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Nature Genetics

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https://www.readbyqxmd.com/read/27893734/an-ipsc-derived-vascular-model-of-marfan-syndrome-identifies-key-mediators-of-smooth-muscle-cell-death
#1
Alessandra Granata, Felipe Serrano, William George Bernard, Madeline McNamara, Lucinda Low, Priya Sastry, Sanjay Sinha
Marfan syndrome (MFS) is a heritable connective tissue disorder caused by mutations in FBN1, which encodes the extracellular matrix protein fibrillin-1. To investigate the pathogenesis of aortic aneurysms in MFS, we generated a vascular model derived from human induced pluripotent stem cells (MFS-hiPSCs). Our MFS-hiPSC-derived smooth muscle cells (SMCs) recapitulated the pathology seen in Marfan aortas, including defects in fibrillin-1 accumulation, extracellular matrix degradation, transforming growth factor-β (TGF-β) signaling, contraction and apoptosis; abnormalities were corrected by CRISPR-based editing of the FBN1 mutation...
November 28, 2016: Nature Genetics
https://www.readbyqxmd.com/read/27893733/adarb1-catalyzes-circadian-a-to-i-editing-and-regulates-rna-rhythm
#2
Hideki Terajima, Hikari Yoshitane, Haruka Ozaki, Yutaka Suzuki, Shigeki Shimba, Shinya Kuroda, Wataru Iwasaki, Yoshitaka Fukada
It has been proposed that the CLOCK-ARNTL (BMAL1) complex drives circadian transcription of thousands of genes, including Per and Cry family genes that encode suppressors of CLOCK-ARNTL-dependent transcription. However, recent studies demonstrated that 70-80% of circadian-oscillating mRNAs have no obvious rhythms in their de novo transcription, indicating the potential importance of post-transcriptional regulation. Our CLOCK-ChIP-seq analysis identified rhythmic expression of adenosine deaminase, RNA-specific, B1 (Adarb1, also known as Adar2), an adenosine-to-inosine (A-to-I) RNA-editing enzyme...
November 28, 2016: Nature Genetics
https://www.readbyqxmd.com/read/27869830/inactivation-of-capicua-drives-cancer-metastasis
#3
Ross A Okimoto, Frank Breitenbuecher, Victor R Olivas, Wei Wu, Beatrice Gini, Matan Hofree, Saurabh Asthana, Gorjan Hrustanovic, Jennifer Flanagan, Asmin Tulpule, Collin M Blakely, Henry J Haringsma, Andrew D Simmons, Kyle Gowen, James Suh, Vincent A Miller, Siraj Ali, Martin Schuler, Trever G Bivona
Metastasis is the leading cause of death in people with lung cancer, yet the molecular effectors underlying tumor dissemination remain poorly defined. Through the development of an in vivo spontaneous lung cancer metastasis model, we show that the developmentally regulated transcriptional repressor Capicua (CIC) suppresses invasion and metastasis. Inactivation of CIC relieves repression of its effector ETV4, driving ETV4-mediated upregulation of MMP24, which is necessary and sufficient for metastasis. Loss of CIC, or an increase in levels of its effectors ETV4 and MMP24, is a biomarker of tumor progression and worse outcomes in people with lung and/or gastric cancer...
November 21, 2016: Nature Genetics
https://www.readbyqxmd.com/read/27869829/contribution-of-copy-number-variants-to-schizophrenia-from-a-genome-wide-study-of-41-321-subjects
#4
(no author information available yet)
Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 × 10(-15)), which persisted after excluding loci implicated in previous studies (OR = 1...
November 21, 2016: Nature Genetics
https://www.readbyqxmd.com/read/27869828/tumor-suppressor-genes-that-escape-from-x-inactivation-contribute-to-cancer-sex-bias
#5
Andrew Dunford, David M Weinstock, Virginia Savova, Steven E Schumacher, John P Cleary, Akinori Yoda, Timothy J Sullivan, Julian M Hess, Alexander A Gimelbrant, Rameen Beroukhim, Michael S Lawrence, Gad Getz, Andrew A Lane
There is a striking and unexplained male predominance across many cancer types. A subset of X-chromosome genes can escape X-inactivation, which would protect females from complete functional loss by a single mutation. To identify putative 'escape from X-inactivation tumor-suppressor' (EXITS) genes, we examined somatic alterations from >4,100 cancers across 21 tumor types for sex bias. Six of 783 non-pseudoautosomal region (PAR) X-chromosome genes (ATRX, CNKSR2, DDX3X, KDM5C, KDM6A, and MAGEC3) harbored loss-of-function mutations more frequently in males (based on a false discovery rate < 0...
November 21, 2016: Nature Genetics
https://www.readbyqxmd.com/read/27869827/titin-truncating-variants-affect-heart-function-in-disease-cohorts-and-the-general-population
#6
Sebastian Schafer, Antonio de Marvao, Eleonora Adami, Lorna R Fiedler, Benjamin Ng, Ester Khin, Owen J L Rackham, Sebastiaan van Heesch, Chee J Pua, Miao Kui, Roddy Walsh, Upasana Tayal, Sanjay K Prasad, Timothy J W Dawes, Nicole S J Ko, David Sim, Laura L H Chan, Calvin W L Chin, Francesco Mazzarotto, Paul J Barton, Franziska Kreuchwig, Dominique P V de Kleijn, Teresa Totman, Carlo Biffi, Nicole Tee, Daniel Rueckert, Valentin Schneider, Allison Faber, Vera Regitz-Zagrosek, Jonathan G Seidman, Christine E Seidman, Wolfgang A Linke, Jean-Paul Kovalik, Declan O'Regan, James S Ware, Norbert Hubner, Stuart A Cook
Titin-truncating variants (TTNtv) commonly cause dilated cardiomyopathy (DCM). TTNtv are also encountered in ∼1% of the general population, where they may be silent, perhaps reflecting allelic factors. To better understand TTNtv, we integrated TTN allelic series, cardiac imaging and genomic data in humans and studied rat models with disparate TTNtv. In patients with DCM, TTNtv throughout titin were significantly associated with DCM. Ribosomal profiling in rat showed the translational footprint of premature stop codons in Ttn, TTNtv-position-independent nonsense-mediated degradation of the mutant allele and a signature of perturbed cardiac metabolism...
November 21, 2016: Nature Genetics
https://www.readbyqxmd.com/read/27869826/pan-cancer-analysis-of-somatic-copy-number-alterations-implicates-irs4-and-igf2-in-enhancer-hijacking
#7
Joachim Weischenfeldt, Taronish Dubash, Alexandros P Drainas, Balca R Mardin, Yuanyuan Chen, Adrian M Stütz, Sebastian M Waszak, Graziella Bosco, Ann Rita Halvorsen, Benjamin Raeder, Theocharis Efthymiopoulos, Serap Erkek, Christine Siegl, Hermann Brenner, Odd Terje Brustugun, Sebastian M Dieter, Paul A Northcott, Iver Petersen, Stefan M Pfister, Martin Schneider, Steinar K Solberg, Erik Thunissen, Wilko Weichert, Thomas Zichner, Roman Thomas, Martin Peifer, Aslaug Helland, Claudia R Ball, Martin Jechlinger, Rocio Sotillo, Hanno Glimm, Jan O Korbel
Extensive prior research focused on somatic copy-number alterations (SCNAs) affecting cancer genes, yet the extent to which recurrent SCNAs exert their influence through rearrangement of cis-regulatory elements (CREs) remains unclear. Here we present a framework for inferring cancer-related gene overexpression resulting from CRE reorganization (e.g., enhancer hijacking) by integrating SCNAs, gene expression data and information on topologically associating domains (TADs). Analysis of 7,416 cancer genomes uncovered several pan-cancer candidate genes, including IRS4, SMARCA1 and TERT...
November 21, 2016: Nature Genetics
https://www.readbyqxmd.com/read/27841882/qki-deficiency-maintains-stemness-of-glioma-stem-cells-in-suboptimal-environment-by-downregulating-endolysosomal-degradation
#8
Takashi Shingu, Allen L Ho, Liang Yuan, Xin Zhou, Congxin Dai, Siyuan Zheng, Qianghu Wang, Yi Zhong, Qing Chang, James W Horner, Brandon D Liebelt, Yu Yao, Baoli Hu, Yiwen Chen, Gregory N Fuller, Roeland G W Verhaak, Amy B Heimberger, Jian Hu
Stem cells, including cancer stem cells (CSCs), require niches to maintain stemness, yet it is unclear how CSCs maintain stemness in the suboptimal environment outside their niches during invasion. Postnatal co-deletion of Pten and Trp53 in mouse neural stem cells (NSCs) leads to the expansion of these cells in their subventricular zone (SVZ) niches but fails to maintain stemness outside the SVZ. We discovered that Qki is a major regulator of NSC stemness. Qk deletion on a Pten(-/-); Trp53(-/-) background helps NSCs maintain their stemness outside the SVZ in Nes-CreER(T2); Qk(L/L); Pten(L/L); Trp53(L/L) mice, which develop glioblastoma with a penetrance of 92% and a median survival time of 105 d...
November 14, 2016: Nature Genetics
https://www.readbyqxmd.com/read/27841881/transient-transcription-in-the-early-embryo-sets-an-epigenetic-state-that-programs-postnatal-growth
#9
Maxim V C Greenberg, Juliane Glaser, Máté Borsos, Fatima El Marjou, Marius Walter, Aurélie Teissandier, Déborah Bourc'his
The potential for early embryonic events to program epigenetic states that influence adult physiology remains an important question in health and development. Using the imprinted Zdbf2 locus as a paradigm for the early programming of phenotypes, we demonstrate here that chromatin changes that occur in the pluripotent embryo can be dispensable for embryogenesis but instead signal essential regulatory information in the adult. The Liz (long isoform of Zdbf2) transcript is transiently expressed in early embryos and embryonic stem cells (ESCs)...
November 14, 2016: Nature Genetics
https://www.readbyqxmd.com/read/27841880/the-genomic-landscape-of-balanced-cytogenetic-abnormalities-associated-with-human-congenital-anomalies
#10
Claire Redin, Harrison Brand, Ryan L Collins, Tammy Kammin, Elyse Mitchell, Jennelle C Hodge, Carrie Hanscom, Vamsee Pillalamarri, Catarina M Seabra, Mary-Alice Abbott, Omar A Abdul-Rahman, Erika Aberg, Rhett Adley, Sofia L Alcaraz-Estrada, Fowzan S Alkuraya, Yu An, Mary-Anne Anderson, Caroline Antolik, Kwame Anyane-Yeboa, Joan F Atkin, Tina Bartell, Jonathan A Bernstein, Elizabeth Beyer, Ian Blumenthal, Ernie M H F Bongers, Eva H Brilstra, Chester W Brown, Hennie T Brüggenwirth, Bert Callewaert, Colby Chiang, Ken Corning, Helen Cox, Edwin Cuppen, Benjamin B Currall, Tom Cushing, Dezso David, Matthew A Deardorff, Annelies Dheedene, Marc D'Hooghe, Bert B A de Vries, Dawn L Earl, Heather L Ferguson, Heather Fisher, David R FitzPatrick, Pamela Gerrol, Daniela Giachino, Joseph T Glessner, Troy Gliem, Margo Grady, Brett H Graham, Cristin Griffis, Karen W Gripp, Andrea L Gropman, Andrea Hanson-Kahn, David J Harris, Mark A Hayden, Rosamund Hill, Ron Hochstenbach, Jodi D Hoffman, Robert J Hopkin, Monika W Hubshman, A Micheil Innes, Mira Irons, Melita Irving, Jessie C Jacobsen, Sandra Janssens, Tamison Jewett, John P Johnson, Marjolijn C Jongmans, Stephen G Kahler, David A Koolen, Jerome Korzelius, Peter M Kroisel, Yves Lacassie, William Lawless, Emmanuelle Lemyre, Kathleen Leppig, Alex V Levin, Haibo Li, Hong Li, Eric C Liao, Cynthia Lim, Edward J Lose, Diane Lucente, Michael J Macera, Poornima Manavalan, Giorgia Mandrile, Carlo L Marcelis, Lauren Margolin, Tamara Mason, Diane Masser-Frye, Michael W McClellan, Cinthya J Zepeda Mendoza, Björn Menten, Sjors Middelkamp, Liya R Mikami, Emily Moe, Shehla Mohammed, Tarja Mononen, Megan E Mortenson, Graciela Moya, Aggie W Nieuwint, Zehra Ordulu, Sandhya Parkash, Susan P Pauker, Shahrin Pereira, Danielle Perrin, Katy Phelan, Raul E Piña Aguilar, Pino J Poddighe, Giulia Pregno, Salmo Raskin, Linda Reis, William Rhead, Debra Rita, Ivo Renkens, Filip Roelens, Jayla Ruliera, Patrick Rump, Samantha L P Schilit, Ranad Shaheen, Rebecca Sparkes, Erica Spiegel, Blair Stevens, Matthew R Stone, Julia Tagoe, Joseph V Thakuria, Bregje W van Bon, Jiddeke van de Kamp, Ineke van Der Burgt, Ton van Essen, Conny M van Ravenswaaij-Arts, Markus J van Roosmalen, Sarah Vergult, Catharina M L Volker-Touw, Dorothy P Warburton, Matthew J Waterman, Susan Wiley, Anna Wilson, Maria de la Concepcion A Yerena-de Vega, Roberto T Zori, Brynn Levy, Han G Brunner, Nicole de Leeuw, Wigard P Kloosterman, Erik C Thorland, Cynthia C Morton, James F Gusella, Michael E Talkowski
Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5...
November 14, 2016: Nature Genetics
https://www.readbyqxmd.com/read/27841879/vrs2-regulates-hormone-mediated-inflorescence-patterning-in-barley
#11
Helmy M Youssef, Kai Eggert, Ravi Koppolu, Ahmad M Alqudah, Naser Poursarebani, Arash Fazeli, Shun Sakuma, Akemi Tagiri, Twan Rutten, Geetha Govind, Udda Lundqvist, Andreas Graner, Takao Komatsuda, Nese Sreenivasulu, Thorsten Schnurbusch
Plant architecture has clear agronomic and economic implications for crops such as wheat and barley, as it is a critical factor for determining grain yield. Despite this, only limited molecular information is available about how grain-bearing inflorescences, called spikes, are formed and maintain their regular, distichous pattern. Here we elucidate the molecular and hormonal role of Six-rowed spike 2 (Vrs2), which encodes a SHORT INTERNODES (SHI) transcriptional regulator during barley inflorescence and shoot development...
November 14, 2016: Nature Genetics
https://www.readbyqxmd.com/read/27841878/genome-wide-association-analyses-using-electronic-health-records-identify-new-loci-influencing-blood-pressure-variation
#12
Thomas J Hoffmann, Georg B Ehret, Priyanka Nandakumar, Dilrini Ranatunga, Catherine Schaefer, Pui-Yan Kwok, Carlos Iribarren, Aravinda Chakravarti, Neil Risch
Longitudinal electronic health records on 99,785 Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort individuals provided 1,342,814 systolic and diastolic blood pressure measurements for a genome-wide association study on long-term average systolic, diastolic, and pulse pressure. We identified 39 new loci among 75 genome-wide significant loci (P ≤ 5 × 10(-8)), with most replicating in the combined International Consortium for Blood Pressure (ICBP; n = 69,396) and UK Biobank (UKB; n = 152,081) studies...
November 14, 2016: Nature Genetics
https://www.readbyqxmd.com/read/27841877/integrative-genomic-analysis-implicates-limited-peripheral-adipose-storage-capacity-in-the-pathogenesis-of-human-insulin-resistance
#13
Luca A Lotta, Pawan Gulati, Felix R Day, Felicity Payne, Halit Ongen, Martijn van de Bunt, Kyle J Gaulton, John D Eicher, Stephen J Sharp, Jian'an Luan, Emanuella De Lucia Rolfe, Isobel D Stewart, Eleanor Wheeler, Sara M Willems, Claire Adams, Hanieh Yaghootkar, Nita G Forouhi, Kay-Tee Khaw, Andrew D Johnson, Robert K Semple, Timothy Frayling, John R B Perry, Emmanouil Dermitzakis, Mark I McCarthy, Inês Barroso, Nicholas J Wareham, David B Savage, Claudia Langenberg, Stephen O'Rahilly, Robert A Scott
Insulin resistance is a key mediator of obesity-related cardiometabolic disease, yet the mechanisms underlying this link remain obscure. Using an integrative genomic approach, we identify 53 genomic regions associated with insulin resistance phenotypes (higher fasting insulin levels adjusted for BMI, lower HDL cholesterol levels and higher triglyceride levels) and provide evidence that their link with higher cardiometabolic risk is underpinned by an association with lower adipose mass in peripheral compartments...
November 14, 2016: Nature Genetics
https://www.readbyqxmd.com/read/27819666/a-cis-cold-memory-element-and-a-trans-epigenome-reader-mediate-polycomb-silencing-of-flc-by-vernalization-in-arabidopsis
#14
Wenya Yuan, Xiao Luo, Zicong Li, Wannian Yang, Yizhong Wang, Rui Liu, Jiamu Du, Yuehui He
Some plants acquire competence to flower in spring after experiencing a seasonal temperature drop-winter cold, in a process termed vernalization. In Arabidopsis thaliana, prolonged exposure to cold induces epigenetic silencing of the potent floral repressor locus FLOWERING LOCUS C (FLC) by Polycomb group (PcG) proteins, and this silencing is stably maintained in subsequent growth and development upon return to warm temperatures. Here we show that a cis-regulatory DNA element in the nucleation region for PcG silencing at FLC and two homologous trans-acting epigenome readers, VAL1 and VAL2, control vernalization-mediated FLC silencing...
November 7, 2016: Nature Genetics
https://www.readbyqxmd.com/read/27798628/mycobacterium-tuberculosis-lineage-4-comprises-globally-distributed-and-geographically-restricted-sublineages
#15
David Stucki, Daniela Brites, Leïla Jeljeli, Mireia Coscolla, Qingyun Liu, Andrej Trauner, Lukas Fenner, Liliana Rutaihwa, Sonia Borrell, Tao Luo, Qian Gao, Midori Kato-Maeda, Marie Ballif, Matthias Egger, Rita Macedo, Helmi Mardassi, Milagros Moreno, Griselda Tudo Vilanova, Janet Fyfe, Maria Globan, Jackson Thomas, Frances Jamieson, Jennifer L Guthrie, Adwoa Asante-Poku, Dorothy Yeboah-Manu, Eddie Wampande, Willy Ssengooba, Moses Joloba, W Henry Boom, Indira Basu, James Bower, Margarida Saraiva, Sidra E G Vasconcellos, Philip Suffys, Anastasia Koch, Robert Wilkinson, Linda Gail-Bekker, Bijaya Malla, Serej D Ley, Hans-Peter Beck, Bouke C de Jong, Kadri Toit, Elisabeth Sanchez-Padilla, Maryline Bonnet, Ana Gil-Brusola, Matthias Frank, Veronique N Penlap Beng, Kathleen Eisenach, Issam Alani, Perpetual Wangui Ndung'u, Gunturu Revathi, Florian Gehre, Suriya Akter, Francine Ntoumi, Lynsey Stewart-Isherwood, Nyanda E Ntinginya, Andrea Rachow, Michael Hoelscher, Daniela Maria Cirillo, Girts Skenders, Sven Hoffner, Daiva Bakonyte, Petras Stakenas, Roland Diel, Valeriu Crudu, Olga Moldovan, Sahal Al-Hajoj, Larissa Otero, Francesca Barletta, E Jane Carter, Lameck Diero, Philip Supply, Iñaki Comas, Stefan Niemann, Sebastien Gagneux
Generalist and specialist species differ in the breadth of their ecological niches. Little is known about the niche width of obligate human pathogens. Here we analyzed a global collection of Mycobacterium tuberculosis lineage 4 clinical isolates, the most geographically widespread cause of human tuberculosis. We show that lineage 4 comprises globally distributed and geographically restricted sublineages, suggesting a distinction between generalists and specialists. Population genomic analyses showed that, whereas the majority of human T cell epitopes were conserved in all sublineages, the proportion of variable epitopes was higher in generalists...
October 31, 2016: Nature Genetics
https://www.readbyqxmd.com/read/27798627/genome-wide-analysis-identifies-12-loci-influencing-human-reproductive-behavior
#16
Nicola Barban, Rick Jansen, Ronald de Vlaming, Ahmad Vaez, Jornt J Mandemakers, Felix C Tropf, Xia Shen, James F Wilson, Daniel I Chasman, Ilja M Nolte, Vinicius Tragante, Sander W van der Laan, John R B Perry, Augustine Kong, Tarunveer S Ahluwalia, Eva Albrecht, Laura Yerges-Armstrong, Gil Atzmon, Kirsi Auro, Kristin Ayers, Andrew Bakshi, Danny Ben-Avraham, Klaus Berger, Aviv Bergman, Lars Bertram, Lawrence F Bielak, Gyda Bjornsdottir, Marc Jan Bonder, Linda Broer, Minh Bui, Caterina Barbieri, Alana Cavadino, Jorge E Chavarro, Constance Turman, Maria Pina Concas, Heather J Cordell, Gail Davies, Peter Eibich, Nicholas Eriksson, Tõnu Esko, Joel Eriksson, Fahimeh Falahi, Janine F Felix, Mark Alan Fontana, Lude Franke, Ilaria Gandin, Audrey J Gaskins, Christian Gieger, Erica P Gunderson, Xiuqing Guo, Caroline Hayward, Chunyan He, Edith Hofer, Hongyan Huang, Peter K Joshi, Stavroula Kanoni, Robert Karlsson, Stefan Kiechl, Annette Kifley, Alexander Kluttig, Peter Kraft, Vasiliki Lagou, Cecile Lecoeur, Jari Lahti, Ruifang Li-Gao, Penelope A Lind, Tian Liu, Enes Makalic, Crysovalanto Mamasoula, Lindsay Matteson, Hamdi Mbarek, Patrick F McArdle, George McMahon, S Fleur W Meddens, Evelin Mihailov, Mike Miller, Stacey A Missmer, Claire Monnereau, Peter J van der Most, Ronny Myhre, Mike A Nalls, Teresa Nutile, Ioanna Panagiota Kalafati, Eleonora Porcu, Inga Prokopenko, Kumar B Rajan, Janet Rich-Edwards, Cornelius A Rietveld, Antonietta Robino, Lynda M Rose, Rico Rueedi, Kathleen A Ryan, Yasaman Saba, Daniel Schmidt, Jennifer A Smith, Lisette Stolk, Elizabeth Streeten, Anke Tönjes, Gudmar Thorleifsson, Sheila Ulivi, Juho Wedenoja, Juergen Wellmann, Peter Willeit, Jie Yao, Loic Yengo, Jing Hua Zhao, Wei Zhao, Daria V Zhernakova, Najaf Amin, Howard Andrews, Beverley Balkau, Nir Barzilai, Sven Bergmann, Ginevra Biino, Hans Bisgaard, Klaus Bønnelykke, Dorret I Boomsma, Julie E Buring, Harry Campbell, Stefania Cappellani, Marina Ciullo, Simon R Cox, Francesco Cucca, Daniela Toniolo, George Davey-Smith, Ian J Deary, George Dedoussis, Panos Deloukas, Cornelia M van Duijn, Eco J C de Geus, Johan G Eriksson, Denis A Evans, Jessica D Faul, Cinzia Felicita Sala, Philippe Froguel, Paolo Gasparini, Giorgia Girotto, Hans-Jörgen Grabe, Karin Halina Greiser, Patrick J F Groenen, Hugoline G de Haan, Johannes Haerting, Tamara B Harris, Andrew C Heath, Kauko Heikkilä, Albert Hofman, Georg Homuth, Elizabeth G Holliday, John Hopper, Elina Hyppönen, Bo Jacobsson, Vincent W V Jaddoe, Magnus Johannesson, Astanand Jugessur, Mika Kähönen, Eero Kajantie, Sharon L R Kardia, Bernard Keavney, Ivana Kolcic, Päivikki Koponen, Peter Kovacs, Florian Kronenberg, Zoltan Kutalik, Martina La Bianca, Genevieve Lachance, William G Iacono, Sandra Lai, Terho Lehtimäki, David C Liewald, Cecilia M Lindgren, Yongmei Liu, Robert Luben, Michael Lucht, Riitta Luoto, Per Magnus, Patrik K E Magnusson, Nicholas G Martin, Matt McGue, Ruth McQuillan, Sarah E Medland, Christa Meisinger, Dan Mellström, Andres Metspalu, Michela Traglia, Lili Milani, Paul Mitchell, Grant W Montgomery, Dennis Mook-Kanamori, Renée de Mutsert, Ellen A Nohr, Claes Ohlsson, Jørn Olsen, Ken K Ong, Lavinia Paternoster, Alison Pattie, Brenda W J H Penninx, Markus Perola, Patricia A Peyser, Mario Pirastu, Ozren Polasek, Chris Power, Jaakko Kaprio, Leslie J Raffel, Katri Räikkönen, Olli Raitakari, Paul M Ridker, Susan M Ring, Kathryn Roll, Igor Rudan, Daniela Ruggiero, Dan Rujescu, Veikko Salomaa, David Schlessinger, Helena Schmidt, Reinhold Schmidt, Nicole Schupf, Johannes Smit, Rossella Sorice, Tim D Spector, John M Starr, Doris Stöckl, Konstantin Strauch, Michael Stumvoll, Morris A Swertz, Unnur Thorsteinsdottir, A Roy Thurik, Nicholas J Timpson, Joyce Y Tung, André G Uitterlinden, Simona Vaccargiu, Jorma Viikari, Veronique Vitart, Henry Völzke, Peter Vollenweider, Dragana Vuckovic, Johannes Waage, Gert G Wagner, Jie Jin Wang, Nicholas J Wareham, David R Weir, Gonneke Willemsen, Johann Willeit, Alan F Wright, Krina T Zondervan, Kari Stefansson, Robert F Krueger, James J Lee, Daniel J Benjamin, David Cesarini, Philipp D Koellinger, Marcel den Hoed, Harold Snieder, Melinda C Mills
The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort...
October 31, 2016: Nature Genetics
https://www.readbyqxmd.com/read/27798625/the-genomic-landscape-of-core-binding-factor-acute-myeloid-leukemias
#17
Zachary J Faber, Xiang Chen, Amanda Larson Gedman, Kristy Boggs, Jinjun Cheng, Jing Ma, Ina Radtke, Jyh-Rong Chao, Michael P Walsh, Guangchun Song, Anna K Andersson, Jinjun Dang, Li Dong, Yu Liu, Robert Huether, Zhongling Cai, Heather Mulder, Gang Wu, Michael Edmonson, Michael Rusch, Chunxu Qu, Yongjin Li, Bhavin Vadodaria, Jianmin Wang, Erin Hedlund, Xueyuan Cao, Donald Yergeau, Joy Nakitandwe, Stanley B Pounds, Sheila Shurtleff, Robert S Fulton, Lucinda L Fulton, John Easton, Evan Parganas, Ching-Hon Pui, Jeffrey E Rubnitz, Li Ding, Elaine R Mardis, Richard K Wilson, Tanja A Gruber, Charles G Mullighan, Richard F Schlenk, Peter Paschka, Konstanze Döhner, Hartmut Döhner, Lars Bullinger, Jinghui Zhang, Jeffery M Klco, James R Downing
Acute myeloid leukemia (AML) comprises a heterogeneous group of leukemias frequently defined by recurrent cytogenetic abnormalities, including rearrangements involving the core-binding factor (CBF) transcriptional complex. To better understand the genomic landscape of CBF-AMLs, we analyzed both pediatric (n = 87) and adult (n = 78) samples, including cases with RUNX1-RUNX1T1 (n = 85) or CBFB-MYH11 (n = 80) rearrangements, by whole-genome or whole-exome sequencing. In addition to known mutations in the Ras pathway, we identified recurrent stabilizing mutations in CCND2, suggesting a previously unappreciated cooperating pathway in CBF-AML...
October 31, 2016: Nature Genetics
https://www.readbyqxmd.com/read/27798624/identification-of-genomic-loci-associated-with-resting-heart-rate-and-shared-genetic-predictors-with-all-cause-mortality
#18
Ruben N Eppinga, Yanick Hagemeijer, Stephen Burgess, David A Hinds, Kari Stefansson, Daniel F Gudbjartsson, Dirk J van Veldhuisen, Patricia B Munroe, Niek Verweij, Pim van der Harst
Resting heart rate is a heritable trait correlated with life span. Little is known about the genetic contribution to resting heart rate and its relationship with mortality. We performed a genome-wide association discovery and replication analysis starting with 19.9 million genetic variants and studying up to 265,046 individuals to identify 64 loci associated with resting heart rate (P < 5 × 10(-8)); 46 of these were novel. We then used the genetic variants identified to study the association between resting heart rate and all-cause mortality...
October 31, 2016: Nature Genetics
https://www.readbyqxmd.com/read/27776119/fetus-derived-dlk1-is-required-for-maternal-metabolic-adaptations-to-pregnancy-and-is-associated-with-fetal-growth-restriction
#19
Mary A M Cleaton, Claire L Dent, Mark Howard, Jennifer A Corish, Isabelle Gutteridge, Ulla Sovio, Francesca Gaccioli, Nozomi Takahashi, Steven R Bauer, D Steven Charnock-Jones, Theresa L Powell, Gordon C S Smith, Anne C Ferguson-Smith, Marika Charalambous
Pregnancy is a state of high metabolic demand. Fasting diverts metabolism to fatty acid oxidation, and the fasted response occurs much more rapidly in pregnant women than in non-pregnant women. The product of the imprinted DLK1 gene (delta-like homolog 1) is an endocrine signaling molecule that reaches a high concentration in the maternal circulation during late pregnancy. By using mouse models with deleted Dlk1, we show that the fetus is the source of maternal circulating DLK1. In the absence of fetally derived DLK1, the maternal fasting response is impaired...
December 2016: Nature Genetics
https://www.readbyqxmd.com/read/27776117/m-cap-eliminates-a-majority-of-variants-of-uncertain-significance-in-clinical-exomes-at-high-sensitivity
#20
Karthik A Jagadeesh, Aaron M Wenger, Mark J Berger, Harendra Guturu, Peter D Stenson, David N Cooper, Jonathan A Bernstein, Gill Bejerano
Variant pathogenicity classifiers such as SIFT, PolyPhen-2, CADD, and MetaLR assist in interpretation of the hundreds of rare, missense variants in the typical patient genome by deprioritizing some variants as likely benign. These widely used methods misclassify 26 to 38% of known pathogenic mutations, which could lead to missed diagnoses if the classifiers are trusted as definitive in a clinical setting. We developed M-CAP, a clinical pathogenicity classifier that outperforms existing methods at all thresholds and correctly dismisses 60% of rare, missense variants of uncertain significance in a typical genome at 95% sensitivity...
December 2016: Nature Genetics
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