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TABLE OF CONTENTS
| July 2017 Volume 49, Issue 7 |  | | |  |  Editorial
News and Views
Analysis
Articles
Letters
| | | | | |
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npj Precision Oncology is a new open access, online-only, peer-reviewed journal committed to publishing cutting-edge scientific research in all aspects of precision oncology from basic science to translational applications, to clinical medicine.
The journal is part of the Nature Partner Journals series and published in partnership with The Hormel Institute, University of Minnesota.
Explore the benefits of submitting your manuscript. |  | | | | | | Editorial |  Top | |  | | Data models to GO-FAIR p971
doi:10.1038/ng.3910
This journal and Scientific Data are calling for submissions containing linked open data models that embody and extend the FAIR principles: that data should be findable, accessible, interoperable and reusable by both humans and machines. These principles are achievable with existing resources, languages and vocabularies to enable computers to combine and reanalyze data sets automatically and lead humans to new discoveries.
| | News and Views | Top | | | | Promoting transcription over long distances pp972 - 973
Rui R Catarino, Christoph Neumayr & Alexander Stark
doi:10.1038/ng.3904
Promoters and enhancers have long been regarded as distinct elements, a notion that has been challenged more recently. Two new studies now identify promoters that function as long-range enhancers in vivo to regulate the transcription of distal genes.
See also: Article by Dao et al.
| | | | Epigenetic modifier drugs trigger widespread transcription of endogenous retroviruses pp974 - 975
Dixie L Mager & Matthew C Lorincz
doi:10.1038/ng.3902
A study in this issue demonstrates that epigenome-modifying drugs used in cancer chemotherapy induce transcription from thousands of previously unannotated transcription start sites, most of which are derived from ancient endogenous retroviruses (ERVs). This work, coupled with previous related findings, suggests that induction of ERVs, rather than direct effects on specific genes, may have a central role in the cellular responses to such agents and, in turn, their therapeutic efficacy.
See also: Article by Brocks et al.
| | | | Transposase-driven rearrangements in human tumors pp975 - 977
Stephen C Mack, Hiromichi Suzuki & Michael D Taylor
doi:10.1038/ng.3908
A new study shows that aberrant DNA transposase activity promotes structural alterations that are clonally selected to drive tumor development. This discovery uncovers novel mechanisms of tumor-suppressor gene inactivation and highlights a new approach to cancer gene identification.
See also: Article by Henssen et al.
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| | Analysis | Top | | | | Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders pp978 - 985
Daniel J Weiner, Emilie M Wigdor, Stephan Ripke, Raymond K Walters, Jack A Kosmicki, Jakob Grove, Kaitlin E Samocha, Jacqueline I Goldstein, Aysu Okbay, Jonas Bybjerg-Grauholm, Thomas Werge, David M Hougaard, Jacob Taylor, iPSYCH-Broad Autism Group, Psychiatric Genomics Consortium Autism Group, David Skuse, Bernie Devlin, Richard Anney, Stephan J Sanders, Somer Bishop, Preben Bo Mortensen, Anders D Børglum, George Davey Smith, Mark J Daly & Elise B Robinson
doi:10.1038/ng.3863
Elise Robinson and colleagues present the polygenic transmission disequilibrium test (pTDT) for evaluating transmission of polygenic risk in family-based study designs. The authors apply pTDT to a cohort of autism spectrum disorder (ASD) families and find that common polygenic variation acts additively with de novo variants to contribute to ASD risk.
| | | Advertisement | | | | | | | Articles | Top | | | | Reevaluation of SNP heritability in complex human traits pp986 - 992
Doug Speed, Na Cai, the UCLEB Consortium, Michael R Johnson, Sergey Nejentsev & David J Balding
doi:10.1038/ng.3865
By analyzing imputed genetic data for 42 human traits, Doug Speed and colleagues derive a model that describes how heritability varies with minor allele frequency, linkage disequilibrium and genotype certainty. Using this model, they show that common SNPs contribute substantially more heritability than previously thought.
| | | | Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci pp993 - 1004
Tin Aung, Mineo Ozaki, Mei Chin Lee, Ursula Schlötzer-Schrehardt, Gudmar Thorleifsson, Takanori Mizoguchi, Robert P Igo Jr, Aravind Haripriya, Susan E Williams, Yury S Astakhov, Andrew C Orr, Kathryn P Burdon, Satoko Nakano, Kazuhiko Mori, Khaled Abu-Amero, Michael Hauser, Zheng Li, Gopalakrishnan Prakadeeswari, Jessica N Cooke Bailey, Alina Popa Cherecheanu, Jae H Kang, Sarah Nelson, Ken Hayashi, Shin-ichi Manabe, Shigeyasu Kazama, Tomasz Zarnowski, Kenji Inoue, Murat Irkec, Miguel Coca-Prados, Kazuhisa Sugiyama, Irma Järvelä, Patricio Schlottmann, S Fabian Lerner, Hasnaa Lamari, Yildirim Nilgün, Mukharram Bikbov, Ki Ho Park, Soon Cheol Cha, Kenji Yamashiro, Juan C Zenteno, Jost B Jonas, Rajesh S Kumar, Shamira A Perera, Anita S Y Chan, Nino Kobakhidze, Ronnie George, Lingam Vijaya, Tan Do, Deepak P Edward, Lourdes de Juan Marcos, Mohammad Pakravan, Sasan Moghimi, Ryuichi Ideta, Daniella Bach-Holm, Per Kappelgaard, Barbara Wirostko, Samuel Thomas, Daniel Gaston, Karen Bedard, Wenda L Greer, Zhenglin Yang, Xueyi Chen, Lulin Huang, Jinghong Sang, Hongyan Jia, Liyun Jia, Chunyan Qiao, Hui Zhang, Xuyang Liu, Bowen Zhao, Ya-Xing Wang, Liang Xu, Stéphanie Leruez, Pascal Reynier, George Chichua, Sergo Tabagari, Steffen Uebe, Matthias Zenkel, Daniel Berner, Georg Mossböck, Nicole Weisschuh, Ursula Hoja, Ulrich-Christoph Welge-Luessen, Christian Mardin, Panayiota Founti, Anthi Chatzikyriakidou, Theofanis Pappas, Eleftherios Anastasopoulos, Alexandros Lambropoulos, Arkasubhra Ghosh, Rohit Shetty, Natalia Porporato, Vijayan Saravanan, Rengaraj Venkatesh, Chandrashekaran Shivkumar, Narendran Kalpana, Sripriya Sarangapani, Mozhgan R Kanavi, Afsaneh Naderi Beni, Shahin Yazdani, Alireza lashay, Homa Naderifar, Nassim Khatibi, Antonio Fea, Carlo Lavia, Laura Dallorto, Teresa Rolle, Paolo Frezzotti, Daniela Paoli, Erika Salvi, Paolo Manunta, Yosai Mori, Kazunori Miyata, Tomomi Higashide, Etsuo Chihara, Satoshi Ishiko, Akitoshi Yoshida, Masahide Yanagi, Yoshiaki Kiuchi, Tsutomu Ohashi, Toshiya Sakurai, Takako Sugimoto, Hideki Chuman, Makoto Aihara, Masaru Inatani, Masahiro Miyake, Norimoto Gotoh, Fumihiko Matsuda, Nagahisa Yoshimura, Yoko Ikeda, Morio Ueno, Chie Sotozono, Jin Wook Jeoung, Min Sagong, Kyu Hyung Park, Jeeyun Ahn, Marisa Cruz-Aguilar, Sidi M Ezzouhairi, Abderrahman Rafei, Yaan Fun Chong, Xiao Yu Ng, Shuang Ru Goh, Yueming Chen, Victor H K Yong, Muhammad Imran Khan, Olusola O Olawoye, Adeyinka O Ashaye, Idakwo Ugbede, Adeola Onakoya, Nkiru Kizor-Akaraiwe, Chaiwat Teekhasaenee, Yanin Suwan, Wasu Supakontanasan, Suhanya Okeke, Nkechi J Uche, Ifeoma Asimadu, Humaira Ayub, Farah Akhtar, Ewa Kosior-Jarecka, Urszula Lukasik, Ignacio Lischinsky, Vania Castro, Rodolfo Perez Grossmann, Gordana Sunaric Megevand, Sylvain Roy, Edward Dervan, Eoin Silke, Aparna Rao, Priti Sahay, Pablo Fornero, Osvaldo Cuello, Delia Sivori, Tamara Zompa, Richard A Mills, Emmanuelle Souzeau, Paul Mitchell, Jie Jin Wang, Alex W Hewitt, Michael Coote, Jonathan G Crowston, Sergei Y Astakhov, Eugeny L Akopov, Anton Emelyanov, Vera Vysochinskaya, Gyulli Kazakbaeva, Rinat Fayzrakhmanov, Saleh A Al-Obeidan, Ohoud Owaidhah, Leyla Ali Aljasim, Balram Chowbay, Jia Nee Foo, Raphael Q Soh, Kar Seng Sim, Zhicheng Xie, Augustine W O Cheong, Shi Qi Mok, Hui Meng Soo, Xiao Yin Chen, Su Qin Peh, Khai Koon Heng, Rahat Husain, Su-Ling Ho, Axel M Hillmer, Ching-Yu Cheng, Francisco A Escudero-Domínguez, Rogelio González-Sarmiento, Frederico Martinon-Torres, Antonio Salas, Kessara Pathanapitoon, Linda Hansapinyo, Boonsong Wanichwecharugruang, Naris Kitnarong, Anavaj Sakuntabhai, Hip X Nguyn, Giang T T Nguyn, Trình V Nguyn, Werner Zenz, Alexander Binder, Daniela S Klobassa, Martin L Hibberd, Sonia Davila, Stefan Herms, Markus M Nöthen, Susanne Moebus, Robyn M Rautenbach, Ari Ziskind, Trevor R Carmichael, Michele Ramsay, Lydia Álvarez, Montserrat García, Héctor González-Iglesias, Pedro P Rodríguez-Calvo, Luis Fernández-Vega Cueto, Çilingir Oguz, Nevbahar Tamcelik, Eray Atalay, Bilge Batu, Dilek Aktas, Burcu Kasım, M Roy Wilson, Anne L Coleman, Yutao Liu, Pratap Challa, Leon Herndon, Rachel W Kuchtey, John Kuchtey, Karen Curtin, Craig J Chaya, Alan Crandall, Linda M Zangwill, Tien Yin Wong, Masakazu Nakano, Shigeru Kinoshita, Anneke I den Hollander, Eija Vesti, John H Fingert, Richard K Lee, Arthur J Sit, Bradford J Shingleton, Ningli Wang, Daniele Cusi, Raheel Qamar, Peter Kraft, Margaret A Pericak-Vance, Soumya Raychaudhuri, Steffen Heegaard, Tero Kivelä, André Reis, Friedrich E Kruse, Robert N Weinreb, Louis R Pasquale, Jonathan L Haines, Unnur Thorsteinsdottir, Fridbert Jonasson, R Rand Allingham, Dan Milea, Robert Ritch, Toshiaki Kubota, Kei Tashiro, Eranga N Vithana, Shazia Micheal, Fotis Topouzis, Jamie E Craig, Michael Dubina, Periasamy Sundaresan, Kari Stefansson, Janey L Wiggs, Francesca Pasutto & Chiea Chuen Khor
doi:10.1038/ng.3875
Chiea Chuen Khor, Tin Aung, Francesca Pasutto, Janey Wiggs and colleagues report a global genome-wide association study of exfoliation syndrome and a fine-mapping analysis of a previously identified disease-associated locus, LOXL1. They identify a rare protective variant in LOXL1 exclusive to the Japanese population and five new common variant susceptibility loci.
| | | | PGBD5 promotes site-specific oncogenic mutations in human tumors pp1005 - 1014
Anton G Henssen, Richard Koche, Jiali Zhuang, Eileen Jiang, Casie Reed, Amy Eisenberg, Eric Still, Ian C MacArthur, Elias Rodríguez-Fos, Santiago Gonzalez, Montserrat Puiggròs, Andrew N Blackford, Christopher E Mason, Elisa de Stanchina, Mithat Gönen, Anne-Katrin Emde, Minita Shah, Kanika Arora, Catherine Reeves, Nicholas D Socci, Elizabeth Perlman, Cristina R Antonescu, Charles W M Roberts, Hanno Steen, Elizabeth Mullen, Stephen P Jackson, David Torrents, Zhiping Weng, Scott A Armstrong & Alex Kentsis
doi:10.1038/ng.3866
Alex Kentsis and colleagues identify somatic genomic rearrangements in primary human rhabdoid tumors characterized by deletions and inversions involving PGBD5-specific signal sequences at their breakpoints. They further show that ectopic expression of PGBD5 in primary immortalized human cells is sufficient to promote cell transformation in vitro and in immunodeficient mice in vivo, thus defining PGBD5 as an oncogenic mutator and providing a plausible mechanism for site-specific DNA rearrangements in solid tumors.
See also: News and Views by Mack et al.
| | | | Between-region genetic divergence reflects the mode and tempo of tumor evolution pp1015 - 1024
Ruping Sun, Zheng Hu, Andrea Sottoriva, Trevor A Graham, Arbel Harpak, Zhicheng Ma, Jared M Fischer, Darryl Shibata & Christina Curtis
doi:10.1038/ng.3891
Christina Curtis and colleagues simulate spatial tumor growth under different evolutionary models and compare their results to multiregion sequencing data. They find that it is possible to distinguish tumors driven by strong positive selection from those evolving neutrally or under weak selection and infer different evolutionary modes within and between tumor types.
| | | | Mutations in DZIP1L, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease pp1025 - 1034
Hao Lu, Maria C Rondón Galeano, Elisabeth Ott, Geraldine Kaeslin, P Jaya Kausalya, Carina Kramer, Nadina Ortiz-Brüchle, Nadescha Hilger, Vicki Metzis, Milan Hiersche, Shang Yew Tay, Robert Tunningley, Shubha Vij, Andrew D Courtney, Belinda Whittle, Elke Wühl, Udo Vester, Björn Hartleben, Steffen Neuber, Valeska Frank, Melissa H Little, Daniel Epting, Peter Papathanasiou, Andrew C Perkins, Graham D Wright, Walter Hunziker, Heon Yung Gee, Edgar A Otto, Klaus Zerres, Friedhelm Hildebrandt, Sudipto Roy, Carol Wicking & Carsten Bergmann
doi:10.1038/ng.3871
Sudipto Roy, Carol Wicking, Carsten Bergmann and colleagues report that mutations in DZIP1L cause autosomal recessive polycystic kidney disease (ARPKD). Through studies of mouse and zebrafish models of DZIP1L loss of function, the authors demonstrate that DZIP1L is required for proper function of the periciliary diffusion barrier.
| | | | Hyperactivation of HUSH complex function by Charcot-Marie-Tooth disease mutation in MORC2 pp1035 - 1044
Iva A Tchasovnikarova, Richard T Timms, Christopher H Douse, Rhys C Roberts, Gordon Dougan, Robert E Kingston, Yorgo Modis & Paul J Lehner
doi:10.1038/ng.3878
Paul Lehner and colleagues identify an essential role for MORC2 in HUSH complex-mediated epigenetic silencing. They show that loss of MORC2 causes chromatin decompaction at HUSH-target loci and that a MORC2 mutation that causes Charcot-Marie-Tooth disease results in hyperactivation of HUSH-mediated repression in neuronal cells.
| | | | Paused RNA polymerase II inhibits new transcriptional initiation pp1045 - 1051
Wanqing Shao & Julia Zeitlinger
doi:10.1038/ng.3867
Julia Zeitlinger and Wanqing Shao use ChIP-nexus to study RNA polymerase II (Pol II) promoter pausing and its relation to the formation of new initiation complexes in Drosophila cells. They find that pausing affects the initiation of new transcripts and propose that paused RNA Pol II helps to prevent new initiation between transcription bursts.
| | | | DNMT and HDAC inhibitors induce cryptic transcription start sites encoded in long terminal repeats pp1052 - 1060
David Brocks, Christopher R Schmidt, Michael Daskalakis, Hyo Sik Jang, Nakul M Shah, Daofeng Li, Jing Li, Bo Zhang, Yiran Hou, Sara Laudato, Daniel B Lipka, Johanna Schott, Holger Bierhoff, Yassen Assenov, Monika Helf, Alzbeta Ressnerova, Md Saiful Islam, Anders M Lindroth, Simon Haas, Marieke Essers, Charles D Imbusch, Benedikt Brors, Ina Oehme, Olaf Witt, Michael Lübbert, Jan-Philipp Mallm, Karsten Rippe, Rainer Will, Dieter Weichenhan, Georg Stoecklin, Clarissa Gerhäuser, Christopher C Oakes, Ting Wang & Christoph Plass
doi:10.1038/ng.3889
Christoph Plass and colleagues investigate the transcriptomic and epigenomic changes induced by treatment with inhibitors of DNMT and HDAC in cancer cell lines. They observe large numbers of treatment-induced non-annotated TSSs (TINATs) encoded in long-terminal repeats that are normally repressed in most cell types.
See also: News and Views by Mager & Lorincz
| | | | Lineage-specific functions of TET1 in the postimplantation mouse embryo pp1061 - 1072
Rita Khoueiry, Abhishek Sohni, Bernard Thienpont, Xinlong Luo, Joris Vande Velde, Michela Bartoccetti, Bram Boeckx, An Zwijsen, Anjana Rao, Diether Lambrechts & Kian Peng Koh
doi:10.1038/ng.3868
Kian Peng Koh and colleagues report that TET1 regulates lineage-specific genes in the mouse postimplantation embryo, many of them independently of DNA methylation changes, through regulation of JMJD8 expression. They show that Tet1 deletion causes embryonic defects, which are partially penetrant in an inbred strain but fully lethal in non-inbred mice.
| | | | Genome-wide characterization of mammalian promoters with distal enhancer functions pp1073 - 1081
Lan T M Dao, Ariel O Galindo-Albarrán, Jaime A Castro-Mondragon, Charlotte Andrieu-Soler, Alejandra Medina-Rivera, Charbel Souaid, Guillaume Charbonnier, Aurélien Griffon, Laurent Vanhille, Tharshana Stephen, Jaafar Alomairi, David Martin, Magali Torres, Nicolas Fernandez, Eric Soler, Jacques van Helden, Denis Puthier & Salvatore Spicuglia
doi:10.1038/ng.3884
Salvatore Spicuglia and colleagues use a high-throughput reporter assay to identify a set of mammalian promoters, termed Epromoters, that display enhancer activity and have distinct genomic and epigenomic features. Through CRISPR-Cas9 gene editing experiments, they show that Epromoters are involved in long-range gene regulation in cis.
See also: News and Views by Catarino et al.
| | | | Whole-genome resequencing of 292 pigeonpea accessions identifies genomic regions associated with domestication and agronomic traits pp1082 - 1088
Rajeev K Varshney, Rachit K Saxena, Hari D Upadhyaya, Aamir W Khan, Yue Yu, Changhoon Kim, Abhishek Rathore, Dongseon Kim, Jihun Kim, Shaun An, Vinay Kumar, Ghanta Anuradha, Kalinati Narasimhan Yamini, Wei Zhang, Sonnappa Muniswamy, Jong-So Kim, R Varma Penmetsa, Eric von Wettberg & Swapan K Datta
doi:10.1038/ng.3872
Rajeev Varshney and colleagues resequence the whole genomes of 292 pigeonpea (Cajanus cajan) cultivars, landraces and wild species. They find genomic regions that were likely targets of domestication and perform genome-wide association analysis to identify candidate genes for agriculturally relevant traits.
| | | | Genomic analyses in cotton identify signatures of selection and loci associated with fiber quality and yield traits pp1089 - 1098
Lei Fang, Qiong Wang, Yan Hu, Yinhua Jia, Jiedan Chen, Bingliang Liu, Zhiyuan Zhang, Xueying Guan, Shuqi Chen, Baoliang Zhou, Gaofu Mei, Junling Sun, Zhaoe Pan, Shoupu He, Songhua Xiao, Weijun Shi, Wenfang Gong, Jianguang Liu, Jun Ma, Caiping Cai, Xiefei Zhu, Wangzhen Guo, Xiongming Du & Tianzhen Zhang
doi:10.1038/ng.3887
Tianzhen Zhang, Xiongming Du and colleagues report whole-genome resequencing of 318 upland cotton (Gossypium hirsutum) accessions. They carried out genome-wide association analyses to identify loci associated with fiber quality, lint yield and resistance to Verticillium wilt, and identify two ethylene-pathway genes associated with the increased lint yield observed in improved cultivars.
| | | | High-quality de novo assembly of the apple genome and methylome dynamics of early fruit development OPEN pp1099 - 1106
Nicolas Daccord, Jean-Marc Celton, Gareth Linsmith, Claude Becker, Nathalie Choisne, Elio Schijlen, Henri van de Geest, Luca Bianco, Diego Micheletti, Riccardo Velasco, Erica Adele Di Pierro, Jérôme Gouzy, D Jasper G Rees, Philippe Guérif, Hélène Muranty, Charles-Eric Durel, François Laurens, Yves Lespinasse, Sylvain Gaillard, Sébastien Aubourg, Hadi Quesneville, Detlef Weigel, Eric van de Weg, Michela Troggio & Etienne Bucher
doi:10.1038/ng.3886
Etienne Bucher and colleagues use a combination of short- and long-read sequencing, along with optical mapping technologies, to produce the high-quality de novo assembly of the apple genome. They identify a new repetitive retrotransposon sequence and analyze DNA methylation data in relation to important agronomic traits.
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LEARN MORE |  | | | | | | Letters | Top | | | | Genome-wide association meta-analysis of 78,308 individuals identifies new loci and genes influencing human intelligence pp1107 - 1112
Suzanne Sniekers, Sven Stringer, Kyoko Watanabe, Philip R Jansen, Jonathan R I Coleman, Eva Krapohl, Erdogan Taskesen, Anke R Hammerschlag, Aysu Okbay, Delilah Zabaneh, Najaf Amin, Gerome Breen, David Cesarini, Christopher F Chabris, William G Iacono, M Arfan Ikram, Magnus Johannesson, Philipp Koellinger, James J Lee, Patrik K E Magnusson, Matt McGue, Mike B Miller, William E R Ollier, Antony Payton, Neil Pendleton, Robert Plomin, Cornelius A Rietveld, Henning Tiemeier, Cornelia M van Duijn & Danielle Posthuma
doi:10.1038/ng.3869
Danielle Posthuma and colleagues perform a large meta-analysis for intelligence and determine genetic overlap with several neuropsychiatric and metabolic traits. They find 15 new significant loci and implicate 40 new genes, most of which are predominantly expressed in the brain.
| | | | Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms pp1113 - 1119
Joanna M M Howson, Wei Zhao, Daniel R Barnes, Weang-Kee Ho, Robin Young, Dirk S Paul, Lindsay L Waite, Daniel F Freitag, Eric B Fauman, Elias L Salfati, Benjamin B Sun, John D Eicher, Andrew D Johnson, Wayne H H Sheu, Sune F Nielsen, Wei-Yu Lin, Praveen Surendran, Anders Malarstig, Jemma B Wilk, Anne Tybjærg-Hansen, Katrine L Rasmussen, Pia R Kamstrup, Panos Deloukas, Jeanette Erdmann, Sekar Kathiresan, Nilesh J Samani, Heribert Schunkert, Hugh Watkins, CARDIoGRAMplusC4D, Ron Do, Daniel J Rader, Julie A Johnson, Stanley L Hazen, Arshed A Quyyumi, John A Spertus, Carl J Pepine, Nora Franceschini, Anne Justice, Alex P Reiner, Steven Buyske, Lucia A Hindorff, Cara L Carty, Kari E North, Charles Kooperberg, Eric Boerwinkle, Kristin Young, Mariaelisa Graff, Ulrike Peters, Devin Absher, Chao A Hsiung, Wen-Jane Lee, Kent D Taylor, Ying-Hsiang Chen, I-Te Lee, Xiuqing Guo, Ren-Hua Chung, Yi-Jen Hung, Jerome I Rotter, Jyh-Ming J Juang, Thomas Quertermous, Tzung-Dau Wang, Asif Rasheed, Philippe Frossard, Dewan S Alam, Abdulla al Shafi Majumder, Emanuele Di Angelantonio, Rajiv Chowdhury, EPIC-CVD, Yii-Der Ida Chen, Børge G Nordestgaard, Themistocles L Assimes, John Danesh, Adam S Butterworth & Danish Saleheen
doi:10.1038/ng.3874
Joanna Howson and colleagues perform a genome-wide association study and meta-analysis for coronary artery disease in large, trans-ancestry cohorts. They identify 15 new loci and correlate these regions with cell-type-specific gene expression and plasma protein levels to find novel pathways and potential mechanisms of disease.
| | | | Polygenic burdens on cell-specific pathways underlie the risk of rheumatoid arthritis pp1120 - 1125
Kazuyoshi Ishigaki, Yuta Kochi, Akari Suzuki, Yumi Tsuchida, Haruka Tsuchiya, Shuji Sumitomo, Kensuke Yamaguchi, Yasuo Nagafuchi, Shinichiro Nakachi, Rika Kato, Keiichi Sakurai, Hirofumi Shoda, Katsunori Ikari, Atsuo Taniguchi, Hisashi Yamanaka, Fuyuki Miya, Tatsuhiko Tsunoda, Yukinori Okada, Yukihide Momozawa, Yoichiro Kamatani, Ryo Yamada, Michiaki Kubo, Keishi Fujio & Kazuhiko Yamamoto
doi:10.1038/ng.3885
Yuta Kochi and colleagues perform expression quantitative trait loci (eQTL) analysis on five subsets of immune cells individually sorted from blood from 105 individuals. They develop an integrated analysis pipeline of expression and epigenomic data along with gene association to identify cell-specific candidate causal genes and apply this to rheumatoid arthritis.
| | | | Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes pp1126 - 1132
James D McKay, Rayjean J Hung, Younghun Han, Xuchen Zong, Robert Carreras-Torres, David C Christiani, Neil E Caporaso, Mattias Johansson, Xiangjun Xiao, Yafang Li, Jinyoung Byun, Alison Dunning, Karen A Pooley, David C Qian, Xuemei Ji, Geoffrey Liu, Maria N Timofeeva, Stig E Bojesen, Xifeng Wu, Loic Le Marchand, Demetrios Albanes, Heike Bickeböller, Melinda C Aldrich, William S Bush, Adonina Tardon, Gad Rennert, M Dawn Teare, John K Field, Lambertus A Kiemeney, Philip Lazarus, Aage Haugen, Stephen Lam, Matthew B Schabath, Angeline S Andrew, Hongbing Shen, Yun-Chul Hong, Jian-Min Yuan, Pier Alberto Bertazzi, Angela C Pesatori, Yuanqing Ye, Nancy Diao, Li Su, Ruyang Zhang, Yonathan Brhane, Natasha Leighl, Jakob S Johansen, Anders Mellemgaard, Walid Saliba, Christopher A Haiman, Lynne R Wilkens, Ana Fernandez-Somoano, Guillermo Fernandez-Tardon, Henricus F M van der Heijden, Jin Hee Kim, Juncheng Dai, Zhibin Hu, Michael P A Davies, Michael W Marcus, Hans Brunnström, Jonas Manjer, Olle Melander, David C Muller, Kim Overvad, Antonia Trichopoulou, Rosario Tumino, Jennifer A Doherty, Matt P Barnett, Chu Chen, Gary E Goodman, Angela Cox, Fiona Taylor, Penella Woll, Irene Brüske, H-Erich Wichmann, Judith Manz, Thomas R Muley, Angela Risch, Albert Rosenberger, Kjell Grankvist, Mikael Johansson, Frances A Shepherd, Ming-Sound Tsao, Susanne M Arnold, Eric B Haura, Ciprian Bolca, Ivana Holcatova, Vladimir Janout, Milica Kontic, Jolanta Lissowska, Anush Mukeria, Simona Ognjanovic, Tadeusz M Orlowski, Ghislaine Scelo, Beata Swiatkowska, David Zaridze, Per Bakke, Vidar Skaug, Shanbeh Zienolddiny, Eric J Duell, Lesley M Butler, Woon-Puay Koh, Yu-Tang Gao, Richard S Houlston, John McLaughlin, Victoria L Stevens, Philippe Joubert, Maxime Lamontagne, David C Nickle, Ma'en Obeidat, Wim Timens, Bin Zhu, Lei Song, Linda Kachuri, María Soler Artigas, Martin D Tobin, Louise V Wain, SpiroMeta Consortium, Thorunn Rafnar, Thorgeir E Thorgeirsson, Gunnar W Reginsson, Kari Stefansson, Dana B Hancock, Laura J Bierut, Margaret R Spitz, Nathan C Gaddis, Sharon M Lutz, Fangyi Gu, Eric O Johnson, Ahsan Kamal, Claudio Pikielny, Dakai Zhu, Sara Lindströem, Xia Jiang, Rachel F Tyndale, Georgia Chenevix-Trench, Jonathan Beesley, Yohan Bossé, Stephen Chanock, Paul Brennan, Maria Teresa Landi & Christopher I Amos
doi:10.1038/ng.3892
Christopher Amos and colleagues perform genome-wide association analysis for lung cancer using cohorts genotyped on the OncoArray and combing these with existing data. They identify 18 loci, 10 of which are new, finding heterogeneity across the different lung cancer subtypes, and explore candidate genes through eQTL analysis in lung tissue.
| | | | Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor pp1133 - 1140
Kevin Litchfield, Max Levy, Giulia Orlando, Chey Loveday, Philip J Law, Gabriele Migliorini, Amy Holroyd, Peter Broderick, Robert Karlsson, Trine B Haugen, Wenche Kristiansen, Jérémie Nsengimana, Kerry Fenwick, Ioannis Assiotis, ZSofia Kote-Jarai, Alison M Dunning, Kenneth Muir, Julian Peto, Rosalind Eeles, Douglas F Easton, Darshna Dudakia, Nick Orr, Nora Pashayan, UK Testicular Cancer Collaboration, The PRACTICAL Consortium, D Timothy Bishop, Alison Reid, Robert A Huddart, Janet Shipley, Tom Grotmol, Fredrik Wiklund, Richard S Houlston & Clare Turnbull
doi:10.1038/ng.3896
Clare Turnbull and colleagues report discovery of 19 new susceptibility loci for testicular germ cell tumor (TGCT) and provide evidence for a network of physical interactions between TGCT risk variants and candidate causal genes. Their findings implicate widespread disruption of developmental transcriptional regulators in TGCT susceptibility, consistent with failed primordial germ cell differentiation as an initiating step in oncogenesis.
| | | | Meta-analysis of five genome-wide association studies identifies multiple new loci associated with testicular germ cell tumor pp1141 - 1147
Zhaoming Wang, Katherine A McGlynn, Ewa Rajpert-De Meyts, D Timothy Bishop, Charles C Chung, Marlene D Dalgaard, Mark H Greene, Ramneek Gupta, Tom Grotmol, Trine B Haugen, Robert Karlsson, Kevin Litchfield, Nandita Mitra, Kasper Nielsen, Louise C Pyle, Stephen M Schwartz, Vésteinn Thorsson, Saran Vardhanabhuti, Fredrik Wiklund, Clare Turnbull, Stephen J Chanock, Peter A Kanetsky, Katherine L Nathanson & the Testicular Cancer Consortium
doi:10.1038/ng.3879
Katherine Nathanson, Peter Kanetsky and colleagues present a meta-analysis of five genome-wide association studies of testicular germ cell tumor (TGCT). They identify eight new susceptibility loci and new independent signals at two previously reported loci, providing further clues to the etiology of TGCT.
| | | | Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation pp1148 - 1151
Shawn Yost, Bas de Wolf, Sandra Hanks, Anna Zachariou, Chiara Marcozzi, Matthew Clarke, Richarda M de Voer, Banafsheh Etemad, Esther Uijttewaal, Emma Ramsay, Harriet Wylie, Anna Elliott, Susan Picton, Audrey Smith, Sarah Smithson, Sheila Seal, Elise Ruark, Gunnar Houge, Jonathon Pines, Geert J P L Kops & Nazneen Rahman
doi:10.1038/ng.3883
Nazneen Rahman, Geert Kops and colleagues report the identification of biallelic loss-of-function mutations in TRIP13 in six individuals with Wilms tumor who presented with features of mosaic variegated aneuploidy. They show that TRIP13-mutant cells show spindle assembly checkpoint defects and suggest that mechanisms leading to aneuploidy may contribute directly to increased cancer risk.
| | | | The complex genetics of hypoplastic left heart syndrome pp1152 - 1159
Xiaoqin Liu, Hisato Yagi, Shazina Saeed, Abha S Bais, George C Gabriel, Zhaohan Chen, Kevin A Peterson, You Li, Molly C Schwartz, William T Reynolds, Manush Saydmohammed, Brian Gibbs, Yijen Wu, William Devine, Bishwanath Chatterjee, Nikolai T Klena, Dennis Kostka, Karen L de Mesy Bentley, Madhavi K Ganapathiraju, Phillip Dexheimer, Linda Leatherbury, Omar Khalifa, Anchit Bhagat, Maliha Zahid, William Pu, Simon Watkins, Paul Grossfeld, Stephen A Murray, George A Porter Jr, Michael Tsang, Lisa J Martin, D Woodrow Benson, Bruce J Aronow & Cecilia W Lo
doi:10.1038/ng.3870
Cecilia Lo and colleagues report the recovery of mice with hypoplastic left heart syndrome (HLHS) from a large mutagenesis screen. They find genetic heterogeneity among HLHS mice and functionally validate mutations in two genes, Sap130 and Pcdha, as contributing to HLHS in a combinatorial manner.
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Recognising the work of individuals who promote science in the face of hostility. Winners will be announced at a reception in London, as well as in Nature, and will receive £2,000.
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