J. - Malats, N. - Kogevinas, M. - Wacholder, S. - Troisi, R. - Helman, L. - Fraumeni, J. F. Jr - Yeager, M. - Hoover, R. N. - Chanock, S. J.
Journal: Nat Genet

Osteosarcoma is the most common primary bone malignancy of adolescents and young adults. To better understand the genetic etiology of osteosarcoma, we performed a multistage genome-wide association study consisting of 941 individuals with osteosarcoma (cases) and 3,291 cancer-free adult controls of European ancestry. Two loci achieved genome-wide significance: a locus in the GRM4 gene at 6p21.3 (encoding glutamate receptor metabotropic 4; rs1906953; P = 8.1 x 10-9) and a locus in the gene desert at 2p25.2 (rs7591996 and rs10208273; P = 1.0 x 10-8 and 2.9 x 10-7, respectively). These two loci warrant further exploration to uncover the biological mechanisms underlying susceptibility to osteosarcoma.

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Zbtb7a suppresses prostate cancer through repression of a Sox9-dependent pathway for cellular senescence bypass and tumor invasion.

Publication Date: 2013 Jun 2 PMID: 23727861
Authors: Wang, G. - Lunardi, A. - Zhang, J. - Chen, Z. - Ala, U. - Webster, K. A. - Tay, Y. - Gonzalez-Billalabeitia, E. - Egia, A. - Shaffer, D. R. - Carver, B. - Liu, X. S. - Taulli, R. - Kuo, W. P. - Nardella, C. - Signoretti, S. - Cordon-Cardo, C. - Gerald, W. L. - Pandolfi, P. P.
Journal: Nat Genet

Zbtb7a has previously been described as a powerful proto-oncogene. Here we unexpectedly demonstrate that Zbtb7a has a critical oncosuppressive role in the prostate. Prostate-specific inactivation of Zbtb7a leads to a marked acceleration of Pten loss-driven prostate tumorigenesis through bypass of Pten loss-induced cellular senescence (PICS). We show that ZBTB7A physically interacts with SOX9 and functionally antagonizes its transcriptional activity on key target genes such as MIA, which is involved in tumor cell invasion, and H19, a long noncoding RNA precursor for an RB-targeting microRNA. Inactivation of Zbtb7a in vivo leads to Rb downregulation, PICS bypass and invasive prostate cancer. Notably, we found that ZBTB7A is genetically lost, as well as downregulated at both the mRNA and protein levels, in a subset of human advanced prostate cancers. Thus, we identify ZBTB7A as a context-dependent cancer gene that can act as an oncogene in some contexts but also has oncosuppressive-like activity in PTEN-null tumors.

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A co-clinical approach identifies mechanisms and potential therapies for androgen deprivation resistance in prostate cancer.

Publication Date: 2013 Jun 2 PMID: 23727860
Authors: Lunardi, A. - Ala, U. - Epping, M. T. - Salmena, L. - Clohessy, J. G. - Webster, K. A. - Wang, G. - Mazzucchelli, R. - Bianconi, M. - Stack, E. C. - Lis, R. - Patnaik, A. - Cantley, L. C. - Bubley, G. - Cordon-Cardo, C. - Gerald, W. L. - Montironi, R. - Signoretti, S. - Loda, M. - Nardella, C. - Pandolfi, P. P.
Journal: Nat Genet

Here we report an integrated analysis that leverages data from treatment of genetic mouse models of prostate cancer along with clinical data from patients to elucidate new mechanisms of castration resistance. We show that castration counteracts tumor progression in a Pten loss-driven mouse model of prostate cancer through the induction of apoptosis and proliferation block. Conversely, this response is bypassed with deletion of either Trp53 or Zbtb7a together with Pten, leading to the development of castration-resistant prostate cancer (CRPC). Mechanistically, the integrated acquisition of data from mouse models and patients identifies the expression patterns of XAF1, XIAP and SRD5A1 as a predictive and actionable signature for CRPC. Notably, we show that combined inhibition of XIAP, SRD5A1 and AR pathways overcomes castration resistance. Thus, our co-clinical approach facilitates the stratification of patients and the development of tailored and innovative therapeutic treatments.

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High-density genotyping study identifies four new susceptibility loci for atopic dermatitis.

Publication Date: 2013 Jun 2 PMID: 23727859
Authors: Ellinghaus, D. - Baurecht, H. - Esparza-Gordillo, J. - Rodriguez, E. - Matanovic, A. - Marenholz, I. - Hubner, N. - Schaarschmidt, H. - Novak, N. - Michel, S. - Maintz, L. - Werfel, T. - Meyer-Hoffert, U. - Hotze, M. - Prokisch, H. - Heim, K. - Herder, C. - Hirota, T. - Tamari, M. - Kubo, M. - Takahashi, A. - Nakamura, Y. - Tsoi, L. C. - Stuart, P. - Elder, J. T. - Sun, L. - Zuo, X. - Yang, S. - Zhang, X. - Hoffmann, P. - Nothen, M. M. - Folster-Holst, R. - Winkelmann, J. - Illig, T. - Boehm, B. O. - Duerr, R. H. - Buning, C. - Brand, S. - Glas, J. - McAleer, M. A. - Fahy, C. M. - Kabesch, M. - Brown, S. - McLean, W. H. - Irvine, A. D. - Schreiber, S. - Lee, Y. A. - Franke, A. - Weidinger, S.
Journal: Nat Genet

Atopic dermatitis is a common inflammatory skin disease with a strong heritable component. Pathogenetic models consider keratinocyte differentiation defects and immune alterations as scaffolds, and recent data indicate a role for autoreactivity in at least a subgroup of patients. FLG (encoding filaggrin) has been identified as a major locus causing skin barrier deficiency. To better define risk variants and identify additional susceptibility loci, we densely genotyped 2,425 German individuals with atopic dermatitis (cases) and 5,449 controls using the Immunochip array followed by replication in 7,196 cases and 15,480 controls from Germany, Ireland, Japan and China. We identified four new susceptibility loci for atopic dermatitis and replicated previous associations. This brings the number of atopic dermatitis risk loci reported in individuals of European ancestry to 11. We estimate that these susceptibility loci together account for 14.4% of the heritability for atopic dermatitis.

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Genome-wide association analyses in Han Chinese identify two new susceptibility loci for amyotrophic lateral sclerosis.

Publication Date: 2013 May 29 PMID: 23715337
Authors: Deng, M. - Wei, L. - Zuo, X. - Tian, Y. - Xie, F. - Hu, P. - Zhu, C. - Yu, F. - Meng, Y. - Wang, H. - Zhang, F. - Ma, H. - Ye, R. - Cheng, H. - Du, J. - Dong, W. - Zhou, S. - Wang, C. - Wang, Y. - Wang, J. - Chen, X. - Sun, Z. - Zhou, N. - Jiang, Y. - Liu, X. - Li, X. - Zhang, N. - Liu, N. - Guan, Y. - Han, Y. - Han, Y. - Lv, X. - Fu, Y. - Yu, H. - Xi, C. - Xie, D. - Zhao, Q. - Xie, P. - Wang, X. - Zhang, Z. - Shen, L. - Cui, Y. - Yin, X. - Cheng, H. - Liang, B. - Zheng, X. - Lee, T. M. - Chen, G. - Zhou, F. - Veldink, J. H. - Robberecht, W. - Landers, J. E. - Andersen, P. M. - Al-Chalabi, A. - Shaw, C. - Liu, C. - Tang, B. - Xiao, S. - Robertson, J. - Zhang, F. - van den Berg, L. H. - Sun, L. - Liu, J. - Yang, S. - Ju, X. - Wang, K. - Zhang, X.
Journal: Nat Genet

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Common variants at 6q22 and 17q21 are associated with intracranial volume.

Publication Date: 2013 May 29 PMID: 23715335
Authors: Ikram, M. A. - Fornage, M. - Smith, A. V. - Seshadri, S. - Schmidt, R. - Debette, S. - Vrooman, H. A. - Sigurdsson, S. - Ropele, S. - Taal, H. R. - Mook-Kanamori, D. O. - Coker, L. H. - Longstreth, W. T. Jr - Niessen, W. J. - Destefano, A. L. - Beiser, A. - Zijdenbos, A. P. - Struchalin, M. - Jack, C. R. Jr - Rivadeneira, F. - Uitterlinden, A. G. - Knopman, D. S. - Hartikainen, A. L. - Pennell, C. E. - Thiering, E. - Steegers, E. A. - Hakonarson, H. - Heinrich, J. - Palmer, L. J. - Jarvelin, M. R. - McCarthy, M. I. - Grant, S. F. - Pourcain, B. S. - Timpson, N. J. - Smith, G. D. - Sovio, U. - Nalls, M. A. - Au, R. - Hofman, A. - Gudnason, H. - van der Lugt, A. - Harris, T. B. - Meeks, W. M. - Vernooij, M. W. - van Buchem, M. A. - Catellier, D. - Jaddoe, V. W. - Gudnason, V. - Windham, B. G. - Wolf, P. A. - van Duijn, C. M. - Mosley, T. H. Jr - Schmidt, H. - Launer, L. J. - Breteler, M. M. - Decarli, C. - Adair, L. S. - Ang, W. - Atalay, M. - van Beijsterveldt, T. - Bergen, N. - Benke, K. - Berry, D. - Coin, L. - Davis, O. S. - Elliott, P. - Flexeder, C. - Frayling, T. - Gaillard, R. - Groen-Blokhuis, M. - Goh, L. K. - Haworth, C. M. - Hadley, D. - Hedebrand, J. - Hinney, A. - Hirschhorn, J. N. - Holloway, J. W. - Holst, C. - Jan Hottenga, J. - Horikoshi, M. - Huikari, V. - Hypponen, E. - Kilpelainen, T. O. - Kirin, M. - Kowgier, M. - Lakka, H. M. - Lange, L. A. - Lawlor, D. A. - Lehtimaki, T. - Lewin, A. - Lindgren, C. - Lindi, V. - Maggi, R. - Marsh, J. - Middeldorp, C. - Millwood, I. - Murray, J. C. - Nivard, M. - Nohr, E. A. - Ntalla, I. - Oken, E. - Panoutsopoulou, K. - Pararajasingham, J. - Rodriguez, A. - Salem, R. M. - Sebert, S. - Siitonen, N. - Strachan, D. P. - Teo, Y. Y. - Valcarcel, B. - Willemsen, G. - Zeggini, E. - Boomsma, D. I. - Cooper, C. - Gillman, M. - Hocher, B. - Lakka, T. A. - Mohlke, K. L. - Dedoussis, G. V. - Ong, K. K. - Pearson, E. R. - Price, T. S. - Power, C. - Raitakari, O. T. - Saw, S. M. - Scherag, A. - Simell, O. - Wilson, J. F.
Journal: Nat Genet

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Common variants at 12q15 and 12q24 are associated with infant head circumference.

Publication Date: 2013 May 29 PMID: 23715334
Authors: Taal, H. R. - St Pourcain, B. - Thiering, E. - Das, S. - Mook-Kanamori, D. O. - Warrington, N. M. - Kaakinen, M. - Kreiner-Moller, E. - Bradfield, J. P. - Freathy, R. M. - Geller, F. - Guxens, M. - Cousminer, D. L. - Kerkhof, M. - Timpson, N. J. - Ikram, M. A. - Beilin, L. J. - Bonnelykke, K. - Buxton, J. L. - Charoen, P. - Chawes, B. L. - Eriksson, J. - Evans, D. M. - Hofman, A. - Kemp, J. P. - Kim, C. E. - Klopp, N. - Lahti, J. - Lye, S. J. - McMahon, G. - Mentch, F. D. - Muller-Nurasyid, M. - O'Reilly, P. F. - Prokopenko, I. - Rivadeneira, F. - Steegers, E. A. - Sunyer, J. - Tiesler, C. - Yaghootkar, H. - Ikram, M. A. - Fornage, M. - Smith, A. V. - Seshadri, S. - Schmidt, R. - Debette, S. - Vrooman, H. A. - Sigurdsson, S. - Ropele, S. - Coker, L. H. - Longstreth, W. T. Jr - Niessen, W. J. - Destefano, A. L. - Beiser, A. - Zijdenbos, A. P. - Struchalin, M. - Jack, C. R. Jr - Nalls, M. A. - Au, R. - Hofman, A. - Gudnason, H. - van der Lugt, A. - Harris, T. B. - Meeks, W. M. - Vernooij, M. W. - van Buchem, M. A. - Catellier, D. - Gudnason, V. - Windham, B. G. - Wolf, P. A. - van Duijn, C. M. - Mosley, T. H. Jr - Schmidt, H. - Launer, L. J. - Breteler, M. M. - Decarli, C. - Breteler, M. M. - Debette, S. - Fornage, M. - Gudnason, V. - Launer, L. J. - van der Lugt, A. - Mosley, T. H. Jr - Seshadri, S. - Smith, A. V. - Vernooij, M. W. - Ang, W. - van Beijsterveldt, T. - Bergen, N. - Benke, K. - Berry, D. - Bradfield, J. P. - Charoen, P. - Coin, L. - Cousminer, D. L. - Das, S. - Elliott, P. - Evans, D. M. - Frayling, T. - Freathy, R. M. - Gaillard, R. - Groen-Blokhuis, M. - Guxens, M. - Hadley, D. - Hottenga, J. J. - Huikari, V. - Hypponen, E. - Kaakinen, M. - Kowgier, M. - Lawlor, D. A. - Lewin, A. - Lindgren, C. - Marsh, J. - Middeldorp, C. - Millwood, I. - Mook-Kanamori, D. O. - Nivard, M. - O'Reilly, P. F. - Palmer, L. J. - Prokopenko, I. - Rodriguez, A. - Sebert, S. - Sovio, U. - St Pourcain, B. - Standl, M. - Strachan, D. P. - Sunyer, J. - Taal, H. R. - Thiering, E. - Tiesler, C. - Uitterlinden, A. G. - Valcarcel, B. - Warrington, N. M. - White, S. - Willemsen, G. - Yaghootkar, H. - Boomsma, D. I. - Estivill, X. - Grant, S. F. - Hakonarson, H. - Hattersley, A. T. - Heinrich, J. - Jaddoe, V. W. - Jarvelin, M. R. - McCarthy, M. I. - Pennell, C. E. - Power, C. - Timpson, N. J. - Widen, E. - Blakemore, A. I. - Chiavacci, R. M. - Feenstra, B. - Fernandez-Banet, J. - Grant, S. F. - Hartikainen, A. L. - van der Heijden, A. J. - Iniguez, C. - Lathrop, M. - McArdle, W. L. - Molgaard, A. - Newnham, J. P. - Palmer, L. J. - Palotie, A. - Pouta, A. - Ring, S. M. - Sovio, U. - Standl, M. - Uitterlinden, A. G. - Wichmann, H. E. - Vissing, N. H. - Decarli, C. - van Duijn, C. M. - McCarthy, M. I. - Koppelman, G. H. - Estivill, X. - Hattersley, A. T. - Melbye, M. - Bisgaard, H. - Pennell, C. E. - Widen, E. - Hakonarson, H. - Smith, G. D. - Heinrich, J. - Jarvelin, M. R. - Jaddoe, V. W. - Adair, L. S. - Ang, W. - Atalay, M. - van Beijsterveldt, T. - Bergen, N. - Benke, K. - Berry, D. - Bradfield, J. P. - Charoen, P. - Coin, L. - Cousminer, D. L. - Das, S. - Davis, O. S. - Elliott, P. - Evans, D. M. - Feenstra, B. - Flexeder, C. - Frayling, T. - Freathy, R. M. - Gaillard, R. - Geller, F. - Groen-Blokhuis, M. - Goh, L. K. - Guxens, M. - Haworth, C. M. - Hadley, D. - Hedebrand, J. - Hinney, A. - Hirschhorn, J. N. - Holloway, J. W. - Holst, C. - Hottenga, J. J. - Horikoshi, M. - Huikari, V. - Hypponen, E. - Iniguez, C. - Kaakinen, M. - Kilpelainen, T. O. - Kirin, M. - Kowgier, M. - Lakka, H. M. - Lange, L. A. - Lawlor, D. A. - Lehtimaki, T. - Lewin, A. - Lindgren, C. - Lindi, V. - Maggi, R. - Marsh, J. - Middeldorp, C. - Millwood, I. - Mook-Kanamori, D. O. - Murray, J. C. - Nivard, M. - Nohr, E. A. - Ntalla, I. - Oken, E. - O'Reilly, P. F. - Palmer, L. J. - Panoutsopoulou, K. - Pararajasingham, J. - Prokopenko, I. - Rodriguez, A. - Salem, R. M. - Sebert, S. - Siitonen, N. - Sovio, U. - St Pourcain, B. - Strachan, D. P. - Sunyer, J. - Taal, H. R. - Teo, Y. Y. - Thiering, E. - Tiesler, C. - Uitterlinden, A. G. - Valcarcel, B. - Warrington, N. M. - White, S. - Willemsen, G. - Yaghootkar, H. - Zeggini, E. - Boomsma, D. I. - Cooper, C. - Estivill, X. - Gillman, M. - Grant, S. F. - Hakonarson, H. - Hattersley, A. T. - Heinrich, J. - Hocher, B. - Jaddoe, V. W. - Jarvelin, M. R. - Lakka, T. A. - McCarthy, M. I. - Melbye, M. - Mohlke, K. L. - Dedoussis, G. V. - Ong, K. K. - Pearson, E. R. - Pennell, C. E. - Price, T. S. - Power, C. - Raitakari, O. T. - Saw, S. M. - Scherag, A. - Simell, O. - Timpson, N. J. - Widen, E. - Wilson, J. F.
Journal: Nat Genet

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Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease.

Publication Date: 2013 May 29 PMID: 23715333
Authors: Harold, D. - Abraham, R. - Hollingworth, P. - Sims, R. - Gerrish, A. - Hamshere, M. L. - Pahwa, J. S. - Moskvina, V. - Dowzell, K. - Williams, A. - Jones, N. - Thomas, C. - Stretton, A. - Morgan, A. R. - Lovestone, S. - Powell, J. - Proitsi, P. - Lupton, M. K. - Brayne, C. - Rubinsztein, D. C. - Gill, M. - Lawlor, B. - Lynch, A. - Morgan, K. - Brown, K. S. - Passmore, P. A. - Craig, D. - McGuinness, B. - Todd, S. - Holmes, C. - Mann, D. - Smith, A. D. - Love, S. - Kehoe, P. G. - Hardy, J. - Mead, S. - Fox, N. - Rossor, M. - Collinge, J. - Maier, W. - Jessen, F. - Schurmann, B. - Heun, R. - van den Bussche, H. - Heuser, I. - Kornhuber, J. - Wiltfang, J. - Dichgans, M. - Frolich, L. - Hampel, H. - Hull, M. - Rujescu, D. - Goate, A. M. - Kauwe, J. S. - Cruchaga, C. - Nowotny, P. - Morris, J. C. - Mayo, K. - Sleegers, K. - Bettens, K. - Engelborghs, S. - De Deyn, P. P. - Van Broeckhoven, C. - Livingston, G. - Bass, N. J. - Gurling, H. - McQuillin, A. - Gwilliam, R. - Deloukas, P. - Al-Chalabi, A. - Shaw, C. E. - Tsolaki, M. - Singleton, A. B. - Guerreiro, R. - Muhleisen, T. W. - Nothen, M. M. - Moebus, S. - Jockel, K. H. - Klopp, N. - Wichmann, H. E. - Carrasquillo, M. M. - Pankratz, V. S. - Younkin, S. G. - Holmans, P. A. - O'Donovan, M. - Owen, M. J. - Williams, J.
Journal: Nat Genet

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Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia.

Publication Date: 2013 May 29 PMID: 23715332
Authors: Verhoeven, V. J. - Hysi, P. G. - Wojciechowski, R. - Fan, Q. - Guggenheim, J. A. - Hohn, R. - Macgregor, S. - Hewitt, A. W. - Nag, A. - Cheng, C. Y. - Yonova-Doing, E. - Zhou, X. - Ikram, M. K. - Buitendijk, G. H. - McMahon, G. - Kemp, J. P. - Pourcain, B. S. - Simpson, C. L. - Makela, K. M. - Lehtimaki, T. - Kahonen, M. - Paterson, A. D. - Hosseini, S. M. - Wong, H. S. - Xu, L. - Jonas, J. B. - Parssinen, O. - Wedenoja, J. - Yip, S. P. - Ho, D. W. - Pang, C. P. - Chen, L. J. - Burdon, K. P. - Craig, J. E. - Klein, B. E. - Klein, R. - Haller, T. - Metspalu, A. - Khor, C. C. - Tai, E. S. - Aung, T. - Vithana, E. - Tay, W. T. - Barathi, V. A. - Chen, P. - Li, R. - Liao, J. - Zheng, Y. - Ong, R. T. - Doring, A. - Evans, D. M. - Timpson, N. J. - Verkerk, A. J. - Meitinger, T. - Raitakari, O. - Hawthorne, F. - Spector, T. D. - Karssen, L. C. - Pirastu, M. - Murgia, F. - Ang, W. - Mishra, A. - Montgomery, G. W. - Pennell, C. E. - Cumberland, P. M. - Cotlarciuc, I. - Mitchell, P. - Wang, J. J. - Schache, M. - Janmahasatian, S. - Jr, R. P. - Lass, J. H. - Chew, E. - Iyengar, S. K. - Gorgels, T. G. - Rudan, I. - Hayward, C. - Wright, A. F. - Polasek, O. - Vatavuk, Z. - Wilson, J. F. - Fleck, B. - Zeller, T. - Mirshahi, A. - Muller, C. - Uitterlinden, A. G. - Rivadeneira, F. - Vingerling, J. R. - Hofman, A. - Oostra, B. A. - Amin, N. - Bergen, A. A. - Teo, Y. Y. - Rahi, J. S. - Vitart, V. - Williams, C. - Baird, P. N. - Wong, T. Y. - Oexle, K. - Pfeiffer, N. - Mackey, D. A. - Young, T. L. - van Duijn, C. M. - Saw, S. M. - Bailey-Wilson, J. E. - Stambolian, D. - Klaver, C. C. - Hammond, C. J.
Journal: Nat Genet

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Interneurons from pluripotent cells.

Publication Date: 2013 May 29 PMID: 23715331
Authors: Feliciano, P.
Journal: Nat Genet

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Somatic GNAQ mutation.

Publication Date: 2013 May 29 PMID: 23715330
Authors: Niemitz, E.
Journal: Nat Genet

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SETD2 and mismatch repair.

Publication Date: 2013 May 29 PMID: 23715329
Authors: Niemitz, E.
Journal: Nat Genet

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Stimulating beta cell proliferation.

Publication Date: 2013 May 29 PMID: 23715328
Authors: Vogan, K.
Journal: Nat Genet

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Malaria gene allows infection.

Publication Date: 2013 May 29 PMID: 23715327
Authors: Feliciano, P.
Journal: Nat Genet

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Genome sequencing sheds light on emerging drug resistance in malaria parasites.

Publication Date: 2013 May 29 PMID: 23715326
Authors: Neafsey, D. E.
Journal: Nat Genet

Plasmodium falciparum in Southeast Asia are gradually becoming resistant to artemesinin, a standard first-line treatment for malaria. Whole-genome sequencing offers a chance to better understand and perhaps undermine the parasite's evolutionary response to this drug.

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Putting a halt on PRC2 in pediatric glioblastoma.

Publication Date: 2013 May 29 PMID: 23715325
Authors: Voigt, P. - Reinberg, D.
Journal: Nat Genet

Two new studies show that the known histone H3 alteration p.Lys27Met in pediatric glioma leads to globally diminished trimethylation at histone H3 lysine 27. The mutant histone H3 acts as a selective inhibitor of the PRC2 chromatin-modifying complex by binding and presumably sequestering it, shedding light on how this variant may contribute to the etiology of these highly malignant brain tumors.

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A panoramic view of acute myeloid leukemia.

Publication Date: 2013 May 29 PMID: 23715324
Authors: Chen, S. J. - Shen, Y. - Chen, Z.
Journal: Nat Genet

A recent study in the New England Journal of Medicine reports the genomic and epigenomic changes in adult acute myeloid leukemia (AML). The patterns of somatic mutation suggest biologically relevant connections between the functional categories of genes driving AML.

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The Genotype-Tissue Expression (GTEx) project.

Publication Date: 2013 May 29 PMID: 23715323
Authors: Lonsdale, J. - Thomas, J. - Salvatore, M. - Phillips, R. - Lo, E. - Shad, S. - Hasz, R. - Walters, G. - Garcia, F. - Young, N. - Foster, B. - Moser, M. - Karasik, E. - Gillard, B. - Ramsey, K. - Sullivan, S. - Bridge, J. - Magazine, H. - Syron, J. - Fleming, J. - Siminoff, L. - Traino, H. - Mosavel, M. - Barker, L. - Jewell, S. - Rohrer, D. - Maxim, D. - Filkins, D. - Harbach, P. - Cortadillo, E. - Berghuis, B. - Turner, L. - Hudson, E. - Feenstra, K. - Sobin, L. - Robb, J. - Branton, P. - Korzeniewski, G. - Shive, C. - Tabor, D. - Qi, L. - Groch, K. - Nampally, S. - Buia, S. - Zimmerman, A. - Smith, A. - Burges, R. - Robinson, K. - Valentino, K. - Bradbury, D. - Cosentino, M. - Diaz-Mayoral, N. - Kennedy, M. - Engel, T. - Williams, P. - Erickson, K. - Ardlie, K. - Winckler, W. - Getz, G. - Deluca, D. - Macarthur, D. - Kellis, M. - Thomson, A. - Young, T. - Gelfand, E. - Donovan, M. - Meng, Y. - Grant, G. - Mash, D. - Marcus, Y. - Basile, M. - Liu, J. - Zhu, J. - Tu, Z. - Cox, N. J. - Nicolae, D. L. - Gamazon, E. R. - Im, H. K. - Konkashbaev, A. - Pritchard, J. - Stevens, M. - Flutre, T. - Wen, X. - Dermitzakis, E. T. - Lappalainen, T. - Guigo, R. - Monlong, J. - Sammeth, M. - Koller, D. - Battle, A. - Mostafavi, S. - McCarthy, M. - Rivas, M. - Maller, J. - Rusyn, I. - Nobel, A. - Wright, F. - Shabalin, A. - Feolo, M. - Sharopova, N. - Sturcke, A. - Paschal, J. - Anderson, J. M. - Wilder, E. L. - Derr, L. K. - Green, E. D. - Struewing, J. P. - Temple, G. - Volpi, S. - Boyer, J. T. - Thomson, E. J. - Guyer, M. S. - Ng, C. - Abdallah, A. - Colantuoni, D. - Insel, T. R. - Koester, S. E. - Little, A. R. - Bender, P. K. - Lehner, T. - Yao, Y. - Compton, C. C. - Vaught, J. B. - Sawyer, S. - Lockhart, N. C. - Demchok, J. - Moore, H. F.
Journal: Nat Genet

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The case for a cohort.

Publication Date: 2013 May 29 PMID: 23715322
Authors:
Journal: Nat Genet

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Genome-wide association study of multiple congenital heart disease phenotypes identifies a susceptibility locus for atrial septal defect at chromosome 4p16.

Publication Date: 2013 May 26 PMID: 23708191
Authors: Cordell, H. J. - Bentham, J. - Topf, A. - Zelenika, D. - Heath, S. - Mamasoula, C. - Cosgrove, C. - Blue, G. - Granados-Riveron, J. - Setchfield, K. - Thornborough, C. - Breckpot, J. - Soemedi, R. - Martin, R. - Rahman, T. J. - Hall, D. - van Engelen, K. - Moorman, A. F. - Zwinderman, A. H. - Barnett, P. - Koopmann, T. T. - Adriaens, M. E. - Varro, A. - George, A. L. Jr - Dos Remedios, C. - Bishopric, N. H. - Bezzina, C. R. - O'Sullivan, J. - Gewillig, M. - Bu'lock, F. A. - Winlaw, D. - Bhattacharya, S. - Devriendt, K. - Brook, J. D. - Mulder, B. J. - Mital, S. - Postma, A. V. - Lathrop, G. M. - Farrall, M. - Goodship, J. A. - Keavney, B. D.
Journal: Nat Genet

We carried out a genome-wide association study (GWAS) of congenital heart disease (CHD). Our discovery cohort comprised 1,995 CHD cases and 5,159 controls and included affected individuals from each of the 3 major clinical CHD categories (with septal, obstructive and cyanotic defects). When all CHD phenotypes were considered together, no region achieved genome-wide significant association. However, a region on chromosome 4p16, adjacent to the MSX1 and STX18 genes, was associated (P = 9.5 x 10-7) with the risk of ostium secundum atrial septal defect (ASD) in the discovery cohort (N = 340 cases), and this association was replicated in a further 417 ASD cases and 2,520 controls (replication P = 5.0 x 10-5; odds ratio (OR) in replication cohort = 1.40, 95% confidence interval (CI) = 1.19-1.65; combined P = 2.6 x 10-10). Genotype accounted for approximately 9% of the population-attributable risk of ASD.

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A genome-wide association study identifies two risk loci for congenital heart malformations in Han Chinese populations.

Publication Date: 2013 May 26 PMID: 23708190
Authors: Hu, Z. - Shi, Y. - Mo, X. - Xu, J. - Zhao, B. - Lin, Y. - Yang, S. - Xu, Z. - Dai, J. - Pan, S. - Da, M. - Wang, X. - Qian, B. - Wen, Y. - Wen, J. - Xing, J. - Guo, X. - Xia, Y. - Ma, H. - Jin, G. - Yu, S. - Liu, J. - Zhou, Z. - Wang, X. - Chen, Y. - Sha, J. - Shen, H.
Journal: Nat Genet

Congenital heart malformation (CHM) is the most common form of congenital human birth anomaly and is the leading cause of infant mortality. Although some causative genes have been identified, little progress has been made in identifying genes in which low-penetrance susceptibility variants occur in the majority of sporadic CHM cases. To identify common genetic variants associated with sporadic non-syndromic CHM in Han Chinese populations, we performed a multistage genome-wide association study (GWAS) in a total of 4,225 CHM cases and 5,112 non-CHM controls. The GWAS stage included 945 cases and 1,246 controls and was followed by 2-stage validation with 2,160 cases and 3,866 controls. The combined analyses identified significant associations (P < 5.0 x 10-8) at 1p12 (rs2474937 near TBX15; odds ratio (OR) = 1.40; P = 8.44 x 10-10) and 4q31.1 (rs1531070 in MAML3; OR = 1.40; P = 4.99 x 10-12). These results extend current knowledge of genetic contributions to CHM in Han Chinese populations.

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DNA hypomethylation within specific transposable element families associates with tissue-specific enhancer landscape.

Publication Date: 2013 May 26 PMID: 23708189
Authors: Xie, M. - Hong, C. - Zhang, B. - Lowdon, R. F. - Xing, X. - Li, D. - Zhou, X. - Lee, H. J. - Maire, C. L. - Ligon, K. L. - Gascard, P. - Sigaroudinia, M. - Tlsty, T. D. - Kadlecek, T. - Weiss, A. - O'Geen, H. - Farnham, P. J. - Madden, P. A. - Mungall, A. J. - Tam, A. - Kamoh, B. - Cho, S. - Moore, R. - Hirst, M. - Marra, M. A. - Costello, J. F. - Wang, T.
Journal: Nat Genet

Transposable element (TE)-derived sequences comprise half of the human genome and DNA methylome and are presumed to be densely methylated and inactive. Examination of genome-wide DNA methylation status within 928 TE subfamilies in human embryonic and adult tissues identified unexpected tissue-specific and subfamily-specific hypomethylation signatures. Genes proximal to tissue-specific hypomethylated TE sequences were enriched for functions important for the relevant tissue type, and their expression correlated strongly with hypomethylation within the TEs. When hypomethylated, these TE sequences gained tissue-specific enhancer marks, including monomethylation of histone H3 at lysine 4 (H3K4me1) and occupancy by p300, and a majority exhibited enhancer activity in reporter gene assays. Many such TEs also harbored binding sites for transcription factors that are important for tissue-specific functions and showed evidence of evolutionary selection. These data suggest that sequences derived from TEs may be responsible for wiring tissue type-specific regulatory networks and may have acquired tissue-specific epigenetic regulation.

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Combined sequence-based and genetic mapping analysis of complex traits in outbred rats.

Publication Date: 2013 May 26 PMID: 23708188
Authors: Baud, A. - Hermsen, R. - Guryev, V. - Stridh, P. - Graham, D. - McBride, M. W. - Foroud, T. - Calderari, S. - Diez, M. - Ockinger, J. - Beyeen, A. D. - Gillett, A. - Abdelmagid, N. - Guerreiro-Cacais, A. O. - Jagodic, M. - Tuncel, J. - Norin, U. - Beattie, E. - Huynh, N. - Miller, W. H. - Koller, D. L. - Alam, I. - Falak, S. - Osborne-Pellegrin, M. - Martinez-Membrives, E. - Canete, T. - Blazquez, G. - Vicens-Costa, E. - Mont-Cardona, C. - Diaz-Moran, S. - Tobena, A. - Hummel, O. - Zelenika, D. - Saar, K. - Patone, G. - Bauerfeind, A. - Bihoreau, M. T. - Heinig, M. - Lee, Y. A. - Rintisch, C. - Schulz, H. - Wheeler, D. A. - Worley, K. C. - Muzny, D. M. - Gibbs, R. A. - Lathrop, M. - Lansu, N. - Toonen, P. - Ruzius, F. P. - de Bruijn, E. - Hauser, H. - Adams, D. J. - Keane, T. - Atanur, S. S. - Aitman, T. J. - Flicek, P. - Malinauskas, T. - Jones, E. Y. - Ekman, D. - Lopez-Aumatell, R. - Dominiczak, A. F. - Johannesson, M. - Holmdahl, R. - Olsson, T. - Gauguier, D. - Hubner, N. - Fernandez-Teruel, A. - Cuppen, E. - Mott, R. - Flint, J.
Journal: Nat Genet

Genetic mapping on fully sequenced individuals is transforming understanding of the relationship between molecular variation and variation in complex traits. Here we report a combined sequence and genetic mapping analysis in outbred rats that maps 355 quantitative trait loci for 122 phenotypes. We identify 35 causal genes involved in 31 phenotypes, implicating new genes in models of anxiety, heart disease and multiple sclerosis. The relationship between sequence and genetic variation is unexpectedly complex: at approximately 40% of quantitative trait loci, a single sequence variant cannot account for the phenotypic effect. Using comparable sequence and mapping data from mice, we show that the extent and spatial pattern of variation in inbred rats differ substantially from those of inbred mice and that the genetic variants in orthologous genes rarely contribute to the same phenotype in both species.

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Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.

Publication Date: 2013 May 26 PMID: 23708187
Authors: Carvill, G. L. - Heavin, S. B. - Yendle, S. C. - McMahon, J. M. - O'Roak, B. J. - Cook, J. - Khan, A. - Dorschner, M. O. - Weaver, M. - Calvert, S. - Malone, S. - Wallace, G. - Stanley, T. - Bye, A. M. - Bleasel, A. - Howell, K. B. - Kivity, S. - Mackay, M. T. - Rodriguez-Casero, V. - Webster, R. - Korczyn, A. - Afawi, Z. - Zelnick, N. - Lerman-Sagie, T. - Lev, D. - Moller, R. S. - Gill, D. - Andrade, D. M. - Freeman, J. L. - Sadleir, L. G. - Shendure, J. - Berkovic, S. F. - Scheffer, I. E. - Mefford, H. C.
Journal: Nat Genet

Epileptic encephalopathies are a devastating group of epilepsies with poor prognosis, of which the majority are of unknown etiology. We perform targeted massively parallel resequencing of 19 known and 46 candidate genes for epileptic encephalopathy in 500 affected individuals (cases) to identify new genes involved and to investigate the phenotypic spectrum associated with mutations in known genes. Overall, we identified pathogenic mutations in 10% of our cohort. Six of the 46 candidate genes had 1 or more pathogenic variants, collectively accounting for 3% of our cohort. We show that de novo CHD2 and SYNGAP1 mutations are new causes of epileptic encephalopathies, accounting for 1.2% and 1% of cases, respectively. We also expand the phenotypic spectra explained by SCN1A, SCN2A and SCN8A mutations. To our knowledge, this is the largest cohort of cases with epileptic encephalopathies to undergo targeted resequencing. Implementation of this rapid and efficient method will change diagnosis and understanding of the molecular etiologies of these disorders.

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The mutational landscape of adenoid cystic carcinoma.

Publication Date: 2013 May 19 PMID: 23685749
Authors: Ho, A. S. - Kannan, K. - Roy, D. M. - Morris, L. G. - Ganly, I. - Katabi, N. - Ramaswami, D. - Walsh, L. A. - Eng, S. - Huse, J. T. - Zhang, J. - Dolgalev, I. - Huberman, K. - Heguy, A. - Viale, A. - Drobnjak, M. - Leversha, M. A. - Rice, C. E. - Singh, B. - Iyer, N. G. - Leemans, C. R. - Bloemena, E. - Ferris, R. L. - Seethala, R. R. - Gross, B. E. - Liang, Y. - Sinha, R. - Peng, L. - Raphael, B. J. - Turcan, S. - Gong, Y. - Schultz, N. - Kim, S. - Chiosea, S. - Shah, J. P. - Sander, C. - Lee, W. - Chan, T. A.
Journal: Nat Genet

Adenoid cystic carcinomas (ACCs) are among the most enigmatic of human malignancies. These aggressive salivary gland cancers frequently recur and metastasize despite definitive treatment, with no known effective chemotherapy regimen. Here we determined the ACC mutational landscape and report the exome or whole-genome sequences of 60 ACC tumor-normal pairs. These analyses identified a low exonic somatic mutation rate (0.31 non-silent events per megabase) and wide mutational diversity. Notably, we found mutations in genes encoding chromatin-state regulators, such as SMARCA2, CREBBP and KDM6A, suggesting that there is aberrant epigenetic regulation in ACC oncogenesis. Mutations in genes central to the DNA damage response and protein kinase A signaling also implicate these processes. We observed MYB-NFIB translocations and somatic mutations in MYB-associated genes, solidifying the role of these aberrations as critical events in ACC. Lastly, we identified recurrent mutations in the FGF-IGF-PI3K pathway (30% of tumors) that might represent new avenues for therapy. Collectively, our observations establish a molecular foundation for understanding and exploring new treatments for ACC.

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A functional variant in the CFI gene confers a high risk of age-related macular degeneration.

Publication Date: 2013 May 19 PMID: 23685748
Authors: van de Ven, J. P. - Nilsson, S. C. - Tan, P. L. - Buitendijk, G. H. - Ristau, T. - Mohlin, F. C. - Nabuurs, S. B. - Schoenmaker-Koller, F. E. - Smailhodzic, D. - Campochiaro, P. A. - Zack, D. J. - Duvvari, M. R. - Bakker, B. - Paun, C. C. - Boon, C. J. - Uitterlinden, A. G. - Liakopoulos, S. - Klevering, B. J. - Fauser, S. - Daha, M. R. - Katsanis, N. - Klaver, C. C. - Blom, A. M. - Hoyng, C. B. - den Hollander, A. I.
Journal: Nat Genet

Up to half of the heritability of age-related macular degeneration (AMD) is explained by common variants. Here, we report the identification of a rare, highly penetrant missense mutation in CFI encoding a p.Gly119Arg substitution that confers high risk of AMD (P = 3.79 x 10-6; odds ratio (OR) = 22.20, 95% confidence interval (CI) = 2.98-164.49). Plasma and sera from cases carrying the p.Gly119Arg substitution mediated the degradation of C3b, both in the fluid phase and on the cell surface, to a lesser extent than those from controls. Recombinant protein studies showed that the Gly119Arg mutant protein is both expressed and secreted at lower levels than wild-type protein. Consistent with these findings, human CFI mRNA encoding Arg119 had reduced activity compared to wild-type mRNA encoding Gly119 in regulating vessel thickness and branching in the zebrafish retina. Taken together, these findings demonstrate that rare, highly penetrant mutations contribute to the genetic burden of AMD.

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Forward genetic screen for malignant peripheral nerve sheath tumor formation identifies new genes and pathways driving tumorigenesis.

Publication Date: 2013 May 19 PMID: 23685747
Authors: Rahrmann, E. P. - Watson, A. L. - Keng, V. W. - Choi, K. - Moriarity, B. S. - Beckmann, D. A. - Wolf, N. K. - Sarver, A. - Collins, M. H. - Moertel, C. L. - Wallace, M. R. - Gel, B. - Serra, E. - Ratner, N. - Largaespada, D. A.
Journal: Nat Genet

Malignant peripheral nerve sheath tumors (MPNSTs) are sarcomas of Schwann cell lineage origin that occur sporadically or in association with the inherited syndrome neurofibromatosis type 1. To identify genetic drivers of MPNST development, we used the Sleeping Beauty (SB) transposon-based somatic mutagenesis system in mice with somatic loss of transformation-related protein p53 (Trp53) function and/or overexpression of human epidermal growth factor receptor (EGFR). Common insertion site (CIS) analysis of 269 neurofibromas and 106 MPNSTs identified 695 and 87 sites with a statistically significant number of recurrent transposon insertions, respectively. Comparison to human data sets identified new and known driver genes for MPNST formation at these sites. Pairwise co-occurrence analysis of CIS-associated genes identified many cooperating mutations that are enriched in Wnt/beta-catenin, PI3K-AKT-mTOR and growth factor receptor signaling pathways. Lastly, we identified several new proto-oncogenes, including Foxr2 (encoding forkhead box R2), which we functionally validated as a proto-oncogene involved in MPNST maintenance.

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Identification of nine new susceptibility loci for testicular cancer, including variants near DAZL and PRDM14.

Publication Date: 2013 May 12 PMID: 23666240
Authors: Ruark, E. - Seal, S. - McDonald, H. - Zhang, F. - Elliot, A. - Lau, K. - Perdeaux, E. - Rapley, E. - Eeles, R. - Peto, J. - Kote-Jarai, Z. - Muir, K. - Nsengimana, J. - Shipley, J. - Bishop, D. T. - Stratton, M. R. - Easton, D. F. - Huddart, R. A. - Rahman, N. - Turnbull, C.
Journal: Nat Genet

Testicular germ cell tumor (TGCT) is the most common cancer in young men and is notable for its high familial risks. So far, six loci associated with TGCT have been reported. From genome-wide association study (GWAS) analysis of 307,291 SNPs in 986 TGCT cases and 4,946 controls, we selected for follow-up 694 SNPs, which we genotyped in a further 1,064 TGCT cases and 10,082 controls from the UK. We identified SNPs at nine new loci (1q22, 1q24.1, 3p24.3, 4q24, 5q31.1, 8q13.3, 16q12.1, 17q22 and 21q22.3) showing association with TGCT (P < 5 x 10(-8)), which together account for an additional 4-6% of the familial risk of TGCT. The loci include genes plausibly related to TGCT development. PRDM14, at 8q13.3, is essential for early germ cell specification, and DAZL, at 3p24.3, is required for the regulation of germ cell development. Furthermore, PITX1, at 5q31.1, regulates TERT expression and is the third TGCT-associated locus implicated in telomerase regulation.

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Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis.

Publication Date: 2013 Apr 14 PMID: 23583980
Authors: Fingerlin, T. E. - Murphy, E. - Zhang, W. - Peljto, A. L. - Brown, K. K. - Steele, M. P. - Loyd, J. E. - Cosgrove, G. P. - Lynch, D. - Groshong, S. - Collard, H. R. - Wolters, P. J. - Bradford, W. Z. - Kossen, K. - Seiwert, S. D. - du Bois, R. M. - Garcia, C. K. - Devine, M. S. - Gudmundsson, G. - Isaksson, H. J. - Kaminski, N. - Zhang, Y. - Gibson, K. F. - Lancaster, L. H. - Cogan, J. D. - Mason, W. R. - Maher, T. M. - Molyneaux, P. L. - Wells, A. U. - Moffatt, M. F. - Selman, M. - Pardo, A. - Kim, D. S. - Crapo, J. D. - Make, B. J. - Regan, E. A. - Walek, D. S. - Daniel, J. J. - Kamatani, Y. - Zelenika, D. - Smith, K. - McKean, D. - Pedersen, B. S. - Talbert, J. - Kidd, R. N. - Markin, C. R. - Beckman, K. B. - Lathrop, M. - Schwarz, M. I. - Schwartz, D. A.
Journal: Nat Genet

We performed a genome-wide association study of non-Hispanic, white individuals with fibrotic idiopathic interstitial pneumonias (IIPs; n = 1,616) and controls (n = 4,683), with follow-up replication analyses in 876 cases and 1,890 controls. We confirmed association with TERT at 5p15, MUC5B at 11p15 and the 3q26 region near TERC, and we identified seven newly associated loci (Pmeta = 2.4 x 10(-8) to 1.1 x 10(-19)), including FAM13A (4q22), DSP (6p24), OBFC1 (10q24), ATP11A (13q34), DPP9 (19p13) and chromosomal regions 7q22 and 15q14-15. Our results suggest that genes involved in host defense, cell-cell adhesion and DNA repair contribute to risk of fibrotic IIPs.

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Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders.

Publication Date: 2013 Apr 14 PMID: 23583979
Authors: den Hoed, M. - Eijgelsheim, M. - Esko, T. - Brundel, B. J. - Peal, D. S. - Evans, D. M. - Nolte, I. M. - Segre, A. V. - Holm, H. - Handsaker, R. E. - Westra, H. J. - Johnson, T. - Isaacs, A. - Yang, J. - Lundby, A. - Zhao, J. H. - Kim, Y. J. - Go, M. J. - Almgren, P. - Bochud, M. - Boucher, G. - Cornelis, M. C. - Gudbjartsson, D. - Hadley, D. - van der Harst, P. - Hayward, C. - den Heijer, M. - Igl, W. - Jackson, A. U. - Kutalik, Z. - Luan, J. - Kemp, J. P. - Kristiansson, K. - Ladenvall, C. - Lorentzon, M. - Montasser, M. E. - Njajou, O. T. - O'Reilly, P. F. - Padmanabhan, S. - St Pourcain, B. - Rankinen, T. - Salo, P. - Tanaka, T. - Timpson, N. J. - Vitart, V. - Waite, L. - Wheeler, W. - Zhang, W. - Draisma, H. H. - Feitosa, M. F. - Kerr, K. F. - Lind, P. A. - Mihailov, E. - Onland-Moret, N. C. - Song, C. - Weedon, M. N. - Xie, W. - Yengo, L. - Absher, D. - Albert, C. M. - Alonso, A. - Arking, D. E. - de Bakker, P. I. - Balkau, B. - Barlassina, C. - Benaglio, P. - Bis, J. C. - Bouatia-Naji, N. - Brage, S. - Chanock, S. J. - Chines, P. S. - Chung, M. - Darbar, D. - Dina, C. - Dorr, M. - Elliott, P. - Felix, S. B. - Fischer, K. - Fuchsberger, C. - de Geus, E. J. - Goyette, P. - Gudnason, V. - Harris, T. B. - Hartikainen, A. L. - Havulinna, A. S. - Heckbert, S. R. - Hicks, A. A. - Hofman, A. - Holewijn, S. - Hoogstra-Berends, F. - Hottenga, J. J. - Jensen, M. K. - Johansson, A. - Junttila, J. - Kaab, S. - Kanon, B. - Ketkar, S. - Khaw, K. T. - Knowles, J. W. - Kooner, A. S. - Kors, J. A. - Kumari, M. - Milani, L. - Laiho, P. - Lakatta, E. G. - Langenberg, C. - Leusink, M. - Liu, Y. - Luben, R. N. - Lunetta, K. L. - Lynch, S. N. - Markus, M. R. - Marques-Vidal, P. - Mateo Leach, I. - McArdle, W. L. - McCarroll, S. A. - Medland, S. E. - Miller, K. A. - Montgomery, G. W. - Morrison, A. C. - Muller-Nurasyid, M. - Navarro, P. - Nelis, M. - O'Connell, J. R. - O'Donnell, C. J. - Ong, K. K. - Newman, A. B. - Peters, A. - Polasek, O. - Pouta, A. - Pramstaller, P. P. - Psaty, B. M. - Rao, D. C. - Ring, S. M. - Rossin, E. J. - Rudan, D. - Sanna, S. - Scott, R. A. - Sehmi, J. S. - Sharp, S. - Shin, J. T. - Singleton, A. B. - Smith, A. V. - Soranzo, N. - Spector, T. D. - Stewart, C. - Stringham, H. M. - Tarasov, K. V. - Uitterlinden, A. G. - Vandenput, L. - Hwang, S. J. - Whitfield, J. B. - Wijmenga, C. - Wild, S. H. - Willemsen, G. - Wilson, J. F. - Witteman, J. C. - Wong, A. - Wong, Q. - Jamshidi, Y. - Zitting, P. - Boer, J. M. - Boomsma, D. I. - Borecki, I. B. - van Duijn, C. M. - Ekelund, U. - Forouhi, N. G. - Froguel, P. - Hingorani, A. - Ingelsson, E. - Kivimaki, M. - Kronmal, R. A. - Kuh, D. - Lind, L. - Martin, N. G. - Oostra, B. A. - Pedersen, N. L. - Quertermous, T. - Rotter, J. I. - van der Schouw, Y. T. - Verschuren, W. M. - Walker, M. - Albanes, D. - Arnar, D. O. - Assimes, T. L. - Bandinelli, S. - Boehnke, M. - de Boer, R. A. - Bouchard, C. - Caulfield, W. L. - Chambers, J. C. - Curhan, G. - Cusi, D. - Eriksson, J. - Ferrucci, L. - van Gilst, W. H. - Glorioso, N. - de Graaf, J. - Groop, L. - Gyllensten, U. - Hsueh, W. C. - Hu, F. B. - Huikuri, H. V. - Hunter, D. J. - Iribarren, C. - Isomaa, B. - Jarvelin, M. R. - Jula, A. - Kahonen, M. - Kiemeney, L. A. - van der Klauw, M. M. - Kooner, J. S. - Kraft, P. - Iacoviello, L. - Lehtimaki, T. - Lokki, M. L. - Mitchell, B. D. - Navis, G. - Nieminen, M. S. - Ohlsson, C. - Poulter, N. R. - Qi, L. - Raitakari, O. T. - Rimm, E. B. - Rioux, J. D. - Rizzi, F. - Rudan, I. - Salomaa, V. - Sever, P. S. - Shields, D. C. - Shuldiner, A. R. - Sinisalo, J. - Stanton, A. V. - Stolk, R. P. - Strachan, D. P. - Tardif, J. C. - Thorsteinsdottir, U. - Tuomilehto, J. - van Veldhuisen, D. J. - Virtamo, J. - Viikari, J. - Vollenweider, P. - Waeber, G. - Widen, E. - Cho, Y. S. - Olsen, J. V. - Visscher, P. M. - Willer, C. - Franke, L. - Erdmann, J. - Thompson, J. R. - Pfeufer, A. - Sotoodehnia, N. - Newton-Cheh, C. - Ellinor, P. T. - Stricker, B. H. - Metspalu, A. - Perola, M. - Beckmann, J. S. - Smith, G. D. - Stefansson, K. - Wareham, N. J. - Munroe, P. B. - Sibon, O. C. - Milan, D. J. - Snieder, H. - Samani, N. J. - Loos, R. J.
Journal: Nat Genet

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.

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A meta-analysis identifies new loci associated with body mass index in individuals of African ancestry.

Publication Date: 2013 Apr 14 PMID: 23583978
Authors: Monda, K. L. - Chen, G. K. - Taylor, K. C. - Palmer, C. - Edwards, T. L. - Lange, L. A. - Ng, M. C. - Adeyemo, A. A. - Allison, M. A. - Bielak, L. F. - Chen, G. - Graff, M. - Irvin, M. R. - Rhie, S. K. - Li, G. - Liu, Y. - Liu, Y. - Lu, Y. - Nalls, M. A. - Sun, Y. V. - Wojczynski, M. K. - Yanek, L. R. - Aldrich, M. C. - Ademola, A. - Amos, C. I. - Bandera, E. V. - Bock, C. H. - Britton, A. - Broeckel, U. - Cai, Q. - Caporaso, N. E. - Carlson, C. S. - Carpten, J. - Casey, G. - Chen, W. M. - Chen, F. - Chen, Y. D. - Chiang, C. W. - Coetzee, G. A. - Demerath, E. - Deming-Halverson, S. L. - Driver, R. W. - Dubbert, P. - Feitosa, M. F. - Feng, Y. - Freedman, B. I. - Gillanders, E. M. - Gottesman, O. - Guo, X. - Haritunians, T. - Harris, T. - Harris, C. C. - Hennis, A. J. - Hernandez, D. G. - McNeill, L. H. - Howard, T. D. - Howard, B. V. - Howard, V. J. - Johnson, K. C. - Kang, S. J. - Keating, B. J. - Kolb, S. - Kuller, L. H. - Kutlar, A. - Langefeld, C. D. - Lettre, G. - Lohman, K. - Lotay, V. - Lyon, H. - Manson, J. E. - Maixner, W. - Meng, Y. A. - Monroe, K. R. - Morhason-Bello, I. - Murphy, A. B. - Mychaleckyj, J. C. - Nadukuru, R. - Nathanson, K. L. - Nayak, U. - N'diaye, A. - Nemesure, B. - Wu, S. Y. - Leske, M. C. - Neslund-Dudas, C. - Neuhouser, M. - Nyante, S. - Ochs-Balcom, H. - Ogunniyi, A. - Ogundiran, T. O. - Ojengbede, O. - Olopade, O. I. - Palmer, J. R. - Ruiz-Narvaez, E. A. - Palmer, N. D. - Press, M. F. - Rampersaud, E. - Rasmussen-Torvik, L. J. - Rodriguez-Gil, J. L. - Salako, B. - Schadt, E. E. - Schwartz, A. G. - Shriner, D. A. - Siscovick, D. - Smith, S. B. - Wassertheil-Smoller, S. - Speliotes, E. K. - Spitz, M. R. - Sucheston, L. - Taylor, H. - Tayo, B. O. - Tucker, M. A. - Van Den Berg, D. J. - Edwards, D. R. - Wang, Z. - Wiencke, J. K. - Winkler, T. W. - Witte, J. S. - Wrensch, M. - Wu, X. - Yang, J. J. - Levin, A. M. - Young, T. R. - Zakai, N. A. - Cushman, M. - Zanetti, K. A. - Zhao, J. H. - Zhao, W. - Zheng, Y. - Zhou, J. - Ziegler, R. G. - Zmuda, J. M. - Fernandes, J. K. - Gilkeson, G. S. - Kamen, D. L. - Hunt, K. J. - Spruill, I. J. - Ambrosone, C. B. - Ambs, S. - Arnett, D. K. - Atwood, L. - Becker, D. M. - Berndt, S. I. - Bernstein, L. - Blot, W. J. - Borecki, I. B. - Bottinger, E. P. - Bowden, D. W. - Burke, G. - Chanock, S. J. - Cooper, R. S. - Ding, J. - Duggan, D. - Evans, M. K. - Fox, C. - Garvey, W. T. - Bradfield, J. P. - Hakonarson, H. - Grant, S. F. - Hsing, A. - Chu, L. - Hu, J. J. - Huo, D. - Ingles, S. A. - John, E. M. - Jordan, J. M. - Kabagambe, E. K. - Kardia, S. L. - Kittles, R. A. - Goodman, P. J. - Klein, E. A. - Kolonel, L. N. - Le Marchand, L. - Liu, S. - McKnight, B. - Millikan, R. C. - Mosley, T. H. - Padhukasahasram, B. - Williams, L. K. - Patel, S. R. - Peters, U. - Pettaway, C. A. - Peyser, P. A. - Psaty, B. M. - Redline, S. - Rotimi, C. N. - Rybicki, B. A. - Sale, M. M. - Schreiner, P. J. - Signorello, L. B. - Singleton, A. B. - Stanford, J. L. - Strom, S. S. - Thun, M. J. - Vitolins, M. - Zheng, W. - Moore, J. H. - Williams, S. M. - Ketkar, S. - Zhu, X. - Zonderman, A. B. - Kooperberg, C. - Papanicolaou, G. J. - Henderson, B. E. - Reiner, A. P. - Hirschhorn, J. N. - Loos, R. J. - North, K. E. - Haiman, C. A.
Journal: Nat Genet

Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one new locus at 5q33 (GALNT10, rs7708584, P = 3.4 x 10(-11)) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 x 10(-10)). We also found suggestive evidence of an association at a third locus at 6q16 in the African-ancestry sample (KLHL32, rs974417, P = 6.9 x 10(-8)). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 x 10(-7)), five of which reached genome-wide significance. These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations.

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