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Nature Genetics

Corina Lesseur, Brenda Diergaarde, Andrew F Olshan, Victor Wünsch-Filho, Andrew R Ness, Geoffrey Liu, Martin Lacko, José Eluf-Neto, Silvia Franceschi, Pagona Lagiou, Gary J Macfarlane, Lorenzo Richiardi, Stefania Boccia, Jerry Polesel, Kristina Kjaerheim, David Zaridze, Mattias Johansson, Ana M Menezes, Maria Paula Curado, Max Robinson, Wolfgang Ahrens, Cristina Canova, Ariana Znaor, Xavier Castellsagué, David I Conway, Ivana Holcátová, Dana Mates, Marta Vilensky, Claire M Healy, Neonila Szeszenia-Dąbrowska, Eleonóra Fabiánová, Jolanta Lissowska, Jennifer R Grandis, Mark C Weissler, Eloiza H Tajara, Fabio D Nunes, Marcos B de Carvalho, Steve Thomas, Rayjean J Hung, Wilbert H M Peters, Rolando Herrero, Gabriella Cadoni, H Bas Bueno-de-Mesquita, Annika Steffen, Antonio Agudo, Oxana Shangina, Xiangjun Xiao, Valérie Gaborieau, Amélie Chabrier, Devasena Anantharaman, Paolo Boffetta, Christopher I Amos, James D McKay, Paul Brennan
We conducted a genome-wide association study of oral cavity and pharyngeal cancer in 6,034 cases and 6,585 controls from Europe, North America and South America. We detected eight significantly associated loci (P < 5 × 10(-8)), seven of which are new for these cancer sites. Oral and pharyngeal cancers combined were associated with loci at 6p21.32 (rs3828805, HLA-DQB1), 10q26.13 (rs201982221, LHPP) and 11p15.4 (rs1453414, OR52N2-TRIM5). Oral cancer was associated with two new regions, 2p23.3 (rs6547741, GPN1) and 9q34...
October 17, 2016: Nature Genetics
Amit R Majithia, Ben Tsuda, Maura Agostini, Keerthana Gnanapradeepan, Robert Rice, Gina Peloso, Kashyap A Patel, Xiaolan Zhang, Marjoleine F Broekema, Nick Patterson, Marc Duby, Ted Sharpe, Eric Kalkhoven, Evan D Rosen, Inês Barroso, Sian Ellard, Sekar Kathiresan, Stephen O'Rahilly, Krishna Chatterjee, Jose C Florez, Tarjei Mikkelsen, David B Savage, David Altshuler
Clinical exome sequencing routinely identifies missense variants in disease-related genes, but functional characterization is rarely undertaken, leading to diagnostic uncertainty. For example, mutations in PPARG cause Mendelian lipodystrophy and increase risk of type 2 diabetes (T2D). Although approximately 1 in 500 people harbor missense variants in PPARG, most are of unknown consequence. To prospectively characterize PPARγ variants, we used highly parallel oligonucleotide synthesis to construct a library encoding all 9,595 possible single-amino acid substitutions...
October 17, 2016: Nature Genetics
Jonathan J Lyons, Xiaomin Yu, Jason D Hughes, Quang T Le, Ali Jamil, Yun Bai, Nancy Ho, Ming Zhao, Yihui Liu, Michael P O'Connell, Neil N Trivedi, Celeste Nelson, Thomas DiMaggio, Nina Jones, Helen Matthews, Katie L Lewis, Andrew J Oler, Ryan J Carlson, Peter D Arkwright, Celine Hong, Sherene Agama, Todd M Wilson, Sofie Tucker, Yu Zhang, Joshua J McElwee, Maryland Pao, Sarah C Glover, Marc E Rothenberg, Robert J Hohman, Kelly D Stone, George H Caughey, Theo Heller, Dean D Metcalfe, Leslie G Biesecker, Lawrence B Schwartz, Joshua D Milner
Elevated basal serum tryptase levels are present in 4-6% of the general population, but the cause and relevance of such increases are unknown. Previously, we described subjects with dominantly inherited elevated basal serum tryptase levels associated with multisystem complaints including cutaneous flushing and pruritus, dysautonomia, functional gastrointestinal symptoms, chronic pain, and connective tissue abnormalities, including joint hypermobility. Here we report the identification of germline duplications and triplications in the TPSAB1 gene encoding α-tryptase that segregate with inherited increases in basal serum tryptase levels in 35 families presenting with associated multisystem complaints...
October 17, 2016: Nature Genetics
Bishoy M Faltas, Davide Prandi, Scott T Tagawa, Ana M Molina, David M Nanus, Cora Sternberg, Jonathan Rosenberg, Juan Miguel Mosquera, Brian Robinson, Olivier Elemento, Andrea Sboner, Himisha Beltran, Francesca Demichelis, Mark A Rubin
Chemotherapy-resistant urothelial carcinoma has no uniformly curative therapy. Understanding how selective pressure from chemotherapy directs the evolution of urothelial carcinoma and shapes its clonal architecture is a central biological question with clinical implications. To address this question, we performed whole-exome sequencing and clonality analysis of 72 urothelial carcinoma samples, including 16 matched sets of primary and advanced tumors prospectively collected before and after chemotherapy. Our analysis provided several insights: (i) chemotherapy-treated urothelial carcinoma is characterized by intra-patient mutational heterogeneity, and the majority of mutations are not shared; (ii) both branching evolution and metastatic spread are very early events in the natural history of urothelial carcinoma; (iii) chemotherapy-treated urothelial carcinoma is enriched with clonal mutations involving L1 cell adhesion molecule (L1CAM) and integrin signaling pathways; and (iv) APOBEC-induced mutagenesis is clonally enriched in chemotherapy-treated urothelial carcinoma and continues to shape the evolution of urothelial carcinoma throughout its lifetime...
October 17, 2016: Nature Genetics
Jia-Jie Hao, De-Chen Lin, Huy Q Dinh, Anand Mayakonda, Yan-Yi Jiang, Chen Chang, Ye Jiang, Chen-Chen Lu, Zhi-Zhou Shi, Xin Xu, Yu Zhang, Yan Cai, Jin-Wu Wang, Qi-Min Zhan, Wen-Qiang Wei, Benjamin P Berman, Ming-Rong Wang, H Phillip Koeffler
Esophageal squamous cell carcinoma (ESCC) is among the most common malignancies, but little is known about its spatial intratumoral heterogeneity (ITH) and temporal clonal evolutionary processes. To address this, we performed multiregion whole-exome sequencing on 51 tumor regions from 13 ESCC cases and multiregion global methylation profiling for 3 of these 13 cases. We found an average of 35.8% heterogeneous somatic mutations with strong evidence of ITH. Half of the driver mutations located on the branches of tumor phylogenetic trees targeted oncogenes, including PIK3CA, NFE2L2 and MTOR, among others...
October 17, 2016: Nature Genetics
Sameer Agnihotri, Shahrzad Jalali, Mark R Wilson, Arnavaz Danesh, Mira Li, George Klironomos, Jonathan R Krieger, Alireza Mansouri, Osaama Khan, Yasin Mamatjan, Natalie Landon-Brace, Takyee Tung, Mark Dowar, Tiantian Li, Jeffrey P Bruce, Kelly E Burrell, Peter D Tonge, Amir Alamsahebpour, Boris Krischek, Pankaj Kumar Agarwalla, Wenya Linda Bi, Ian F Dunn, Rameen Beroukhim, Michael G Fehlings, Vera Bril, Stefano M Pagnotta, Antonio Iavarone, Trevor J Pugh, Kenneth D Aldape, Gelareh Zadeh
Schwannomas are common peripheral nerve sheath tumors that can cause debilitating morbidities. We performed an integrative analysis to determine genomic aberrations common to sporadic schwannomas. Exome sequence analysis with validation by targeted DNA sequencing of 125 samples uncovered, in addition to expected NF2 disruption, recurrent mutations in ARID1A, ARID1B and DDR1. RNA sequencing identified a recurrent in-frame SH3PXD2A-HTRA1 fusion in 12/125 (10%) cases, and genomic analysis demonstrated the mechanism as resulting from a balanced 19-Mb chromosomal inversion on chromosome 10q...
October 10, 2016: Nature Genetics
Kwoneel Kim, Kiwon Jang, Woojin Yang, Eun-Young Choi, Seong-Min Park, Mingyun Bae, Youn-Jae Kim, Jung Kyoon Choi
Recurrence is a hallmark of cancer-driving mutations. Recurrent mutations can arise at the same site or affect the same gene at different sites. Here we identified a set of mutations arising in individual samples and altering different cis-regulatory elements that converge on a common gene via chromatin interactions. The mutations and genes identified in this fashion showed strong relevance to cancer, in contrast to noncoding mutations with site-specific recurrence only. We developed a prediction method that identifies potentially recurrent mutations on the basis of the features shared by mutations whose recurrence is observed in a given cohort...
October 10, 2016: Nature Genetics
Paola G Bronson, Diana Chang, Tushar Bhangale, Michael F Seldin, Ward Ortmann, Ricardo C Ferreira, Elena Urcelay, Luis Fernández Pereira, Javier Martin, Alessandro Plebani, Vassilios Lougaris, Vanda Friman, Tomáš Freiberger, Jiri Litzman, Vojtech Thon, Qiang Pan-Hammarström, Lennart Hammarström, Robert R Graham, Timothy W Behrens
Selective immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency in Europeans. Our genome-wide association study (GWAS) meta-analysis of 1,635 patients with IgAD and 4,852 controls identified four new significant (P < 5 × 10(-8)) loci and association with a rare IFIH1 variant (p.Ile923Val). Peak new variants (PVT1, P = 4.3 × 10(-11); ATG13-AMBRA1, P = 6.7 × 10(-10); AHI1, P = 8.4 × 10(-10); CLEC16A, P = 1.4 × 10(-9)) overlapped with autoimmune markers (3/4) and correlated with 21 putative regulatory variants, including expression quantitative trait loci (eQTLs) for AHI1 and DEXI and DNase hypersensitivity sites in FOXP3(+) regulatory T cells...
October 10, 2016: Nature Genetics
Ying Jin, Genevieve Andersen, Daniel Yorgov, Tracey M Ferrara, Songtao Ben, Kelly M Brownson, Paulene J Holland, Stanca A Birlea, Janet Siebert, Anke Hartmann, Anne Lienert, Nanja van Geel, Jo Lambert, Rosalie M Luiten, Albert Wolkerstorfer, J P Wietze van der Veen, Dorothy C Bennett, Alain Taïeb, Khaled Ezzedine, E Helen Kemp, David J Gawkrodger, Anthony P Weetman, Sulev Kõks, Ele Prans, Külli Kingo, Maire Karelson, Margaret R Wallace, Wayne T McCormack, Andreas Overbeck, Silvia Moretti, Roberta Colucci, Mauro Picardo, Nanette B Silverberg, Mats Olsson, Yan Valle, Igor Korobko, Markus Böhm, Henry W Lim, Iltefat Hamzavi, Li Zhou, Qing-Sheng Mi, Pamela R Fain, Stephanie A Santorico, Richard A Spritz
Vitiligo is an autoimmune disease in which depigmented skin results from the destruction of melanocytes, with epidemiological association with other autoimmune diseases. In previous linkage and genome-wide association studies (GWAS1 and GWAS2), we identified 27 vitiligo susceptibility loci in patients of European ancestry. We carried out a third GWAS (GWAS3) in European-ancestry subjects, with augmented GWAS1 and GWAS2 controls, genome-wide imputation, and meta-analysis of all three GWAS, followed by an independent replication...
October 10, 2016: Nature Genetics
Jun Wang, Louise B Thingholm, Jurgita Skiecevičienė, Philipp Rausch, Martin Kummen, Johannes R Hov, Frauke Degenhardt, Femke-Anouska Heinsen, Malte C Rühlemann, Silke Szymczak, Kristian Holm, Tönu Esko, Jun Sun, Mihaela Pricop-Jeckstadt, Samer Al-Dury, Pavol Bohov, Jörn Bethune, Felix Sommer, David Ellinghaus, Rolf K Berge, Matthias Hübenthal, Manja Koch, Karin Schwarz, Gerald Rimbach, Patricia Hübbe, Wei-Hung Pan, Raheleh Sheibani-Tezerji, Robert Häsler, Philipp Rosenstiel, Mauro D'Amato, Katja Cloppenborg-Schmidt, Sven Künzel, Matthias Laudes, Hanns-Ulrich Marschall, Wolfgang Lieb, Ute Nöthlings, Tom H Karlsen, John F Baines, Andre Franke
Human gut microbiota is an important determinant for health and disease, and recent studies emphasize the numerous factors shaping its diversity. Here we performed a genome-wide association study (GWAS) of the gut microbiota using two cohorts from northern Germany totaling 1,812 individuals. Comprehensively controlling for diet and non-genetic parameters, we identify genome-wide significant associations for overall microbial variation and individual taxa at multiple genetic loci, including the VDR gene (encoding vitamin D receptor)...
October 10, 2016: Nature Genetics
Loïc Broix, Hélène Jagline, Ekaterina L Ivanova, Stéphane Schmucker, Nathalie Drouot, Jill Clayton-Smith, Alistair T Pagnamenta, Kay A Metcalfe, Bertrand Isidor, Ulrike Walther Louvier, Annapurna Poduri, Jenny C Taylor, Peggy Tilly, Karine Poirier, Yoann Saillour, Nicolas Lebrun, Tristan Stemmelen, Gabrielle Rudolf, Giuseppe Muraca, Benjamin Saintpierre, Adrienne Elmorjani, Martin Moïse, Nathalie Bednarek Weirauch, Renzo Guerrini, Anne Boland, Robert Olaso, Cecile Masson, Ratna Tripathy, David Keays, Cherif Beldjord, Laurent Nguyen, Juliette Godin, Usha Kini, Patrick Nischké, Jean-François Deleuze, Nadia Bahi-Buisson, Izabela Sumara, Maria-Victoria Hinckelmann, Jamel Chelly
Neurodevelopmental disorders with periventricular nodular heterotopia (PNH) are etiologically heterogeneous, and their genetic causes remain in many cases unknown. Here we show that missense mutations in NEDD4L mapping to the HECT domain of the encoded E3 ubiquitin ligase lead to PNH associated with toe syndactyly, cleft palate and neurodevelopmental delay. Cellular and expression data showed sensitivity of PNH-associated mutants to proteasome degradation. Moreover, an in utero electroporation approach showed that PNH-related mutants and excess wild-type NEDD4L affect neurogenesis, neuronal positioning and terminal translocation...
October 3, 2016: Nature Genetics
Williams Turpin, Osvaldo Espin-Garcia, Wei Xu, Mark S Silverberg, David Kevans, Michelle I Smith, David S Guttman, Anne Griffiths, Remo Panaccione, Anthony Otley, Lizhen Xu, Konstantin Shestopaloff, Gabriel Moreno-Hagelsieb, Andrew D Paterson, Kenneth Croitoru
Intestinal microbiota is known to be important in health and disease. Its composition is influenced by both environmental and host factors. Few large-scale studies have evaluated the association between host genetic variation and the composition of microbiota. We recruited a cohort of 1,561 healthy individuals, of whom 270 belong in 123 families, and found that almost one-third of fecal bacterial taxa were heritable. In addition, we identified 58 SNPs associated with the relative abundance of 33 taxa in 1,098 discovery subjects...
October 3, 2016: Nature Genetics
Marc Jan Bonder, Alexander Kurilshikov, Ettje F Tigchelaar, Zlatan Mujagic, Floris Imhann, Arnau Vich Vila, Patrick Deelen, Tommi Vatanen, Melanie Schirmer, Sanne P Smeekens, Daria V Zhernakova, Soesma A Jankipersadsing, Martin Jaeger, Marije Oosting, Maria Carmen Cenit, Ad A M Masclee, Morris A Swertz, Yang Li, Vinod Kumar, Leo Joosten, Hermie Harmsen, Rinse K Weersma, Lude Franke, Marten H Hofker, Ramnik J Xavier, Daisy Jonkers, Mihai G Netea, Cisca Wijmenga, Jingyuan Fu, Alexandra Zhernakova
The gut microbiome is affected by multiple factors, including genetics. In this study, we assessed the influence of host genetics on microbial species, pathways and gene ontology categories, on the basis of metagenomic sequencing in 1,514 subjects. In a genome-wide analysis, we identified associations of 9 loci with microbial taxonomies and 33 loci with microbial pathways and gene ontology terms at P < 5 × 10(-8). Additionally, in a targeted analysis of regions involved in complex diseases, innate and adaptive immunity, or food preferences, 32 loci were identified at the suggestive level of P < 5 × 10(-6)...
October 3, 2016: Nature Genetics
Po-Ru Loh, Petr Danecek, Pier Francesco Palamara, Christian Fuchsberger, Yakir A Reshef, Hilary K Finucane, Sebastian Schoenherr, Lukas Forer, Shane McCarthy, Goncalo R Abecasis, Richard Durbin, Alkes L Price
Haplotype phasing is a fundamental problem in medical and population genetics. Phasing is generally performed via statistical phasing in a genotyped cohort, an approach that can yield high accuracy in very large cohorts but attains lower accuracy in smaller cohorts. Here we instead explore the paradigm of reference-based phasing. We introduce a new phasing algorithm, Eagle2, that attains high accuracy across a broad range of cohort sizes by efficiently leveraging information from large external reference panels (such as the Haplotype Reference Consortium; HRC) using a new data structure based on the positional Burrows-Wheeler transform...
October 3, 2016: Nature Genetics
Adam M Schmitt, Julia T Garcia, Tiffany Hung, Ryan A Flynn, Ying Shen, Kun Qu, Alexander Y Payumo, Ashwin Peres-da-Silva, Daniela Kenzelmann Broz, Rachel Baum, Shuling Guo, James K Chen, Laura D Attardi, Howard Y Chang
Long noncoding RNAs (lncRNAs) are prevalent genes with frequently precise regulation but mostly unknown functions. Here we demonstrate that lncRNAs guide the organismal DNA damage response. DNA damage activated transcription of the DINO (Damage Induced Noncoding) lncRNA via p53. DINO was required for p53-dependent gene expression, cell cycle arrest and apoptosis in response to DNA damage, and DINO expression was sufficient to activate damage signaling and cell cycle arrest in the absence of DNA damage. DINO bound to p53 protein and promoted its stabilization, mediating a p53 auto-amplification loop...
September 26, 2016: Nature Genetics
Peter Zeller, Jan Padeken, Robin van Schendel, Veronique Kalck, Marcel Tijsterman, Susan M Gasser
Histone H3 lysine 9 (H3K9) methylation is a conserved modification that generally represses transcription. In Caenorhabditis elegans it is enriched on silent tissue-specific genes and repetitive elements. In met-2 set-25 double mutants, which lack all H3K9 methylation (H3K9me), embryos differentiate normally, although mutant adults are sterile owing to extensive DNA-damage-driven apoptosis in the germ line. Transposons and simple repeats are derepressed in both germline and somatic tissues. This unprogrammed transcription correlates with increased rates of repeat-specific insertions and deletions, copy number variation, R loops and enhanced sensitivity to replication stress...
September 26, 2016: Nature Genetics
Valentina Iotchkova, Jie Huang, John A Morris, Deepti Jain, Caterina Barbieri, Klaudia Walter, Josine L Min, Lu Chen, William Astle, Massimilian Cocca, Patrick Deelen, Heather Elding, Aliki-Eleni Farmaki, Christopher S Franklin, Mattias Franberg, Tom R Gaunt, Albert Hofman, Tao Jiang, Marcus E Kleber, Genevieve Lachance, Jian'an Luan, Giovanni Malerba, Angela Matchan, Daniel Mead, Yasin Memari, Ioanna Ntalla, Kalliope Panoutsopoulou, Raha Pazoki, John R B Perry, Fernando Rivadeneira, Maria Sabater-Lleal, Bengt Sennblad, So-Youn Shin, Lorraine Southam, Michela Traglia, Freerk van Dijk, Elisabeth M van Leeuwen, Gianluigi Zaza, Weihua Zhang, Najaf Amin, Adam Butterworth, John C Chambers, George Dedoussis, Abbas Dehghan, Oscar H Franco, Lude Franke, Mattia Frontini, Giovanni Gambaro, Paolo Gasparini, Anders Hamsten, Aaron Issacs, Jaspal S Kooner, Charles Kooperberg, Claudia Langenberg, Winfried Marz, Robert A Scott, Morris A Swertz, Daniela Toniolo, Andre G Uitterlinden, Cornelia M van Duijn, Hugh Watkins, Eleftheria Zeggini, Mathew T Maurano, Nicholas J Timpson, Alexander P Reiner, Paul L Auer, Nicole Soranzo
Large-scale whole-genome sequence data sets offer novel opportunities to identify genetic variation underlying human traits. Here we apply genotype imputation based on whole-genome sequence data from the UK10K and 1000 Genomes Project into 35,981 study participants of European ancestry, followed by association analysis with 20 quantitative cardiometabolic and hematological traits. We describe 17 new associations, including 6 rare (minor allele frequency (MAF) < 1%) or low-frequency (1% < MAF < 5%) variants with platelet count (PLT), red blood cell indices (MCH and MCV) and HDL cholesterol...
September 26, 2016: Nature Genetics
Björn Reinius, Jeff E Mold, Daniel Ramsköld, Qiaolin Deng, Per Johnsson, Jakob Michaëlsson, Jonas Frisén, Rickard Sandberg
Cellular heterogeneity can emerge from the expression of only one parental allele. However, it has remained controversial whether, or to what degree, random monoallelic expression of autosomal genes (aRME) is mitotically inherited (clonal) or stochastic (dynamic) in somatic cells, particularly in vivo. Here we used allele-sensitive single-cell RNA-seq on clonal primary mouse fibroblasts and freshly isolated human CD8(+) T cells to dissect clonal and dynamic monoallelic expression patterns. Dynamic aRME affected a considerable portion of the cells' transcriptomes, with levels dependent on the cells' transcriptional activity...
September 26, 2016: Nature Genetics
Xavier Caubit, Paolo Gubellini, Joris Andrieux, Pierre L Roubertoux, Mehdi Metwaly, Bernard Jacq, Ahmed Fatmi, Laurence Had-Aissouni, Kenneth Y Kwan, Pascal Salin, Michèle Carlier, Agne Liedén, Eva Rudd, Marwan Shinawi, Catherine Vincent-Delorme, Jean-Marie Cuisset, Marie-Pierre Lemaitre, Fatimetou Abderrehamane, Bénédicte Duban, Jean-François Lemaitre, Adrian S Woolf, Detlef Bockenhauer, Dany Severac, Emeric Dubois, Ying Zhu, Nenad Sestan, Alistair N Garratt, Lydia Kerkerian- Le Goff, Laurent Fasano
TSHZ3, which encodes a zinc-finger transcription factor, was recently positioned as a hub gene in a module of the genes with the highest expression in the developing human neocortex, but its functions remained unknown. Here we identify TSHZ3 as the critical region for a syndrome associated with heterozygous deletions at 19q12-q13.11, which includes autism spectrum disorder (ASD). In Tshz3-null mice, differentially expressed genes include layer-specific markers of cerebral cortical projection neurons (CPNs), and the human orthologs of these genes are strongly associated with ASD...
September 26, 2016: Nature Genetics
Nadeem Riaz, Jonathan J Havel, Sviatoslav M Kendall, Vladimir Makarov, Logan A Walsh, Alexis Desrichard, Nils Weinhold, Timothy A Chan
Immune checkpoint blockade has shown significant promise as an anticancer treatment, yet the determinants of response are not completely understood. Here we show that somatic mutations in SERPINB3 and SERPINB4 are associated with survival after anti-CTLA4 immunotherapy in two independent cohorts of patients with melanoma (n = 174). Interestingly, serpins are homologs of the well-known ovalbumin antigen and are associated with autoimmunity. Our findings have implications for the personalization of immunotherapy...
September 26, 2016: Nature Genetics
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