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Nature Genetics

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https://read.qxmd.com/read/30742113/landscape-of-b-cell-immunity-and-related-immune-evasion-in-human-cancers
#1
Xihao Hu, Jian Zhang, Jin Wang, Jingxin Fu, Taiwen Li, Xiaoqi Zheng, Binbin Wang, Shengqing Gu, Peng Jiang, Jingyu Fan, Xiaomin Ying, Jing Zhang, Michael C Carroll, Kai W Wucherpfennig, Nir Hacohen, Fan Zhang, Peng Zhang, Jun S Liu, Bo Li, X Shirley Liu
Tumor-infiltrating B cells are an important component in the microenvironment but have unclear anti-tumor effects. We enhanced our previous computational algorithm TRUST to extract the B cell immunoglobulin hypervariable regions from bulk tumor RNA-sequencing data. TRUST assembled more than 30 million complementarity-determining region 3 sequences of the B cell heavy chain (IgH) from The Cancer Genome Atlas. Widespread B cell clonal expansions and immunoglobulin subclass switch events were observed in diverse human cancers...
February 11, 2019: Nature Genetics
https://read.qxmd.com/read/30742112/retinal-transcriptome-and-eqtl-analyses-identify-genes-associated-with-age-related-macular-degeneration
#2
Rinki Ratnapriya, Olukayode A Sosina, Margaret R Starostik, Madeline Kwicklis, Rebecca J Kapphahn, Lars G Fritsche, Ashley Walton, Marios Arvanitis, Linn Gieser, Alexandra Pietraszkiewicz, Sandra R Montezuma, Emily Y Chew, Alexis Battle, Gonçalo R Abecasis, Deborah A Ferrington, Nilanjan Chatterjee, Anand Swaroop
Genome-wide association studies (GWAS) have identified genetic variants at 34 loci contributing to age-related macular degeneration (AMD)1-3 . We generated transcriptional profiles of postmortem retinas from 453 controls and cases at distinct stages of AMD and integrated retinal transcriptomes, covering 13,662 protein-coding and 1,462 noncoding genes, with genotypes at more than 9 million common SNPs for expression quantitative trait loci (eQTL) analysis of a tissue not included in Genotype-Tissue Expression (GTEx) and other large datasets4,5 ...
February 11, 2019: Nature Genetics
https://read.qxmd.com/read/30718927/the-landscape-of-selection-in-551-esophageal-adenocarcinomas-defines-genomic-biomarkers-for-the-clinic
#3
Alexander M Frankell, SriGanesh Jammula, Xiaodun Li, Gianmarco Contino, Sarah Killcoyne, Sujath Abbas, Juliane Perner, Lawrence Bower, Ginny Devonshire, Emma Ococks, Nicola Grehan, James Mok, Maria O'Donovan, Shona MacRae, Matthew D Eldridge, Simon Tavaré, Rebecca C Fitzgerald
Esophageal adenocarcinoma (EAC) is a poor-prognosis cancer type with rapidly rising incidence. Understanding of the genetic events driving EAC development is limited, and there are few molecular biomarkers for prognostication or therapeutics. Using a cohort of 551 genomically characterized EACs with matched RNA sequencing data, we discovered 77 EAC driver genes and 21 noncoding driver elements. We identified a mean of 4.4 driver events per tumor, which were derived more commonly from mutations than copy number alterations, and compared the prevelence of these mutations to the exome-wide mutational excess calculated using non-synonymous to synonymous mutation ratios (dN/dS)...
February 4, 2019: Nature Genetics
https://read.qxmd.com/read/30718926/identification-of-28-new-susceptibility-loci-for-type-2-diabetes-in-the-japanese-population
#4
Ken Suzuki, Masato Akiyama, Kazuyoshi Ishigaki, Masahiro Kanai, Jun Hosoe, Nobuhiro Shojima, Atsushi Hozawa, Aya Kadota, Kiyonori Kuriki, Mariko Naito, Kozo Tanno, Yasushi Ishigaki, Makoto Hirata, Koichi Matsuda, Nakao Iwata, Masashi Ikeda, Norie Sawada, Taiki Yamaji, Motoki Iwasaki, Shiro Ikegawa, Shiro Maeda, Yoshinori Murakami, Kenji Wakai, Shoichiro Tsugane, Makoto Sasaki, Masayuki Yamamoto, Yukinori Okada, Michiaki Kubo, Yoichiro Kamatani, Momoko Horikoshi, Toshimasa Yamauchi, Takashi Kadowaki
To understand the genetics of type 2 diabetes in people of Japanese ancestry, we conducted A meta-analysis of four genome-wide association studies (GWAS; 36,614 cases and 155,150 controls of Japanese ancestry). We identified 88 type 2 diabetes-associated loci (P < 5.0 × 10-8 ) with 115 independent signals (P < 5.0 × 10-6 ), of which 28 loci with 30 signals were novel. Twenty-eight missense variants were in linkage disequilibrium (r2  > 0.6) with the lead variants. Among the 28 missense variants, three previously unreported variants had distinct minor allele frequency (MAF) spectra between people of Japanese and European ancestry (MAFJPN  > 0...
February 4, 2019: Nature Genetics
https://read.qxmd.com/read/30696931/author-correction-association-analysis-in-over-329-000-individuals-identifies-116-independent-variants-influencing-neuroticism
#5
Michelle Luciano, Saskia P Hagenaars, Gail Davies, W David Hill, Toni-Kim Clarke, Masoud Shirali, Sarah E Harris, Riccardo E Marioni, David C Liewald, Chloe Fawns-Ritchie, Mark J Adams, David M Howard, Cathryn M Lewis, Catharine R Gale, Andrew M McIntosh, Ian J Deary
In the version of this article initially published, in Table 2, the descriptions of pathways and definitions in the first and last columns did not correctly correspond to the values in the other columns. The error has been corrected in the HTML and PDF versions of the article.
January 29, 2019: Nature Genetics
https://read.qxmd.com/read/30692682/genetic-and-phenotypic-landscape-of-the-major-histocompatibilty-complex-region-in-the-japanese-population
#6
Jun Hirata, Kazuyoshi Hosomichi, Saori Sakaue, Masahiro Kanai, Hirofumi Nakaoka, Kazuyoshi Ishigaki, Ken Suzuki, Masato Akiyama, Toshihiro Kishikawa, Kotaro Ogawa, Tatsuo Masuda, Kenichi Yamamoto, Makoto Hirata, Koichi Matsuda, Yukihide Momozawa, Ituro Inoue, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada
To perform detailed fine-mapping of the major-histocompatibility-complex region, we conducted next-generation sequencing (NGS)-based typing of the 33 human leukocyte antigen (HLA) genes in 1,120 individuals of Japanese ancestry, providing a high-resolution allele catalog and linkage-disequilibrium structure of both classical and nonclassical HLA genes. Together with population-specific deep-whole-genome-sequencing data (n = 1,276), we conducted NGS-based HLA, single-nucleotide-variant and indel imputation of large-scale genome-wide-association-study data from 166,190 Japanese individuals...
January 28, 2019: Nature Genetics
https://read.qxmd.com/read/30692681/ezh2-oncogenic-mutations-drive-epigenetic-transcriptional-and-structural-changes-within-chromatin-domains
#7
Maria C Donaldson-Collier, Stephanie Sungalee, Marie Zufferey, Daniele Tavernari, Natalya Katanayeva, Elena Battistello, Marco Mina, Kyle M Douglass, Timo Rey, Franck Raynaud, Suliana Manley, Giovanni Ciriello, Elisa Oricchio
Chromatin is organized into topologically associating domains (TADs) enriched in distinct histone marks. In cancer, gain-of-function mutations in the gene encoding the enhancer of zeste homolog 2 protein (EZH2) lead to a genome-wide increase in histone-3 Lys27 trimethylation (H3K27me3) associated with transcriptional repression. However, the effects of these epigenetic changes on the structure and function of chromatin domains have not been explored. Here, we found a functional interplay between TADs and epigenetic and transcriptional changes mediated by mutated EZH2...
January 28, 2019: Nature Genetics
https://read.qxmd.com/read/30692680/garfield-classifies-disease-relevant-genomic-features-through-integration-of-functional-annotations-with-association-signals
#8
Valentina Iotchkova, Graham R S Ritchie, Matthias Geihs, Sandro Morganella, Josine L Min, Klaudia Walter, Nicholas John Timpson, Ian Dunham, Ewan Birney, Nicole Soranzo
Loci discovered by genome-wide association studies predominantly map outside protein-coding genes. The interpretation of the functional consequences of non-coding variants can be greatly enhanced by catalogs of regulatory genomic regions in cell lines and primary tissues. However, robust and readily applicable methods are still lacking by which to systematically evaluate the contribution of these regions to genetic variation implicated in diseases or quantitative traits. Here we propose a novel approach that leverages genome-wide association studies' findings with regulatory or functional annotations to classify features relevant to a phenotype of interest...
January 28, 2019: Nature Genetics
https://read.qxmd.com/read/30664746/harnessing-the-potential-of-germplasm-collections
#9
Peter Langridge, Robbie Waugh
No abstract text is available yet for this article.
January 21, 2019: Nature Genetics
https://read.qxmd.com/read/30664745/identification-of-new-therapeutic-targets-for-osteoarthritis-through-genome-wide-analyses-of-uk-biobank-data
#10
Ioanna Tachmazidou, Konstantinos Hatzikotoulas, Lorraine Southam, Jorge Esparza-Gordillo, Valeriia Haberland, Jie Zheng, Toby Johnson, Mine Koprulu, Eleni Zengini, Julia Steinberg, Jeremy M Wilkinson, Sahir Bhatnagar, Joshua D Hoffman, Natalie Buchan, Dániel Süveges, Laura Yerges-Armstrong, George Davey Smith, Tom R Gaunt, Robert A Scott, Linda C McCarthy, Eleftheria Zeggini
Osteoarthritis is the most common musculoskeletal disease and the leading cause of disability globally. Here, we performed a genome-wide association study for osteoarthritis (77,052 cases and 378,169 controls), analyzing four phenotypes: knee osteoarthritis, hip osteoarthritis, knee and/or hip osteoarthritis, and any osteoarthritis. We discovered 64 signals, 52 of them novel, more than doubling the number of established disease loci. Six signals fine-mapped to a single variant. We identified putative effector genes by integrating expression quantitative trait loci (eQTL) colocalization, fine-mapping, and human rare-disease, animal-model, and osteoarthritis tissue expression data...
January 21, 2019: Nature Genetics
https://read.qxmd.com/read/30647471/author-correction-assembly-of-a-pan-genome-from-deep-sequencing-of-910-humans-of-african-descent
#11
Rachel M Sherman, Juliet Forman, Valentin Antonescu, Daniela Puiu, Michelle Daya, Nicholas Rafaels, Meher Preethi Boorgula, Sameer Chavan, Candelaria Vergara, Victor E Ortega, Albert M Levin, Celeste Eng, Maria Yazdanbakhsh, James G Wilson, Javier Marrugo, Leslie A Lange, L Keoki Williams, Harold Watson, Lorraine B Ware, Christopher O Olopade, Olufunmilayo Olopade, Ricardo R Oliveira, Carole Ober, Dan L Nicolae, Deborah A Meyers, Alvaro Mayorga, Jennifer Knight-Madden, Tina Hartert, Nadia N Hansel, Marilyn G Foreman, Jean G Ford, Mezbah U Faruque, Georgia M Dunston, Luis Caraballo, Esteban G Burchard, Eugene R Bleecker, Maria I Araujo, Edwin F Herrera-Paz, Monica Campbell, Cassandra Foster, Margaret A Taub, Terri H Beaty, Ingo Ruczinski, Rasika A Mathias, Kathleen C Barnes, Steven L Salzberg
In the version of this article initially published, the statement "there are no pan-genomes for any other animal or plant species" was incorrect. The statement has been corrected to "there are no reported pan-genomes for any other animal species, to our knowledge." We thank David Edwards for bringing this error to our attention. The error has been corrected in the HTML and PDF versions of the article.
January 15, 2019: Nature Genetics
https://read.qxmd.com/read/30647470/publisher-correction-immune-genes-are-primed-for-robust-transcription-by-proximal-long-noncoding-rnas-located-in-nuclear-compartments
#12
Stephanie Fanucchi, Ezio T Fok, Emiliano Dalla, Youtaro Shibayama, Kathleen Börner, Erin Y Chang, Stoyan Stoychev, Maxim Imakaev, Dirk Grimm, Kevin C Wang, Guoliang Li, Wing-Kin Sung, Musa M Mhlanga
In the version of this article initially published, '+' and '-' labels were missing from the graph keys at the bottom of Fig. 8d. The error has been corrected in the HTML and PDF versions of the article.
January 15, 2019: Nature Genetics
https://read.qxmd.com/read/30643258/genome-wide-association-analyses-of-risk-tolerance-and-risky-behaviors-in-over-1-million-individuals-identify-hundreds-of-loci-and-shared-genetic-influences
#13
Richard Karlsson Linnér, Pietro Biroli, Edward Kong, S Fleur W Meddens, Robbee Wedow, Mark Alan Fontana, Maël Lebreton, Stephen P Tino, Abdel Abdellaoui, Anke R Hammerschlag, Michel G Nivard, Aysu Okbay, Cornelius A Rietveld, Pascal N Timshel, Maciej Trzaskowski, Ronald de Vlaming, Christian L Zünd, Yanchun Bao, Laura Buzdugan, Ann H Caplin, Chia-Yen Chen, Peter Eibich, Pierre Fontanillas, Juan R Gonzalez, Peter K Joshi, Ville Karhunen, Aaron Kleinman, Remy Z Levin, Christina M Lill, Gerardus A Meddens, Gerard Muntané, Sandra Sanchez-Roige, Frank J van Rooij, Erdogan Taskesen, Yang Wu, Futao Zhang, Adam Auton, Jason D Boardman, David W Clark, Andrew Conlin, Conor C Dolan, Urs Fischbacher, Patrick J F Groenen, Kathleen Mullan Harris, Gregor Hasler, Albert Hofman, Mohammad A Ikram, Sonia Jain, Robert Karlsson, Ronald C Kessler, Maarten Kooyman, James MacKillop, Minna Männikkö, Carlos Morcillo-Suarez, Matthew B McQueen, Klaus M Schmidt, Melissa C Smart, Matthias Sutter, A Roy Thurik, André G Uitterlinden, Jon White, Harriet de Wit, Jian Yang, Lars Bertram, Dorret I Boomsma, Tõnu Esko, Ernst Fehr, David A Hinds, Magnus Johannesson, Meena Kumari, David Laibson, Patrik K E Magnusson, Michelle N Meyer, Arcadi Navarro, Abraham A Palmer, Tune H Pers, Danielle Posthuma, Daniel Schunk, Murray B Stein, Rauli Svento, Henning Tiemeier, Paul R H J Timmers, Patrick Turley, Robert J Ursano, Gert G Wagner, James F Wilson, Jacob Gratten, James J Lee, David Cesarini, Daniel J Benjamin, Philipp D Koellinger, Jonathan P Beauchamp
Humans vary substantially in their willingness to take risks. In a combined sample of over 1 million individuals, we conducted genome-wide association studies (GWAS) of general risk tolerance, adventurousness, and risky behaviors in the driving, drinking, smoking, and sexual domains. Across all GWAS, we identified hundreds of associated loci, including 99 loci associated with general risk tolerance. We report evidence of substantial shared genetic influences across risk tolerance and the risky behaviors: 46 of the 99 general risk tolerance loci contain a lead SNP for at least one of our other GWAS, and general risk tolerance is genetically correlated ([Formula: see text] ~ 0...
January 14, 2019: Nature Genetics
https://read.qxmd.com/read/30643257/fast-and-accurate-genomic-analyses-using-genome-graphs
#14
Goran Rakocevic, Vladimir Semenyuk, Wan-Ping Lee, James Spencer, John Browning, Ivan J Johnson, Vladan Arsenijevic, Jelena Nadj, Kaushik Ghose, Maria C Suciu, Sun-Gou Ji, Gülfem Demir, Lizao Li, Berke Ç Toptaş, Alexey Dolgoborodov, Björn Pollex, Iosif Spulber, Irina Glotova, Péter Kómár, Andrew L Stachyra, Yilong Li, Milos Popovic, Morten Källberg, Amit Jain, Deniz Kural
The human reference genome serves as the foundation for genomics by providing a scaffold for alignment of sequencing reads, but currently only reflects a single consensus haplotype, thus impairing analysis accuracy. Here we present a graph reference genome implementation that enables read alignment across 2,800 diploid genomes encompassing 12.6 million SNPs and 4.0 million insertions and deletions (indels). The pipeline processes one whole-genome sequencing sample in 6.5 h using a system with 36 CPU cores...
January 14, 2019: Nature Genetics
https://read.qxmd.com/read/30643256/multivariate-genome-wide-analyses-of-the-well-being-spectrum
#15
Bart M L Baselmans, Rick Jansen, Hill F Ip, Jenny van Dongen, Abdel Abdellaoui, Margot P van de Weijer, Yanchun Bao, Melissa Smart, Meena Kumari, Gonneke Willemsen, Jouke-Jan Hottenga, Dorret I Boomsma, Eco J C de Geus, Michel G Nivard, Meike Bartels
We introduce two novel methods for multivariate genome-wide-association meta-analysis (GWAMA) of related traits that correct for sample overlap. A broad range of simulation scenarios supports the added value of our multivariate methods relative to univariate GWAMA. We applied the novel methods to life satisfaction, positive affect, neuroticism, and depressive symptoms, collectively referred to as the well-being spectrum (Nobs  = 2,370,390), and found 304 significant independent signals. Our multivariate approaches resulted in a 26% increase in the number of independent signals relative to the four univariate GWAMAs and in an ~57% increase in the predictive power of polygenic risk scores...
January 14, 2019: Nature Genetics
https://read.qxmd.com/read/30643255/a-loss-of-function-variant-in-alox15-protects-against-nasal-polyps-and-chronic-rhinosinusitis
#16
Ragnar P Kristjansson, Stefania Benonisdottir, Olafur B Davidsson, Asmundur Oddsson, Vinicius Tragante, Jon K Sigurdsson, Lilja Stefansdottir, Stefan Jonsson, Brynjar O Jensson, Joseph G Arthur, Gudny A Arnadottir, Gerald Sulem, Bjarni V Halldorsson, Bjarni Gunnarsson, Gisli H Halldorsson, Olafur A Stefansson, Gudjon R Oskarsson, Aimee M Deaton, Isleifur Olafsson, Gudmundur I Eyjolfsson, Olof Sigurdardottir, Pall T Onundarson, David Gislason, Thorarinn Gislason, Bjorn R Ludviksson, Dora Ludviksdottir, Thorunn A Olafsdottir, Thorunn Rafnar, Gisli Masson, Florian Zink, Gyda Bjornsdottir, Olafur Th Magnusson, Unnur S Bjornsdottir, Gudmar Thorleifsson, Gudmundur L Norddahl, Daniel F Gudbjartsson, Unnur Thorsteinsdottir, Ingileif Jonsdottir, Patrick Sulem, Kari Stefansson
Nasal polyps (NP) are lesions on the nasal and paranasal sinus mucosa and are a risk factor for chronic rhinosinusitis (CRS). We performed genome-wide association studies on NP and CRS in Iceland and the UK (using UK Biobank data) with 4,366 NP cases, 5,608 CRS cases, and >700,000 controls. We found 10 markers associated with NP and 2 with CRS. We also tested 210 markers reported to associate with eosinophil count, yielding 17 additional NP associations. Of the 27 NP signals, 7 associate with CRS and 13 with asthma...
January 14, 2019: Nature Genetics
https://read.qxmd.com/read/30643254/tumor-mutational-load-predicts-survival-after-immunotherapy-across-multiple-cancer-types
#17
Robert M Samstein, Chung-Han Lee, Alexander N Shoushtari, Matthew D Hellmann, Ronglai Shen, Yelena Y Janjigian, David A Barron, Ahmet Zehir, Emmet J Jordan, Antonio Omuro, Thomas J Kaley, Sviatoslav M Kendall, Robert J Motzer, A Ari Hakimi, Martin H Voss, Paul Russo, Jonathan Rosenberg, Gopa Iyer, Bernard H Bochner, Dean F Bajorin, Hikmat A Al-Ahmadie, Jamie E Chaft, Charles M Rudin, Gregory J Riely, Shrujal Baxi, Alan L Ho, Richard J Wong, David G Pfister, Jedd D Wolchok, Christopher A Barker, Philip H Gutin, Cameron W Brennan, Viviane Tabar, Ingo K Mellinghoff, Lisa M DeAngelis, Charlotte E Ariyan, Nancy Lee, William D Tap, Mrinal M Gounder, Sandra P D'Angelo, Leonard Saltz, Zsofia K Stadler, Howard I Scher, Jose Baselga, Pedram Razavi, Christopher A Klebanoff, Rona Yaeger, Neil H Segal, Geoffrey Y Ku, Ronald P DeMatteo, Marc Ladanyi, Naiyer A Rizvi, Michael F Berger, Nadeem Riaz, David B Solit, Timothy A Chan, Luc G T Morris
Immune checkpoint inhibitor (ICI) treatments benefit some patients with metastatic cancers, but predictive biomarkers are needed. Findings in selected cancer types suggest that tumor mutational burden (TMB) may predict clinical response to ICI. To examine this association more broadly, we analyzed the clinical and genomic data of 1,662 advanced cancer patients treated with ICI, and 5,371 non-ICI-treated patients, whose tumors underwent targeted next-generation sequencing (MSK-IMPACT). Among all patients, higher somatic TMB (highest 20% in each histology) was associated with better overall survival...
January 14, 2019: Nature Genetics
https://read.qxmd.com/read/30643253/repurposing-large-health-insurance-claims-data-to-estimate-genetic-and-environmental-contributions-in-560-phenotypes
#18
Chirag M Lakhani, Braden T Tierney, Arjun K Manrai, Jian Yang, Peter M Visscher, Chirag J Patel
We analysed a large health insurance dataset to assess the genetic and environmental contributions of 560 disease-related phenotypes in 56,396 twin pairs and 724,513 sibling pairs out of 44,859,462 individuals that live in the United States. We estimated the contribution of environmental risk factors (socioeconomic status (SES), air pollution and climate) in each phenotype. Mean heritability (h2  = 0.311) and shared environmental variance (c2  = 0.088) were higher than variance attributed to specific environmental factors such as zip-code-level SES (varSES  = 0...
January 14, 2019: Nature Genetics
https://read.qxmd.com/read/30643252/nuclear-positioning-and-pairing-of-x-chromosome-inactivation-centers-are-not-primary-determinants-during-initiation-of-random-x-inactivation
#19
Tim Pollex, Edith Heard
During X-chromosome inactivation (XCI), one of the two X-inactivation centers (Xics) upregulates the noncoding RNA Xist to initiate chromosomal silencing in cis. How one Xic is chosen to upregulate Xist remains unclear. Models proposed include localization of one Xic at the nuclear envelope or transient homologous Xic pairing followed by asymmetric transcription factor distribution at Xist's antisense Xite/Tsix locus. Here, we use a TetO/TetR system that can inducibly relocate one or both Xics to the nuclear lamina in differentiating mouse embryonic stem cells...
January 14, 2019: Nature Genetics
https://read.qxmd.com/read/30643251/association-studies-of-up-to-1-2-million-individuals-yield-new-insights-into-the-genetic-etiology-of-tobacco-and-alcohol-use
#20
Mengzhen Liu, Yu Jiang, Robbee Wedow, Yue Li, David M Brazel, Fang Chen, Gargi Datta, Jose Davila-Velderrain, Daniel McGuire, Chao Tian, Xiaowei Zhan, Hélène Choquet, Anna R Docherty, Jessica D Faul, Johanna R Foerster, Lars G Fritsche, Maiken Elvestad Gabrielsen, Scott D Gordon, Jeffrey Haessler, Jouke-Jan Hottenga, Hongyan Huang, Seon-Kyeong Jang, Philip R Jansen, Yueh Ling, Reedik Mägi, Nana Matoba, George McMahon, Antonella Mulas, Valeria Orrù, Teemu Palviainen, Anita Pandit, Gunnar W Reginsson, Anne Heidi Skogholt, Jennifer A Smith, Amy E Taylor, Constance Turman, Gonneke Willemsen, Hannah Young, Kendra A Young, Gregory J M Zajac, Wei Zhao, Wei Zhou, Gyda Bjornsdottir, Jason D Boardman, Michael Boehnke, Dorret I Boomsma, Chu Chen, Francesco Cucca, Gareth E Davies, Charles B Eaton, Marissa A Ehringer, Tõnu Esko, Edoardo Fiorillo, Nathan A Gillespie, Daniel F Gudbjartsson, Toomas Haller, Kathleen Mullan Harris, Andrew C Heath, John K Hewitt, Ian B Hickie, John E Hokanson, Christian J Hopfer, David J Hunter, William G Iacono, Eric O Johnson, Yoichiro Kamatani, Sharon L R Kardia, Matthew C Keller, Manolis Kellis, Charles Kooperberg, Peter Kraft, Kenneth S Krauter, Markku Laakso, Penelope A Lind, Anu Loukola, Sharon M Lutz, Pamela A F Madden, Nicholas G Martin, Matt McGue, Matthew B McQueen, Sarah E Medland, Andres Metspalu, Karen L Mohlke, Jonas B Nielsen, Yukinori Okada, Ulrike Peters, Tinca J C Polderman, Danielle Posthuma, Alexander P Reiner, John P Rice, Eric Rimm, Richard J Rose, Valgerdur Runarsdottir, Michael C Stallings, Alena Stančáková, Hreinn Stefansson, Khanh K Thai, Hilary A Tindle, Thorarinn Tyrfingsson, Tamara L Wall, David R Weir, Constance Weisner, John B Whitfield, Bendik Slagsvold Winsvold, Jie Yin, Luisa Zuccolo, Laura J Bierut, Kristian Hveem, James J Lee, Marcus R Munafò, Nancy L Saccone, Cristen J Willer, Marilyn C Cornelis, Sean P David, David A Hinds, Eric Jorgenson, Jaakko Kaprio, Jerry A Stitzel, Kari Stefansson, Thorgeir E Thorgeirsson, Gonçalo Abecasis, Dajiang J Liu, Scott Vrieze
Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1 . They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11 . In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk...
January 14, 2019: Nature Genetics
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