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Nature Genetics

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https://www.readbyqxmd.com/read/29106418/reduced-mutation-rate-in-exons-due-to-differential-mismatch-repair
#1
Joan Frigola, Radhakrishnan Sabarinathan, Loris Mularoni, Ferran Muiños, Abel Gonzalez-Perez, Núria López-Bigas
While recent studies have identified higher than anticipated heterogeneity of mutation rate across genomic regions, mutations in exons and introns are assumed to be generated at the same rate. Here we find fewer somatic mutations in exons than expected from their sequence content and demonstrate that this is not due to purifying selection. Instead, we show that it is caused by higher mismatch-repair activity in exonic than in intronic regions. Our findings have important implications for understanding of mutational and DNA repair processes and knowledge of the evolution of eukaryotic genes, and they have practical ramifications for the study of evolution of both tumors and species...
November 6, 2017: Nature Genetics
https://www.readbyqxmd.com/read/29106417/high-throughput-annotation-of-full-length-long-noncoding-rnas-with-capture-long-read-sequencing
#2
Julien Lagarde, Barbara Uszczynska-Ratajczak, Silvia Carbonell, Sílvia Pérez-Lluch, Amaya Abad, Carrie Davis, Thomas R Gingeras, Adam Frankish, Jennifer Harrow, Roderic Guigo, Rory Johnson
Accurate annotation of genes and their transcripts is a foundation of genomics, but currently no annotation technique combines throughput and accuracy. As a result, reference gene collections remain incomplete-many gene models are fragmentary, and thousands more remain uncataloged, particularly for long noncoding RNAs (lncRNAs). To accelerate lncRNA annotation, the GENCODE consortium has developed RNA Capture Long Seq (CLS), which combines targeted RNA capture with third-generation long-read sequencing. Here we present an experimental reannotation of the GENCODE intergenic lncRNA populations in matched human and mouse tissues that resulted in novel transcript models for 3,574 and 561 gene loci, respectively...
November 6, 2017: Nature Genetics
https://www.readbyqxmd.com/read/29106416/bayesian-inference-of-negative-and-positive-selection-in-human-cancers
#3
Donate Weghorn, Shamil Sunyaev
Cancer genomics efforts have identified genes and regulatory elements driving cancer development and neoplastic progression. From a microevolution standpoint, these are subject to positive selection. Although elusive in current studies, genes whose wild-type coding sequences are needed for tumor growth are also of key interest. They are expected to experience negative selection and stay intact under pressure of incessant mutation. The detection of significantly mutated (or undermutated) genes is completely confounded by the genomic heterogeneity of cancer mutation...
November 6, 2017: Nature Genetics
https://www.readbyqxmd.com/read/29106415/evolution-and-clinical-impact-of-co-occurring-genetic-alterations-in-advanced-stage-egfr-mutant-lung-cancers
#4
Collin M Blakely, Thomas B K Watkins, Wei Wu, Beatrice Gini, Jacob J Chabon, Caroline E McCoach, Nicholas McGranahan, Gareth A Wilson, Nicolai J Birkbak, Victor R Olivas, Julia Rotow, Ashley Maynard, Victoria Wang, Matthew A Gubens, Kimberly C Banks, Richard B Lanman, Aleah F Caulin, John St John, Anibal R Cordero, Petros Giannikopoulos, Andrew D Simmons, Philip C Mack, David R Gandara, Hatim Husain, Robert C Doebele, Jonathan W Riess, Maximilian Diehn, Charles Swanton, Trever G Bivona
A widespread approach to modern cancer therapy is to identify a single oncogenic driver gene and target its mutant-protein product (for example, EGFR-inhibitor treatment in EGFR-mutant lung cancers). However, genetically driven resistance to targeted therapy limits patient survival. Through genomic analysis of 1,122 EGFR-mutant lung cancer cell-free DNA samples and whole-exome analysis of seven longitudinally collected tumor samples from a patient with EGFR-mutant lung cancer, we identified critical co-occurring oncogenic events present in most advanced-stage EGFR-mutant lung cancers...
November 6, 2017: Nature Genetics
https://www.readbyqxmd.com/read/29083409/computational-correction-of-copy-number-effect-improves-specificity-of-crispr-cas9-essentiality-screens-in-cancer-cells
#5
Robin M Meyers, Jordan G Bryan, James M McFarland, Barbara A Weir, Ann E Sizemore, Han Xu, Neekesh V Dharia, Phillip G Montgomery, Glenn S Cowley, Sasha Pantel, Amy Goodale, Yenarae Lee, Levi D Ali, Guozhi Jiang, Rakela Lubonja, William F Harrington, Matthew Strickland, Ting Wu, Derek C Hawes, Victor A Zhivich, Meghan R Wyatt, Zohra Kalani, Jaime J Chang, Michael Okamoto, Kimberly Stegmaier, Todd R Golub, Jesse S Boehm, Francisca Vazquez, David E Root, William C Hahn, Aviad Tsherniak
The CRISPR-Cas9 system has revolutionized gene editing both at single genes and in multiplexed loss-of-function screens, thus enabling precise genome-scale identification of genes essential for proliferation and survival of cancer cells. However, previous studies have reported that a gene-independent antiproliferative effect of Cas9-mediated DNA cleavage confounds such measurement of genetic dependency, thereby leading to false-positive results in copy number-amplified regions. We developed CERES, a computational method to estimate gene-dependency levels from CRISPR-Cas9 essentiality screens while accounting for the copy number-specific effect...
October 30, 2017: Nature Genetics
https://www.readbyqxmd.com/read/29083408/exome-wide-association-study-of-plasma-lipids-in-300-000-individuals
#6
Dajiang J Liu, Gina M Peloso, Haojie Yu, Adam S Butterworth, Xiao Wang, Anubha Mahajan, Danish Saleheen, Connor Emdin, Dewan Alam, Alexessander Couto Alves, Philippe Amouyel, Emanuele Di Angelantonio, Dominique Arveiler, Themistocles L Assimes, Paul L Auer, Usman Baber, Christie M Ballantyne, Lia E Bang, Marianne Benn, Joshua C Bis, Michael Boehnke, Eric Boerwinkle, Jette Bork-Jensen, Erwin P Bottinger, Ivan Brandslund, Morris Brown, Fabio Busonero, Mark J Caulfield, John C Chambers, Daniel I Chasman, Y Eugene Chen, Yii-Der Ida Chen, Rajiv Chowdhury, Cramer Christensen, Audrey Y Chu, John M Connell, Francesco Cucca, L Adrienne Cupples, Scott M Damrauer, Gail Davies, Ian J Deary, George Dedoussis, Joshua C Denny, Anna Dominiczak, Marie-Pierre Dubé, Tapani Ebeling, Gudny Eiriksdottir, Tõnu Esko, Aliki-Eleni Farmaki, Mary F Feitosa, Marco Ferrario, Jean Ferrieres, Ian Ford, Myriam Fornage, Paul W Franks, Timothy M Frayling, Ruth Frikke-Schmidt, Lars G Fritsche, Philippe Frossard, Valentin Fuster, Santhi K Ganesh, Wei Gao, Melissa E Garcia, Christian Gieger, Franco Giulianini, Mark O Goodarzi, Harald Grallert, Niels Grarup, Leif Groop, Megan L Grove, Vilmundur Gudnason, Torben Hansen, Tamara B Harris, Caroline Hayward, Joel N Hirschhorn, Oddgeir L Holmen, Jennifer Huffman, Yong Huo, Kristian Hveem, Sehrish Jabeen, Anne U Jackson, Johanna Jakobsdottir, Marjo-Riitta Jarvelin, Gorm B Jensen, Marit E Jørgensen, J Wouter Jukema, Johanne M Justesen, Pia R Kamstrup, Stavroula Kanoni, Fredrik Karpe, Frank Kee, Amit V Khera, Derek Klarin, Heikki A Koistinen, Jaspal S Kooner, Charles Kooperberg, Kari Kuulasmaa, Johanna Kuusisto, Markku Laakso, Timo Lakka, Claudia Langenberg, Anne Langsted, Lenore J Launer, Torsten Lauritzen, David C M Liewald, Li An Lin, Allan Linneberg, Ruth J F Loos, Yingchang Lu, Xiangfeng Lu, Reedik Mägi, Anders Malarstig, Ani Manichaikul, Alisa K Manning, Pekka Mäntyselkä, Eirini Marouli, Nicholas G D Masca, Andrea Maschio, James B Meigs, Olle Melander, Andres Metspalu, Andrew P Morris, Alanna C Morrison, Antonella Mulas, Martina Müller-Nurasyid, Patricia B Munroe, Matt J Neville, Jonas B Nielsen, Sune F Nielsen, Børge G Nordestgaard, Jose M Ordovas, Roxana Mehran, Christoper J O'Donnell, Marju Orho-Melander, Cliona M Molony, Pieter Muntendam, Sandosh Padmanabhan, Colin N A Palmer, Dorota Pasko, Aniruddh P Patel, Oluf Pedersen, Markus Perola, Annette Peters, Charlotta Pisinger, Giorgio Pistis, Ozren Polasek, Neil Poulter, Bruce M Psaty, Daniel J Rader, Asif Rasheed, Rainer Rauramaa, Dermot F Reilly, Alex P Reiner, Frida Renström, Stephen S Rich, Paul M Ridker, John D Rioux, Neil R Robertson, Dan M Roden, Jerome I Rotter, Igor Rudan, Veikko Salomaa, Nilesh J Samani, Serena Sanna, Naveed Sattar, Ellen M Schmidt, Robert A Scott, Peter Sever, Raquel S Sevilla, Christian M Shaffer, Xueling Sim, Suthesh Sivapalaratnam, Kerrin S Small, Albert V Smith, Blair H Smith, Sangeetha Somayajula, Lorraine Southam, Timothy D Spector, Elizabeth K Speliotes, John M Starr, Kathleen E Stirrups, Nathan Stitziel, Konstantin Strauch, Heather M Stringham, Praveen Surendran, Hayato Tada, Alan R Tall, Hua Tang, Jean-Claude Tardif, Kent D Taylor, Stella Trompet, Philip S Tsao, Jaakko Tuomilehto, Anne Tybjaerg-Hansen, Natalie R van Zuydam, Anette Varbo, Tibor V Varga, Jarmo Virtamo, Melanie Waldenberger, Nan Wang, Nick J Wareham, Helen R Warren, Peter E Weeke, Joshua Weinstock, Jennifer Wessel, James G Wilson, Peter W F Wilson, Ming Xu, Hanieh Yaghootkar, Robin Young, Eleftheria Zeggini, He Zhang, Neil S Zheng, Weihua Zhang, Yan Zhang, Wei Zhou, Yanhua Zhou, Magdalena Zoledziewska, Joanna M M Howson, John Danesh, Mark I McCarthy, Chad A Cowan, Goncalo Abecasis, Panos Deloukas, Kiran Musunuru, Cristen J Willer, Sekar Kathiresan
We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD...
October 30, 2017: Nature Genetics
https://www.readbyqxmd.com/read/29083407/exome-chip-meta-analysis-identifies-novel-loci-and-east-asian-specific-coding-variants-that-contribute-to-lipid-levels-and-coronary-artery-disease
#7
Xiangfeng Lu, Gina M Peloso, Dajiang J Liu, Ying Wu, He Zhang, Wei Zhou, Jun Li, Clara Sze-Man Tang, Rajkumar Dorajoo, Huaixing Li, Jirong Long, Xiuqing Guo, Ming Xu, Cassandra N Spracklen, Yang Chen, Xuezhen Liu, Yan Zhang, Chiea Chuen Khor, Jianjun Liu, Liang Sun, Laiyuan Wang, Yu-Tang Gao, Yao Hu, Kuai Yu, Yiqin Wang, Chloe Yu Yan Cheung, Feijie Wang, Jianfeng Huang, Qiao Fan, Qiuyin Cai, Shufeng Chen, Jinxiu Shi, Xueli Yang, Wanting Zhao, Wayne H-H Sheu, Stacey Shawn Cherny, Meian He, Alan B Feranil, Linda S Adair, Penny Gordon-Larsen, Shufa Du, Rohit Varma, Yii-Der Ida Chen, Xiao-Ou Shu, Karen Siu Ling Lam, Tien Yin Wong, Santhi K Ganesh, Zengnan Mo, Kristian Hveem, Lars G Fritsche, Jonas Bille Nielsen, Hung-Fat Tse, Yong Huo, Ching-Yu Cheng, Y Eugene Chen, Wei Zheng, E Shyong Tai, Wei Gao, Xu Lin, Wei Huang, Goncalo Abecasis, Sekar Kathiresan, Karen L Mohlke, Tangchun Wu, Pak Chung Sham, Dongfeng Gu, Cristen J Willer
Most genome-wide association studies have been of European individuals, even though most genetic variation in humans is seen only in non-European samples. To search for novel loci associated with blood lipid levels and clarify the mechanism of action at previously identified lipid loci, we used an exome array to examine protein-coding genetic variants in 47,532 East Asian individuals. We identified 255 variants at 41 loci that reached chip-wide significance, including 3 novel loci and 14 East Asian-specific coding variant associations...
October 30, 2017: Nature Genetics
https://www.readbyqxmd.com/read/29083406/shared-genetic-origin-of-asthma-hay-fever-and-eczema-elucidates-allergic-disease-biology
#8
Manuel A Ferreira, Judith M Vonk, Hansjörg Baurecht, Ingo Marenholz, Chao Tian, Joshua D Hoffman, Quinta Helmer, Annika Tillander, Vilhelmina Ullemar, Jenny van Dongen, Yi Lu, Franz Rüschendorf, Jorge Esparza-Gordillo, Chris W Medway, Edward Mountjoy, Kimberley Burrows, Oliver Hummel, Sarah Grosche, Ben M Brumpton, John S Witte, Jouke-Jan Hottenga, Gonneke Willemsen, Jie Zheng, Elke Rodríguez, Melanie Hotze, Andre Franke, Joana A Revez, Jonathan Beesley, Melanie C Matheson, Shyamali C Dharmage, Lisa M Bain, Lars G Fritsche, Maiken E Gabrielsen, Brunilda Balliu, Jonas B Nielsen, Wei Zhou, Kristian Hveem, Arnulf Langhammer, Oddgeir L Holmen, Mari Løset, Gonçalo R Abecasis, Cristen J Willer, Andreas Arnold, Georg Homuth, Carsten O Schmidt, Philip J Thompson, Nicholas G Martin, David L Duffy, Natalija Novak, Holger Schulz, Stefan Karrasch, Christian Gieger, Konstantin Strauch, Ronald B Melles, David A Hinds, Norbert Hübner, Stephan Weidinger, Patrik K E Magnusson, Rick Jansen, Eric Jorgenson, Young-Ae Lee, Dorret I Boomsma, Catarina Almqvist, Robert Karlsson, Gerard H Koppelman, Lavinia Paternoster
Asthma, hay fever (or allergic rhinitis) and eczema (or atopic dermatitis) often coexist in the same individuals, partly because of a shared genetic origin. To identify shared risk variants, we performed a genome-wide association study (GWAS; n = 360,838) of a broad allergic disease phenotype that considers the presence of any one of these three diseases. We identified 136 independent risk variants (P < 3 × 10(-8)), including 73 not previously reported, which implicate 132 nearby genes in allergic disease pathophysiology...
October 30, 2017: Nature Genetics
https://www.readbyqxmd.com/read/29083405/genetic-variation-and-gene-expression-across-multiple-tissues-and-developmental-stages-in-a-nonhuman-primate
#9
Anna J Jasinska, Ivette Zelaya, Susan K Service, Christine B Peterson, Rita M Cantor, Oi-Wa Choi, Joseph DeYoung, Eleazar Eskin, Lynn A Fairbanks, Scott Fears, Allison E Furterer, Yu S Huang, Vasily Ramensky, Christopher A Schmitt, Hannes Svardal, Matthew J Jorgensen, Jay R Kaplan, Diego Villar, Bronwen L Aken, Paul Flicek, Rishi Nag, Emily S Wong, John Blangero, Thomas D Dyer, Marina Bogomolov, Yoav Benjamini, George M Weinstock, Ken Dewar, Chiara Sabatti, Richard K Wilson, J David Jentsch, Wesley Warren, Giovanni Coppola, Roger P Woods, Nelson B Freimer
By analyzing multitissue gene expression and genome-wide genetic variation data in samples from a vervet monkey pedigree, we generated a transcriptome resource and produced the first catalog of expression quantitative trait loci (eQTLs) in a nonhuman primate model. This catalog contains more genome-wide significant eQTLs per sample than comparable human resources and identifies sex- and age-related expression patterns. Findings include a master regulatory locus that likely has a role in immune function and a locus regulating hippocampal long noncoding RNAs (lncRNAs), whose expression correlates with hippocampal volume...
October 30, 2017: Nature Genetics
https://www.readbyqxmd.com/read/29083404/ancient-hybridization-and-strong-adaptation-to-viruses-across-african-vervet-monkey-populations
#10
Hannes Svardal, Anna J Jasinska, Cristian Apetrei, Giovanni Coppola, Yu Huang, Christopher A Schmitt, Beatrice Jacquelin, Vasily Ramensky, Michaela Müller-Trutwin, Martin Antonio, George Weinstock, J Paul Grobler, Ken Dewar, Richard K Wilson, Trudy R Turner, Wesley C Warren, Nelson B Freimer, Magnus Nordborg
Vervet monkeys are among the most widely distributed nonhuman primates, show considerable phenotypic diversity, and have long been an important biomedical model for a variety of human diseases and in vaccine research. Using whole-genome sequencing data from 163 vervets sampled from across Africa and the Caribbean, we find high diversity within and between taxa and clear evidence that taxonomic divergence was reticulate rather than following a simple branching pattern. A scan for diversifying selection across taxa identifies strong and highly polygenic selection signals affecting viral processes...
October 30, 2017: Nature Genetics
https://www.readbyqxmd.com/read/29058716/identification-of-ten-variants-associated-with-risk-of-estrogen-receptor-negative-breast-cancer
#11
Roger L Milne, Karoline B Kuchenbaecker, Kyriaki Michailidou, Jonathan Beesley, Siddhartha Kar, Sara Lindström, Shirley Hui, Audrey Lemaçon, Penny Soucy, Joe Dennis, Xia Jiang, Asha Rostamianfar, Hilary Finucane, Manjeet K Bolla, Lesley McGuffog, Qin Wang, Cora M Aalfs, Marcia Adams, Julian Adlard, Simona Agata, Shahana Ahmed, Habibul Ahsan, Kristiina Aittomäki, Fares Al-Ejeh, Jamie Allen, Christine B Ambrosone, Christopher I Amos, Irene L Andrulis, Hoda Anton-Culver, Natalia N Antonenkova, Volker Arndt, Norbert Arnold, Kristan J Aronson, Bernd Auber, Paul L Auer, Margreet G E M Ausems, Jacopo Azzollini, François Bacot, Judith Balmaña, Monica Barile, Laure Barjhoux, Rosa B Barkardottir, Myrto Barrdahl, Daniel Barnes, Daniel Barrowdale, Caroline Baynes, Matthias W Beckmann, Javier Benitez, Marina Bermisheva, Leslie Bernstein, Yves-Jean Bignon, Kathleen R Blazer, Marinus J Blok, Carl Blomqvist, William Blot, Kristie Bobolis, Bram Boeckx, Natalia V Bogdanova, Anders Bojesen, Stig E Bojesen, Bernardo Bonanni, Anne-Lise Børresen-Dale, Aniko Bozsik, Angela R Bradbury, Judith S Brand, Hiltrud Brauch, Hermann Brenner, Brigitte Bressac-de Paillerets, Carole Brewer, Louise Brinton, Per Broberg, Angela Brooks-Wilson, Joan Brunet, Thomas Brüning, Barbara Burwinkel, Saundra S Buys, Jinyoung Byun, Qiuyin Cai, Trinidad Caldés, Maria A Caligo, Ian Campbell, Federico Canzian, Olivier Caron, Angel Carracedo, Brian D Carter, J Esteban Castelao, Laurent Castera, Virginie Caux-Moncoutier, Salina B Chan, Jenny Chang-Claude, Stephen J Chanock, Xiaoqing Chen, Ting-Yuan David Cheng, Jocelyne Chiquette, Hans Christiansen, Kathleen B M Claes, Christine L Clarke, Thomas Conner, Don M Conroy, Jackie Cook, Emilie Cordina-Duverger, Sten Cornelissen, Isabelle Coupier, Angela Cox, David G Cox, Simon S Cross, Katarina Cuk, Julie M Cunningham, Kamila Czene, Mary B Daly, Francesca Damiola, Hatef Darabi, Rosemarie Davidson, Kim De Leeneer, Peter Devilee, Ed Dicks, Orland Diez, Yuan Chun Ding, Nina Ditsch, Kimberly F Doheny, Susan M Domchek, Cecilia M Dorfling, Thilo Dörk, Isabel Dos-Santos-Silva, Stéphane Dubois, Pierre-Antoine Dugué, Martine Dumont, Alison M Dunning, Lorraine Durcan, Miriam Dwek, Bernd Dworniczak, Diana Eccles, Ros Eeles, Hans Ehrencrona, Ursula Eilber, Bent Ejlertsen, Arif B Ekici, A Heather Eliassen, Christoph Engel, Mikael Eriksson, Laura Fachal, Laurence Faivre, Peter A Fasching, Ulrike Faust, Jonine Figueroa, Dieter Flesch-Janys, Olivia Fletcher, Henrik Flyger, William D Foulkes, Eitan Friedman, Lin Fritschi, Debra Frost, Marike Gabrielson, Pragna Gaddam, Marilie D Gammon, Patricia A Ganz, Susan M Gapstur, Judy Garber, Vanesa Garcia-Barberan, José A García-Sáenz, Mia M Gaudet, Marion Gauthier-Villars, Andrea Gehrig, Vassilios Georgoulias, Anne-Marie Gerdes, Graham G Giles, Gord Glendon, Andrew K Godwin, Mark S Goldberg, David E Goldgar, Anna González-Neira, Paul Goodfellow, Mark H Greene, Grethe I Grenaker Alnæs, Mervi Grip, Jacek Gronwald, Anne Grundy, Daphne Gschwantler-Kaulich, Pascal Guénel, Qi Guo, Lothar Haeberle, Eric Hahnen, Christopher A Haiman, Niclas Håkansson, Emily Hallberg, Ute Hamann, Nathalie Hamel, Susan Hankinson, Thomas V O Hansen, Patricia Harrington, Steven N Hart, Jaana M Hartikainen, Catherine S Healey, Alexander Hein, Sonja Helbig, Alex Henderson, Jane Heyworth, Belynda Hicks, Peter Hillemanns, Shirley Hodgson, Frans B Hogervorst, Antoinette Hollestelle, Maartje J Hooning, Bob Hoover, John L Hopper, Chunling Hu, Guanmengqian Huang, Peter J Hulick, Keith Humphreys, David J Hunter, Evgeny N Imyanitov, Claudine Isaacs, Motoki Iwasaki, Louise Izatt, Anna Jakubowska, Paul James, Ramunas Janavicius, Wolfgang Janni, Uffe Birk Jensen, Esther M John, Nichola Johnson, Kristine Jones, Michael Jones, Arja Jukkola-Vuorinen, Rudolf Kaaks, Maria Kabisch, Katarzyna Kaczmarek, Daehee Kang, Karin Kast, Renske Keeman, Michael J Kerin, Carolien M Kets, Machteld Keupers, Sofia Khan, Elza Khusnutdinova, Johanna I Kiiski, Sung-Won Kim, Julia A Knight, Irene Konstantopoulou, Veli-Matti Kosma, Vessela N Kristensen, Torben A Kruse, Ava Kwong, Anne-Vibeke Lænkholm, Yael Laitman, Fiona Lalloo, Diether Lambrechts, Keren Landsman, Christine Lasset, Conxi Lazaro, Loic Le Marchand, Julie Lecarpentier, Andrew Lee, Eunjung Lee, Jong Won Lee, Min Hyuk Lee, Flavio Lejbkowicz, Fabienne Lesueur, Jingmei Li, Jenna Lilyquist, Anne Lincoln, Annika Lindblom, Jolanta Lissowska, Wing-Yee Lo, Sibylle Loibl, Jirong Long, Jennifer T Loud, Jan Lubinski, Craig Luccarini, Michael Lush, Robert J MacInnis, Tom Maishman, Enes Makalic, Ivana Maleva Kostovska, Kathleen E Malone, Siranoush Manoukian, JoAnn E Manson, Sara Margolin, John W M Martens, Maria Elena Martinez, Keitaro Matsuo, Dimitrios Mavroudis, Sylvie Mazoyer, Catriona McLean, Hanne Meijers-Heijboer, Primitiva Menéndez, Jeffery Meyer, Hui Miao, Austin Miller, Nicola Miller, Gillian Mitchell, Marco Montagna, Kenneth Muir, Anna Marie Mulligan, Claire Mulot, Sue Nadesan, Katherine L Nathanson, Susan L Neuhausen, Heli Nevanlinna, Ines Nevelsteen, Dieter Niederacher, Sune F Nielsen, Børge G Nordestgaard, Aaron Norman, Robert L Nussbaum, Edith Olah, Olufunmilayo I Olopade, Janet E Olson, Curtis Olswold, Kai-Ren Ong, Jan C Oosterwijk, Nick Orr, Ana Osorio, V Shane Pankratz, Laura Papi, Tjoung-Won Park-Simon, Ylva Paulsson-Karlsson, Rachel Lloyd, Inge Søkilde Pedersen, Bernard Peissel, Ana Peixoto, Jose I A Perez, Paolo Peterlongo, Julian Peto, Georg Pfeiler, Catherine M Phelan, Mila Pinchev, Dijana Plaseska-Karanfilska, Bruce Poppe, Mary E Porteous, Ross Prentice, Nadege Presneau, Darya Prokofieva, Elizabeth Pugh, Miquel Angel Pujana, Katri Pylkäs, Brigitte Rack, Paolo Radice, Nazneen Rahman, Johanna Rantala, Christine Rappaport-Fuerhauser, Gad Rennert, Hedy S Rennert, Valerie Rhenius, Kerstin Rhiem, Andrea Richardson, Gustavo C Rodriguez, Atocha Romero, Jane Romm, Matti A Rookus, Anja Rudolph, Thomas Ruediger, Emmanouil Saloustros, Joyce Sanders, Dale P Sandler, Suleeporn Sangrajrang, Elinor J Sawyer, Daniel F Schmidt, Minouk J Schoemaker, Fredrick Schumacher, Peter Schürmann, Lukas Schwentner, Christopher Scott, Rodney J Scott, Sheila Seal, Leigha Senter, Caroline Seynaeve, Mitul Shah, Priyanka Sharma, Chen-Yang Shen, Xin Sheng, Hermela Shimelis, Martha J Shrubsole, Xiao-Ou Shu, Lucy E Side, Christian F Singer, Christof Sohn, Melissa C Southey, John J Spinelli, Amanda B Spurdle, Christa Stegmaier, Dominique Stoppa-Lyonnet, Grzegorz Sukiennicki, Harald Surowy, Christian Sutter, Anthony Swerdlow, Csilla I Szabo, Rulla M Tamimi, Yen Y Tan, Jack A Taylor, Maria-Isabel Tejada, Maria Tengström, Soo H Teo, Mary B Terry, Daniel C Tessier, Alex Teulé, Kathrin Thöne, Darcy L Thull, Maria Grazia Tibiletti, Laima Tihomirova, Marc Tischkowitz, Amanda E Toland, Rob A E M Tollenaar, Ian Tomlinson, Ling Tong, Diana Torres, Martine Tranchant, Thérèse Truong, Kathy Tucker, Nadine Tung, Jonathan Tyrer, Hans-Ulrich Ulmer, Celine Vachon, Christi J van Asperen, David Van Den Berg, Ans M W van den Ouweland, Elizabeth J van Rensburg, Liliana Varesco, Raymonda Varon-Mateeva, Ana Vega, Alessandra Viel, Joseph Vijai, Daniel Vincent, Jason Vollenweider, Lisa Walker, Zhaoming Wang, Shan Wang-Gohrke, Barbara Wappenschmidt, Clarice R Weinberg, Jeffrey N Weitzel, Camilla Wendt, Jelle Wesseling, Alice S Whittemore, Juul T Wijnen, Walter Willett, Robert Winqvist, Alicja Wolk, Anna H Wu, Lucy Xia, Xiaohong R Yang, Drakoulis Yannoukakos, Daniela Zaffaroni, Wei Zheng, Bin Zhu, Argyrios Ziogas, Elad Ziv, Kristin K Zorn, Manuela Gago-Dominguez, Arto Mannermaa, Håkan Olsson, Manuel R Teixeira, Jennifer Stone, Kenneth Offit, Laura Ottini, Sue K Park, Mads Thomassen, Per Hall, Alfons Meindl, Rita K Schmutzler, Arnaud Droit, Gary D Bader, Paul D P Pharoah, Fergus J Couch, Douglas F Easton, Peter Kraft, Georgia Chenevix-Trench, Montserrat García-Closas, Marjanka K Schmidt, Antonis C Antoniou, Jacques Simard
Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10(-8) with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies...
October 23, 2017: Nature Genetics
https://www.readbyqxmd.com/read/29058715/estimating-the-causal-tissues-for-complex-traits-and-diseases
#12
Halit Ongen, Andrew A Brown, Olivier Delaneau, Nikolaos I Panousis, Alexandra C Nica, Emmanouil T Dermitzakis
How to interpret the biological causes underlying the predisposing markers identified through genome-wide association studies (GWAS) remains an open question. One direct and powerful way to assess the genetic causality behind GWAS is through analysis of expression quantitative trait loci (eQTLs). Here we describe a new approach to estimate the tissues behind the genetic causality of a variety of GWAS traits, using the cis-eQTLs in 44 tissues from the Genotype-Tissue Expression (GTEx) Consortium. We have adapted the regulatory trait concordance (RTC) score to measure the probability of eQTLs being active in multiple tissues and to calculate the probability that a GWAS-associated variant and an eQTL tag the same functional effect...
October 23, 2017: Nature Genetics
https://www.readbyqxmd.com/read/29058714/predicting-causal-variants-affecting-expression-by-using-whole-genome-sequencing-and-rna-seq-from-multiple-human-tissues
#13
Andrew Anand Brown, Ana Viñuela, Olivier Delaneau, Tim D Spector, Kerrin S Small, Emmanouil T Dermitzakis
Genetic association mapping produces statistical links between phenotypes and genomic regions, but identifying causal variants remains difficult. Whole-genome sequencing (WGS) can help by providing complete knowledge of all genetic variants, but it is financially prohibitive for well-powered GWAS studies. We performed mapping of expression quantitative trait loci (eQTLs) with WGS and RNA-seq, and found that lead eQTL variants called with WGS were more likely to be causal. Through simulations, we derived properties of causal variants and used them to develop a method for identifying likely causal SNPs...
October 23, 2017: Nature Genetics
https://www.readbyqxmd.com/read/29038596/a-quantitative-genetic-framework-highlights-the-role-of-epistatic-effects-for-grain-yield-heterosis-in-bread-wheat
#14
Yong Jiang, Renate H Schmidt, Yusheng Zhao, Jochen C Reif
Increasing wheat yield is a key global challenge to producing sufficient food for a growing human population. Wheat grain yield can be boosted by exploiting heterosis, the superior performance of hybrids compared with midparents. Here we present a tailored quantitative genetic framework to study the genetic basis of midparent heterosis in hybrid populations derived from crosses among diverse parents. We applied this framework to an extensive data set assembled for winter wheat. Grain yield was assessed for 1,604 hybrids and their 135 parental elite breeding lines in 11 environments...
October 16, 2017: Nature Genetics
https://www.readbyqxmd.com/read/29038595/covariate-selection-for-association-screening-in-multiphenotype-genetic-studies
#15
Hugues Aschard, Vincent Guillemot, Bjarni Vilhjalmsson, Chirag J Patel, David Skurnik, Chun J Ye, Brian Wolpin, Peter Kraft, Noah Zaitlen
Testing for associations in big data faces the problem of multiple comparisons, wherein true signals are difficult to detect on the background of all associations queried. This difficulty is particularly salient in human genetic association studies, in which phenotypic variation is often driven by numerous variants of small effect. The current strategy to improve power to identify these weak associations consists of applying standard marginal statistical approaches and increasing study sample sizes. Although successful, this approach does not leverage the environmental and genetic factors shared among the multiple phenotypes collected in contemporary cohorts...
October 16, 2017: Nature Genetics
https://www.readbyqxmd.com/read/29019975/enhancing-gtex-by-bridging-the-gaps-between-genotype-gene-expression-and-disease
#16
(no author information available yet)
Genetic variants have been associated with myriad molecular phenotypes that provide new insight into the range of mechanisms underlying genetic traits and diseases. Identifying any particular genetic variant's cascade of effects, from molecule to individual, requires assaying multiple layers of molecular complexity. We introduce the Enhancing GTEx (eGTEx) project that extends the GTEx project to combine gene expression with additional intermediate molecular measurements on the same tissues to provide a resource for studying how genetic differences cascade through molecular phenotypes to impact human health...
October 11, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28991257/contribution-of-rare-inherited-and-de-novo-variants-in-2-871-congenital-heart-disease-probands
#17
Sheng Chih Jin, Jason Homsy, Samir Zaidi, Qiongshi Lu, Sarah Morton, Steven R DePalma, Xue Zeng, Hongjian Qi, Weni Chang, Michael C Sierant, Wei-Chien Hung, Shozeb Haider, Junhui Zhang, James Knight, Robert D Bjornson, Christopher Castaldi, Irina R Tikhonoa, Kaya Bilguvar, Shrikant M Mane, Stephan J Sanders, Seema Mital, Mark W Russell, J William Gaynor, John Deanfield, Alessandro Giardini, George A Porter, Deepak Srivastava, Cecelia W Lo, Yufeng Shen, W Scott Watkins, Mark Yandell, H Joseph Yost, Martin Tristani-Firouzi, Jane W Newburger, Amy E Roberts, Richard Kim, Hongyu Zhao, Jonathan R Kaltman, Elizabeth Goldmuntz, Wendy K Chung, Jonathan G Seidman, Bruce D Gelb, Christine E Seidman, Richard P Lifton, Martina Brueckner
Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Here, exome sequencing of a single cohort of 2,871 CHD probands, including 2,645 parent-offspring trios, implicated rare inherited mutations in 1.8%, including a recessive founder mutation in GDF1 accounting for ∼5% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for ∼11% of Shone complex, and dominant FLT4 mutations accounting for 2.3% of Tetralogy of Fallot. De novo mutations (DNMs) accounted for 8% of cases, including ∼3% of isolated CHD patients and ∼28% with both neurodevelopmental and extra-cardiac congenital anomalies...
November 2017: Nature Genetics
https://www.readbyqxmd.com/read/28991256/genome-wide-association-analysis-identifies-30-new-susceptibility-loci-for-schizophrenia
#18
Zhiqiang Li, Jianhua Chen, Hao Yu, Lin He, Yifeng Xu, Dai Zhang, Qizhong Yi, Changgui Li, Xingwang Li, Jiawei Shen, Zhijian Song, Weidong Ji, Meng Wang, Juan Zhou, Boyu Chen, Yahui Liu, Jiqiang Wang, Peng Wang, Ping Yang, Qingzhong Wang, Guoyin Feng, Benxiu Liu, Wensheng Sun, Baojie Li, Guang He, Weidong Li, Chunling Wan, Qi Xu, Wenjin Li, Zujia Wen, Ke Liu, Fang Huang, Jue Ji, Stephan Ripke, Weihua Yue, Patrick F Sullivan, Michael C O'Donovan, Yongyong Shi
We conducted a genome-wide association study (GWAS) with replication in 36,180 Chinese individuals and performed further transancestry meta-analyses with data from the Psychiatry Genomics Consortium (PGC2). Approximately 95% of the genome-wide significant (GWS) index alleles (or their proxies) from the PGC2 study were overrepresented in Chinese schizophrenia cases, including ∼50% that achieved nominal significance and ∼75% that continued to be GWS in the transancestry analysis. The Chinese-only analysis identified seven GWS loci; three of these also were GWS in the transancestry analyses, which identified 109 GWS loci, thus yielding a total of 113 GWS loci (30 novel) in at least one of these analyses...
November 2017: Nature Genetics
https://www.readbyqxmd.com/read/28991255/patient-derived-xenografts-undergo-mouse-specific-tumor-evolution
#19
Uri Ben-David, Gavin Ha, Yuen-Yi Tseng, Noah F Greenwald, Coyin Oh, Juliann Shih, James M McFarland, Bang Wong, Jesse S Boehm, Rameen Beroukhim, Todd R Golub
Patient-derived xenografts (PDXs) have become a prominent cancer model system, as they are presumed to faithfully represent the genomic features of primary tumors. Here we monitored the dynamics of copy number alterations (CNAs) in 1,110 PDX samples across 24 cancer types. We observed rapid accumulation of CNAs during PDX passaging, often due to selection of preexisting minor clones. CNA acquisition in PDXs was correlated with the tissue-specific levels of aneuploidy and genetic heterogeneity observed in primary tumors...
November 2017: Nature Genetics
https://www.readbyqxmd.com/read/28991254/the-draft-genome-of-tropical-fruit-durian-durio-zibethinus
#20
Bin Tean Teh, Kevin Lim, Chern Han Yong, Cedric Chuan Young Ng, Sushma Ramesh Rao, Vikneswari Rajasegaran, Weng Khong Lim, Choon Kiat Ong, Ki Chan, Vincent Kin Yuen Cheng, Poh Sheng Soh, Sanjay Swarup, Steven G Rozen, Niranjan Nagarajan, Patrick Tan
Durian (Durio zibethinus) is a Southeast Asian tropical plant known for its hefty, spine-covered fruit and sulfury and onion-like odor. Here we present a draft genome assembly of D. zibethinus, representing the third plant genus in the Malvales order and first in the Helicteroideae subfamily to be sequenced. Single-molecule sequencing and chromosome contact maps enabled assembly of the highly heterozygous durian genome at chromosome-scale resolution. Transcriptomic analysis showed upregulation of sulfur-, ethylene-, and lipid-related pathways in durian fruits...
November 2017: Nature Genetics
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