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Nature Genetics

Johannes Waage, Marie Standl, John A Curtin, Leon E Jessen, Jonathan Thorsen, Chao Tian, Nathan Schoettler, Carlos Flores, Abdel Abdellaoui, Tarunveer S Ahluwalia, Alexessander C Alves, Andre F S Amaral, Josep M Antó, Andreas Arnold, Amalia Barreto-Luis, Hansjörg Baurecht, Catharina E M van Beijsterveldt, Eugene R Bleecker, Sílvia Bonàs-Guarch, Dorret I Boomsma, Susanne Brix, Supinda Bunyavanich, Esteban G Burchard, Zhanghua Chen, Ivan Curjuric, Adnan Custovic, Herman T den Dekker, Shyamali C Dharmage, Julia Dmitrieva, Liesbeth Duijts, Markus J Ege, W James Gauderman, Michel Georges, Christian Gieger, Frank Gilliland, Raquel Granell, Hongsheng Gui, Torben Hansen, Joachim Heinrich, John Henderson, Natalia Hernandez-Pacheco, Patrick Holt, Medea Imboden, Vincent W V Jaddoe, Marjo-Riitta Jarvelin, Deborah L Jarvis, Kamilla K Jensen, Ingileif Jónsdóttir, Michael Kabesch, Jaakko Kaprio, Ashish Kumar, Young-Ae Lee, Albert M Levin, Xingnan Li, Fabian Lorenzo-Diaz, Erik Melén, Josep M Mercader, Deborah A Meyers, Rachel Myers, Dan L Nicolae, Ellen A Nohr, Teemu Palviainen, Lavinia Paternoster, Craig E Pennell, Göran Pershagen, Maria Pino-Yanes, Nicole M Probst-Hensch, Franz Rüschendorf, Angela Simpson, Kari Stefansson, Jordi Sunyer, Gardar Sveinbjornsson, Elisabeth Thiering, Philip J Thompson, Maties Torrent, David Torrents, Joyce Y Tung, Carol A Wang, Stephan Weidinger, Scott Weiss, Gonneke Willemsen, L Keoki Williams, Carole Ober, David A Hinds, Manuel A Ferreira, Hans Bisgaard, David P Strachan, Klaus Bønnelykke
Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries1,2 . To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls...
July 16, 2018: Nature Genetics
Gang Li, Marta Martínez-Bonet, Di Wu, Yu Yang, Jing Cui, Hung N Nguyen, Pierre Cunin, Anaïs Levescot, Ming Bai, Harm-Jan Westra, Yukinori Okada, Michael B Brenner, Soumya Raychaudhuri, Eric A Hendrickson, Richard L Maas, Peter A Nigrovic
Genome-wide association studies (GWAS) have identified many disease-associated noncoding variants, but cannot distinguish functional single-nucleotide polymorphisms (fSNPs) from others that reside incidentally within risk loci. To address this challenge, we developed an unbiased high-throughput screen that employs type IIS enzymatic restriction to identify fSNPs that allelically modulate the binding of regulatory proteins. We coupled this approach, termed SNP-seq, with flanking restriction enhanced pulldown (FREP) to identify regulation of CD40 by three disease-associated fSNPs via four regulatory proteins, RBPJ, RSRC2 and FUBP-1/TRAP150...
July 16, 2018: Nature Genetics
Parker L Sulkowski, Ranjini K Sundaram, Sebastian Oeck, Christopher D Corso, Yanfeng Liu, Seth Noorbakhsh, Monica Niger, Marta Boeke, Daiki Ueno, Aravind Nambiar Kalathil, Xun Bao, Jing Li, Brian Shuch, Ranjit S Bindra, Peter M Glazer
The hereditary cancer syndromes hereditary leiomyomatosis and renal cell cancer (HLRCC) and succinate dehydrogenase-related hereditary paraganglioma and pheochromocytoma (SDH PGL/PCC) are linked to germline loss-of-function mutations in genes encoding the Krebs cycle enzymes fumarate hydratase and succinate dehydrogenase, thus leading to elevated levels of fumarate and succinate, respectively1-3 . Here, we report that fumarate and succinate both suppress the homologous recombination (HR) DNA-repair pathway required for the resolution of DNA double-strand breaks (DSBs) and for the maintenance of genomic integrity, thus rendering tumor cells vulnerable to synthetic-lethal targeting with poly(ADP)-ribose polymerase (PARP) inhibitors...
July 16, 2018: Nature Genetics
Ashleigh E Schaffer, Martin W Breuss, Ahmet Okay Caglayan, Nouriya Al-Sanaa, Hind Y Al-Abdulwahed, Hande Kaymakçalan, Cahide Yılmaz, Maha S Zaki, Rasim O Rosti, Brett Copeland, Seung Tae Baek, Damir Musaev, Eric C Scott, Tawfeg Ben-Omran, Ariana Kariminejad, Hulya Kayserili, Faezeh Mojahedi, Majdi Kara, Na Cai, Jennifer L Silhavy, Seham Elsharif, Elif Fenercioglu, Bruce A Barshop, Bulent Kara, Rengang Wang, Valentina Stanley, Kiely N James, Rahul Nachnani, Aneesha Kalur, Hisham Megahed, Faruk Incecik, Sumita Danda, Yasemin Alanay, Eissa Faqeih, Gia Melikishvili, Lobna Mansour, Ian Miller, Biayna Sukhudyan, Jamel Chelly, William B Dobyns, Kaya Bilguvar, Rami Abou Jamra, Murat Gunel, Joseph G Gleeson
Neuronal migration defects, including pachygyria, are among the most severe developmental brain defects in humans. Here, we identify biallelic truncating mutations in CTNNA2, encoding αN-catenin, in patients with a distinct recessive form of pachygyria. CTNNA2 was expressed in human cerebral cortex, and its loss in neurons led to defects in neurite stability and migration. The αN-catenin paralog, αE-catenin, acts as a switch regulating the balance between β-catenin and Arp2/3 actin filament activities1 ...
July 16, 2018: Nature Genetics
Jian Zhou, Chandra L Theesfeld, Kevin Yao, Kathleen M Chen, Aaron K Wong, Olga G Troyanskaya
Key challenges for human genetics, precision medicine and evolutionary biology include deciphering the regulatory code of gene expression and understanding the transcriptional effects of genome variation. However, this is extremely difficult because of the enormous scale of the noncoding mutation space. We developed a deep learning-based framework, ExPecto, that can accurately predict, ab initio from a DNA sequence, the tissue-specific transcriptional effects of mutations, including those that are rare or that have not been observed...
July 16, 2018: Nature Genetics
Craig M Bielski, Ahmet Zehir, Alexander V Penson, Mark T A Donoghue, Walid Chatila, Joshua Armenia, Matthew T Chang, Alison M Schram, Philip Jonsson, Chaitanya Bandlamudi, Pedram Razavi, Gopa Iyer, Mark E Robson, Zsofia K Stadler, Nikolaus Schultz, Jose Baselga, David B Solit, David M Hyman, Michael F Berger, Barry S Taylor
Ploidy abnormalities are a hallmark of cancer, but their impact on the evolution and outcomes of cancers is unknown. Here, we identified whole-genome doubling (WGD) in the tumors of nearly 30% of 9,692 prospectively sequenced advanced cancer patients. WGD varied by tumor lineage and molecular subtype, and arose early in carcinogenesis after an antecedent transforming driver mutation. While associated with TP53 mutations, 46% of all WGD arose in TP53-wild-type tumors and in such cases was associated with an E2F-mediated G1 arrest defect, although neither aberration was obligate in WGD tumors...
July 16, 2018: Nature Genetics
Kaarina Kowalec, Galen E B Wright, Britt I Drögemöller, Folefac Aminkeng, Amit P Bhavsar, Elaine Kingwell, Eric M Yoshida, Anthony Traboulsee, Ruth Ann Marrie, Marcelo Kremenchutzky, Trudy L Campbell, Pierre Duquette, Naga Chalasani, Mia Wadelius, Pär Hallberg, Zongqi Xia, Philip L De Jager, Joshua C Denny, Mary F Davis, Colin J D Ross, Helen Tremlett, Bruce C Carleton
Multiple sclerosis (MS) is a disease of the central nervous system treated with disease-modifying therapies, including the biologic, interferon-β (IFN-β). Up to 60% of IFN-β-exposed MS patients develop abnormal biochemical liver test results1,2 , and 1 in 50 experiences drug-induced liver injury3 . Since genomic variation contributes to other forms of drug-induced liver injury4,5 , we aimed to identify biomarkers of IFN-β-induced liver injury using a two-stage genome-wide association study. The rs2205986 variant, previously linked to differential expression of IRF6, surpassed genome-wide significance in the combined two-stage analysis (P = 2...
July 16, 2018: Nature Genetics
Rachel E Gate, Christine S Cheng, Aviva P Aiden, Atsede Siba, Marcin Tabaka, Dmytro Lituiev, Ido Machol, M Grace Gordon, Meena Subramaniam, Muhammad Shamim, Kendrick L Hougen, Ivo Wortman, Su-Chen Huang, Neva C Durand, Ting Feng, Philip L De Jager, Howard Y Chang, Erez Lieberman Aiden, Christophe Benoist, Michael A Beer, Chun J Ye, Aviv Regev
Over 90% of genetic variants associated with complex human traits map to non-coding regions, but little is understood about how they modulate gene regulation in health and disease. One possible mechanism is that genetic variants affect the activity of one or more cis-regulatory elements leading to gene expression variation in specific cell types. To identify such cases, we analyzed ATAC-seq and RNA-seq profiles from stimulated primary CD4+ T cells in up to 105 healthy donors. We found that regions of accessible chromatin (ATAC-peaks) are co-accessible at kilobase and megabase resolution, consistent with the three-dimensional chromatin organization measured by in situ Hi-C in T cells...
July 9, 2018: Nature Genetics
Amin Allahyar, Carlo Vermeulen, Britta A M Bouwman, Peter H L Krijger, Marjon J A M Verstegen, Geert Geeven, Melissa van Kranenburg, Mark Pieterse, Roy Straver, Judith H I Haarhuis, Kees Jalink, Hans Teunissen, Ivo J Renkens, Wigard P Kloosterman, Benjamin D Rowland, Elzo de Wit, Jeroen de Ridder, Wouter de Laat
Chromatin folding contributes to the regulation of genomic processes such as gene activity. Existing conformation capture methods characterize genome topology through analysis of pairwise chromatin contacts in populations of cells but cannot discern whether individual interactions occur simultaneously or competitively. Here we present multi-contact 4C (MC-4C), which applies Nanopore sequencing to study multi-way DNA conformations of individual alleles. MC-4C distinguishes cooperative from random and competing interactions and identifies previously missed structures in subpopulations of cells...
July 9, 2018: Nature Genetics
Joan Frigola, Radhakrishnan Sabarinathan, Loris Mularoni, Ferran Muiños, Abel Gonzalez-Perez, Núria López-Bigas
In the version of this article initially published, the x axis on the fourth plot in Fig. 2e was incorrectly labeled "H3K36me3 exon-to-intron ratio (lower to higher)." The x axis on this plot should read "Genic H3K36me3 coverage bins (higher to lower)".
July 4, 2018: Nature Genetics
Marie Verbanck, Chia-Yen Chen, Benjamin Neale, Ron Do
In the version of this article initially published, the Supplementary Text and Figures file was missing Supplementary Tables 4, 6, 8 and 10-14. The correct file has now been provided online.
July 2, 2018: Nature Genetics
Rebecca N Johnson, Denis O'Meally, Zhiliang Chen, Graham J Etherington, Simon Y W Ho, Will J Nash, Catherine E Grueber, Yuanyuan Cheng, Camilla M Whittington, Siobhan Dennison, Emma Peel, Wilfried Haerty, Rachel J O'Neill, Don Colgan, Tonia L Russell, David E Alquezar-Planas, Val Attenbrow, Jason G Bragg, Parice A Brandies, Amanda Yoon-Yee Chong, Janine E Deakin, Federica Di Palma, Zachary Duda, Mark D B Eldridge, Kyle M Ewart, Carolyn J Hogg, Greta J Frankham, Arthur Georges, Amber K Gillett, Merran Govendir, Alex D Greenwood, Takashi Hayakawa, Kristofer M Helgen, Matthew Hobbs, Clare E Holleley, Thomas N Heider, Elizabeth A Jones, Andrew King, Danielle Madden, Jennifer A Marshall Graves, Katrina M Morris, Linda E Neaves, Hardip R Patel, Adam Polkinghorne, Marilyn B Renfree, Charles Robin, Ryan Salinas, Kyriakos Tsangaras, Paul D Waters, Shafagh A Waters, Belinda Wright, Marc R Wilkins, Peter Timms, Katherine Belov
The koala, the only extant species of the marsupial family Phascolarctidae, is classified as 'vulnerable' due to habitat loss and widespread disease. We sequenced the koala genome, producing a complete and contiguous marsupial reference genome, including centromeres. We reveal that the koala's ability to detoxify eucalypt foliage may be due to expansions within a cytochrome P450 gene family, and its ability to smell, taste and moderate ingestion of plant secondary metabolites may be due to expansions in the vomeronasal and taste receptors...
July 2, 2018: Nature Genetics
Eric R Gamazon, Ayellet V Segrè, Martijn van de Bunt, Xiaoquan Wen, Hualin S Xi, Farhad Hormozdiari, Halit Ongen, Anuar Konkashbaev, Eske M Derks, François Aguet, Jie Quan, Dan L Nicolae, Eleazar Eskin, Manolis Kellis, Gad Getz, Mark I McCarthy, Emmanouil T Dermitzakis, Nancy J Cox, Kristin G Ardlie
We apply integrative approaches to expression quantitative loci (eQTLs) from 44 tissues from the Genotype-Tissue Expression project and genome-wide association study data. About 60% of known trait-associated loci are in linkage disequilibrium with a cis-eQTL, over half of which were not found in previous large-scale whole blood studies. Applying polygenic analyses to metabolic, cardiovascular, anthropometric, autoimmune, and neurodegenerative traits, we find that eQTLs are significantly enriched for trait associations in relevant pathogenic tissues and explain a substantial proportion of the heritability (40-80%)...
June 28, 2018: Nature Genetics
Ingo Braasch, Julien Bobe, Yann Guiguen, John H Postlethwait
No abstract text is available yet for this article.
June 28, 2018: Nature Genetics
(no author information available yet)
No abstract text is available yet for this article.
June 28, 2018: Nature Genetics
Simen R Sandve, Rori V Rohlfs, Torgeir R Hvidsten
No abstract text is available yet for this article.
June 28, 2018: Nature Genetics
Jeanne E Savage, Philip R Jansen, Sven Stringer, Kyoko Watanabe, Julien Bryois, Christiaan A de Leeuw, Mats Nagel, Swapnil Awasthi, Peter B Barr, Jonathan R I Coleman, Katrina L Grasby, Anke R Hammerschlag, Jakob A Kaminski, Robert Karlsson, Eva Krapohl, Max Lam, Marianne Nygaard, Chandra A Reynolds, Joey W Trampush, Hannah Young, Delilah Zabaneh, Sara Hägg, Narelle K Hansell, Ida K Karlsson, Sten Linnarsson, Grant W Montgomery, Ana B Muñoz-Manchado, Erin B Quinlan, Gunter Schumann, Nathan G Skene, Bradley T Webb, Tonya White, Dan E Arking, Dimitrios Avramopoulos, Robert M Bilder, Panos Bitsios, Katherine E Burdick, Tyrone D Cannon, Ornit Chiba-Falek, Andrea Christoforou, Elizabeth T Cirulli, Eliza Congdon, Aiden Corvin, Gail Davies, Ian J Deary, Pamela DeRosse, Dwight Dickinson, Srdjan Djurovic, Gary Donohoe, Emily Drabant Conley, Johan G Eriksson, Thomas Espeseth, Nelson A Freimer, Stella Giakoumaki, Ina Giegling, Michael Gill, David C Glahn, Ahmad R Hariri, Alex Hatzimanolis, Matthew C Keller, Emma Knowles, Deborah Koltai, Bettina Konte, Jari Lahti, Stephanie Le Hellard, Todd Lencz, David C Liewald, Edythe London, Astri J Lundervold, Anil K Malhotra, Ingrid Melle, Derek Morris, Anna C Need, William Ollier, Aarno Palotie, Antony Payton, Neil Pendleton, Russell A Poldrack, Katri Räikkönen, Ivar Reinvang, Panos Roussos, Dan Rujescu, Fred W Sabb, Matthew A Scult, Olav B Smeland, Nikolaos Smyrnis, John M Starr, Vidar M Steen, Nikos C Stefanis, Richard E Straub, Kjetil Sundet, Henning Tiemeier, Aristotle N Voineskos, Daniel R Weinberger, Elisabeth Widen, Jin Yu, Goncalo Abecasis, Ole A Andreassen, Gerome Breen, Lene Christiansen, Birgit Debrabant, Danielle M Dick, Andreas Heinz, Jens Hjerling-Leffler, M Arfan Ikram, Kenneth S Kendler, Nicholas G Martin, Sarah E Medland, Nancy L Pedersen, Robert Plomin, Tinca J C Polderman, Stephan Ripke, Sophie van der Sluis, Patrick F Sullivan, Scott I Vrieze, Margaret J Wright, Danielle Posthuma
Intelligence is highly heritable 1 and a major determinant of human health and well-being 2 . Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence3-7 , but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis...
June 25, 2018: Nature Genetics
Mats Nagel, Philip R Jansen, Sven Stringer, Kyoko Watanabe, Christiaan A de Leeuw, Julien Bryois, Jeanne E Savage, Anke R Hammerschlag, Nathan G Skene, Ana B Muñoz-Manchado, Tonya White, Henning Tiemeier, Sten Linnarsson, Jens Hjerling-Leffler, Tinca J C Polderman, Patrick F Sullivan, Sophie van der Sluis, Danielle Posthuma
Neuroticism is an important risk factor for psychiatric traits, including depression 1 , anxiety2,3 , and schizophrenia4-6 . At the time of analysis, previous genome-wide association studies7-12 (GWAS) reported 16 genomic loci associated to neuroticism10-12 . Here we conducted a large GWAS meta-analysis (n = 449,484) of neuroticism and identified 136 independent genome-wide significant loci (124 new at the time of analysis), which implicate 599 genes. Functional follow-up analyses showed enrichment in several brain regions and involvement of specific cell types, including dopaminergic neuroblasts (P = 3...
June 25, 2018: Nature Genetics
Daryl Domman, Fahima Chowdhury, Ashraful I Khan, Matthew J Dorman, Ankur Mutreja, Muhammad Ikhtear Uddin, Anik Paul, Yasmin A Begum, Richelle C Charles, Stephen B Calderwood, Taufiqur R Bhuiyan, Jason B Harris, Regina C LaRocque, Edward T Ryan, Firdausi Qadri, Nicholas R Thomson
Although much focus is placed on cholera epidemics, the greatest burden occurs in settings in which cholera is endemic, including areas of South Asia, Africa and now Haiti1,2 . Dhaka, Bangladesh is a megacity that is hyper-endemic for cholera, and experiences two regular seasonal outbreaks of cholera each year 3 . Despite this, a detailed understanding of the diversity of Vibrio cholerae strains circulating in this setting, and their relationships to annual outbreaks, has not yet been obtained. Here we performed whole-genome sequencing of V...
June 25, 2018: Nature Genetics
Farhad Hormozdiari, Steven Gazal, Bryce van de Geijn, Hilary K Finucane, Chelsea J-T Ju, Po-Ru Loh, Armin Schoech, Yakir Reshef, Xuanyao Liu, Luke O'Connor, Alexander Gusev, Eleazar Eskin, Alkes L Price
There is increasing evidence that many risk loci found using genome-wide association studies are molecular quantitative trait loci (QTLs). Here we introduce a new set of functional annotations based on causal posterior probabilities of fine-mapped molecular cis-QTLs, using data from the Genotype-Tissue Expression (GTEx) and BLUEPRINT consortia. We show that these annotations are more strongly enriched for heritability (5.84× for eQTLs; P = 1.19 × 10-31 ) across 41 diseases and complex traits than annotations containing all significant molecular QTLs (1...
June 25, 2018: Nature Genetics
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