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1. Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms

Author

Victor Rusu, Eitan Hoch, Josep M. Mercader, Danielle E. Tenen, Melissa Gymrek, Christina R. Hartigan, Michael DeRan, Marcin von Grotthuss, Pierre Fontanillas, Alexandra Spooner, Gaelen Guzman, Amy A. Deik, Kerry A. Pierce, Courtney Dennis, Clary B. Clish, Steven A. Carr, Bridget K. Wagner, Monica Schenone, Maggie C.Y. Ng, Brian H. Chen, Federico Centeno-Cruz, Carlos Zerrweck, Lorena Orozco, David M. Altshuler, Stuart L. Schreiber, Jose C. Florez, Suzanne B.R. Jacobs, Eric S. Lander, Daniel Shriner, Jiang Li, Wei-Min Chen, Xiuqing Guo, Jiankang Liu, Suzette J. Bielinski, Lisa R. Yanek, Michael A. Nalls, Mary E. Comeau, Laura J. Rasmussen-Torvik, Richard A. Jensen, Daniel S. Evans, Yan V. Sun, Ping An, Sanjay R. Patel, Yingchang Lu, Jirong Long, Loren L. Armstrong, Lynne Wagenknecht, Lingyao Yang, Beverly M. Snively, Nicholette D. Palmer, Poorva Mudgal, Carl D. Langefeld, Keith L. Keene, Barry I. Freedman, Josyf C. Mychaleckyj, Uma Nayak, Leslie J. Raffel, Mark O. Goodarzi, Y-D Ida Chen, Herman A. Taylor, Adolfo Correa, Mario Sims, David Couper, James S. Pankow, Eric Boerwinkle, Adebowale Adeyemo, Ayo Doumatey, Guanjie Chen, Rasika A. Mathias, Dhananjay Vaidya, Andrew B. Singleton, Alan B. Zonderman, Robert P. Igo, John R. Sedor, Edmond K. Kabagambe, David S. Siscovick, Barbara McKnight, Kenneth Rice, Yongmei Liu, Wen-Chi Hsueh, Wei Zhao, Lawrence F. Bielak, Aldi Kraja, Michael A. Province, Erwin P. Bottinger, Omri Gottesman, Qiuyin Cai, Wei Zheng, William J. Blot, William L. Lowe, Jennifer A. Pacheco, Dana C. Crawford, Elin Grundberg, Stephen S. Rich, M. Geoffrey Hayes, Xiao-Ou Shu, Ruth J.F. Loos, Ingrid B. Borecki, Patricia A. Peyser, Steven R. Cummings, Bruce M. Psaty, Myriam Fornage, Sudha K. Iyengar, Michele K. Evans, Diane M. Becker, W.H. Linda Kao, James G. Wilson, Jerome I. Rotter, Michèle M. Sale, Simin Liu, Charles N. Rotimi, Donald W. Bowden, Alicia Huerta-Chagoya, Humberto García-Ortiz, Hortensia Moreno-Macías, Alisa Manning, Lizz Caulkins, Noël P. Burtt, Jason Flannick, Nick Patterson, Carlos A. Aguilar-Salinas, Teresa Tusié-Luna, David Altshuler, Angélica Martínez-Hernández, Francisco Martin Barajas-Olmos, Cecilia Contreras-Cubas, Elvia Mendoza-Caamal, Cristina Revilla-Monsalve, Sergio Islas-Andrade, Emilio Córdova, Xavier Soberón, Clicerio González-Villalpando, María Elena González-Villalpando, Christopher A. Haiman, Lynne Wilkens, Loic Le Marchand, Kristine Monroe, Laurence Kolonel, Olimpia Arellano-Campos, Maria L. Ordóñez-Sánchez, Maribel Rodríguez-Torres, Yayoi Segura-Kato, Rosario Rodríguez-Guillén, Ivette Cruz-Bautista, Linda Liliana Muñoz-Hernandez, Tamara Sáenz, Donají Gómez, Ulices Alvirde, Paloma Almeda-Valdés, Maria L. Cortes, Massachusetts Institute of Technology. Department of Biology, Altshuler, David M, and Lander, Eric Steven

Subjects
0301 basic medicine, Models, Molecular, Monocarboxylic Acid Transporters, Heterozygote, endocrine system diseases, Locus (genetics), Type 2 diabetes, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Allele, Monocarboxylate transporter, Genetics, biology, Haplotype, Cell Membrane, nutritional and metabolic diseases, Lipid metabolism, Heterozygote advantage, medicine.disease, Histone Code, 030104 developmental biology, Diabetes Mellitus, Type 2, Haplotypes, Liver, Basigin, Gene Knockdown Techniques, biology.protein, Hepatocytes, 030217 neurology & neurosurgery, Chromosomes, Human, Pair 17
Abstract

Type 2 diabetes (T2D) affects Latinos at twice the rate seen in populations of European descent. We recently identified a risk haplotype spanning SLC16A11 that explains ∼20% of the increased T2D prevalence in Mexico. Here, through genetic fine-mapping, we define a set of tightly linked variants likely to contain the causal allele(s). We show that variants on the T2D-associated haplotype have two distinct effects: (1) decreasing SLC16A11 expression in liver and (2) disrupting a key interaction with basigin, thereby reducing cell-surface localization. Both independent mechanisms reduce SLC16A11 function and suggest SLC16A11 is the causal gene at this locus. To gain insight into how SLC16A11 disruption impacts T2D risk, we demonstrate that SLC16A11 is a proton-coupled monocarboxylate transporter and that genetic perturbation of SLC16A11 induces changes in fatty acid and lipid metabolism that are associated with increased T2D risk. Our findings suggest that increasing SLC16A11 function could be therapeutically beneficial for T2D. Video Abstract [Figure presented] Keywords: type 2 diabetes (T2D); genetics; disease mechanism; SLC16A11; MCT11; solute carrier (SLC); monocarboxylates; fatty acid metabolism; lipid metabolism; precision medicine

Published
2016

2. A global reference for human genetic variation

Author

Colonna V. (1000 Genomes Project Consortium) Adam Auton, Gonçalo R Abecasis, David M Altshuler, Richard M Durbin, David R Bentley, Aravinda Chakravarti, Andrew G Clark, Peter Donnelly, Evan E Eichler, Paul Flicek, Stacey B Gabriel, Richard A Gibbs, Eric D Green, Matthew E Hurles, Bartha M Knoppers, Jan O Korbel, Eric S Lander, Charles Lee, Hans Lehrach, Elaine R Mardis, Gabor T Marth, Gil A McVean, Deborah A Nickerson, Jeanette P Schmidt, Stephen T Sherry, Jun Wang, Richard K Wilson, Eric Boerwinkle, Harsha Doddapaneni, Yi Han, Viktoriya Korchina, Christie Kovar, Sandra Lee, Donna Muzny, Jeffrey G Reid, Yiming Zhu, Yuqi Chang, Qiang Feng, Xiaodong Fang, Xiaosen Guo, Min Jian, Hui Jiang, Xin Jin, Tianming Lan, Guoqing Li, Jingxiang Li, Yingrui Li, Shengmao Liu, Xiao Liu, Yao Lu, Xuedi Ma, Meifang Tang, Bo Wang, Guangbiao Wang, Honglong Wu, Renhua Wu, Xun Xu, Ye Yin, Dandan Zhang, Wenwei Zhang, Jiao Zhao, Meiru Zhao, Xiaole Zheng, Namrata Gupta, Neda Gharani, Lorraine H Toji, Norman P Gerry, Alissa M Resch, Jonathan Barker, Laura Clarke, Laurent Gil, Sarah E Hunt, Gavin Kelman, Eugene Kulesha, Rasko Leinonen, William M McLaren, Rajesh Radhakrishnan, Asier Roa, Dmitriy Smirnov, Richard E Smith, Ian Streeter, Anja Thormann, Iliana Toneva, Brendan Vaughan, Xiangqun Zheng-Bradley, Russell Grocock, Sean Humphray, Terena James, Zoya Kingsbury, Ralf Sudbrak, Marcus W Albrecht, Vyacheslav S Amstislavskiy, Tatiana A Borodina, Matthias Lienhard, Florian Mertes, Marc Sultan, Bernd Timmermann, Marie-Laure Yaspo, Lucinda Fulton, Robert Fulton, Victor Ananiev, Zinaida Belaia, Dimitriy Beloslyudtsev, Nathan Bouk, Chao Chen, Deanna Church, Robert Cohen, Charles Cook, John Garner, Timothy Hefferon, Mikhail Kimelman, Chunlei Liu, John Lopez, Peter Meric, Chris O'Sullivan, Yuri Ostapchuk, Lon Phan, Sergiy Ponomarov, Valerie Schneider, Eugene Shekhtman, Karl Sirotkin, Douglas Slotta, Hua Zhang, Senduran Balasubramaniam, John Burton, Petr Danecek, Thomas M Keane, Anja Kolb-Kokocinski, Shane McCarthy, James Stalker, Michael Quail, Christopher J Davies, Jeremy Gollub, Teresa Webster, Brant Wong, Yiping Zhan, Adam Auton, Christopher L Campbell, Yu Kong, Anthony Marcketta, Fuli Yu, Lilian Antunes, Matthew Bainbridge, Aniko Sabo, Zhuoyi Huang, Lachlan J M Coin, Lin Fang, Qibin Li, Zhenyu Li, Haoxiang Lin, Binghang Liu, Ruibang Luo, Haojing Shao, Yinlong Xie, Chen Ye, Chang Yu, Fan Zhang, Hancheng Zheng, Hongmei Zhu, Can Alkan, Elif Dal, Fatma Kahveci, Erik P Garrison, Deniz Kural, Wan-Ping Lee, Wen Fung Leong, Michael Stromberg, Alistair N Ward, Jiantao Wu, Mengyao Zhang, Mark J Daly, Mark A DePristo, Robert E Handsaker, Eric Banks, Gaurav Bhatia, Guillermo Del Angel, Giulio Genovese, Heng Li, Seva Kashin, Steven A McCarroll, James C Nemesh, Ryan E Poplin, Seungtai C Yoon, Jayon Lihm, Vladimir Makarov, Srikanth Gottipati, Alon Keinan, Juan L Rodriguez-Flores, Tobias Rausch, Markus H Fritz, Adrian M Stütz, Kathryn Beal, Avik Datta, Javier Herrero, Graham R S Ritchie, Daniel Zerbino, Pardis C Sabeti, Ilya Shlyakhter, Stephen F Schaffner, Joseph Vitti, David N Cooper, Edward V Ball, Peter D Stenson, Bret Barnes, Markus Bauer, R Keira Cheetham, Anthony Cox, Michael Eberle, Scott Kahn, Lisa Murray, John Peden, Richard Shaw, Eimear E Kenny, Mark A Batzer, Miriam K Konkel, Jerilyn A Walker, Daniel G MacArthur, Monkol Lek, Ralf Herwig, Li Ding, Daniel C Koboldt, David Larson, Kai Ye, Simon Gravel, Anand Swaroop, Emily Chew, Tuuli Lappalainen, Yaniv Erlich, Melissa Gymrek, Thomas Frederick Willems, Jared T Simpson, Mark D Shriver, Jeffrey A Rosenfeld, Carlos D Bustamante, Stephen B Montgomery, Francisco M De La Vega, Jake K Byrnes, Andrew W Carroll, Marianne K DeGorter, Phil Lacroute, Brian K Maples, Alicia R Martin, Andres Moreno-Estrada, Suyash S Shringarpure, Fouad Zakharia, Eran Halperin, Yael Baran, Eliza Cerveira, Jaeho Hwang, Ankit Malhotra, Dariusz Plewczynski, Kamen Radew, Mallory Romanovitch, Chengsheng Zhang, Fiona C L Hyland, David W Craig, Alexis Christoforides, Nils Homer, Tyler Izatt, Ahmet A Kurdoglu, Shripad A Sinari, Kevin Squire, Chunlin Xiao, Jonathan Sebat, Danny Antaki, Madhusudan Gujral, Amina Noor, Kenny Ye, Esteban G Burchard, Ryan D Hernandez, Christopher R Gignoux, David Haussler, Sol J Katzman, W James Kent, Bryan Howie, Andres Ruiz-Linares, Emmanouil T Dermitzakis, Scott E Devine, Hyun Min Kang, Jeffrey M Kidd, Tom Blackwell, Sean Caron, Wei Chen, Sarah Emery, Lars Fritsche, Christian Fuchsberger, Goo Jun, Bingshan Li, Robert Lyons, Chris Scheller, Carlo Sidore, Shiya Song, Elzbieta Sliwerska, Daniel Taliun, Adrian Tan, Ryan Welch, Mary Kate Wing, Xiaowei Zhan, Philip Awadalla, Alan Hodgkinson, Yun Li, Xinghua Shi, Andrew Quitadamo, Gerton Lunter, Jonathan L Marchini, Simon Myers, Claire Churchhouse, Olivier Delaneau, Anjali Gupta-Hinch, Warren Kretzschmar, Zamin Iqbal, Iain Mathieson, Androniki Menelaou, Andy Rimmer, Dionysia K Xifara, Taras K Oleksyk, Yunxin Fu, Xiaoming Liu, Momiao Xiong, Lynn Jorde, David Witherspoon, Jinchuan Xing, Brian L Browning, Sharon R Browning, Fereydoun Hormozdiari, Peter H Sudmant, Ekta Khurana, Chris Tyler-Smith, Cornelis A Albers, Qasim Ayub, Yuan Chen, Vincenza Colonna, Luke Jostins, Klaudia Walter, Yali Xue, Mark B Gerstein, Alexej Abyzov, Suganthi Balasubramanian, Jieming Chen, Declan Clarke, Yao Fu, Arif O Harmanci, Mike Jin, Donghoon Lee, Jeremy Liu, Xinmeng Jasmine Mu, Jing Zhang, Yan Zhang, Chris Hartl, Khalid Shakir, Jeremiah Degenhardt, Sascha Meiers, Benjamin Raeder, Francesco Paolo Casale, Oliver Stegle, Eric-Wubbo Lameijer, Ira Hall, Vineet Bafna, Jacob Michaelson, Eugene J Gardner, Ryan E Mills, Gargi Dayama, Ken Chen, Xian Fan, Zechen Chong, Tenghui Chen, Mark J Chaisson, John Huddleston, Maika Malig, Bradley J Nelson, Nicholas F Parrish, Ben Blackburne, Sarah J Lindsay, Zemin Ning, Yujun Zhang, Hugo Lam, Cristina Sisu, Danny Challis, Uday S Evani, James Lu, Uma Nagaswamy, Jin Yu, Wangshen Li, Lukas Habegger, Haiyuan Yu, Fiona Cunningham, Ian Dunham, Kasper Lage, Jakob Berg Jespersen, Heiko Horn, Donghoon Kim, Rob Desalle, Apurva Narechania, Melissa A Wilson Sayres, Fernando L Mendez, G David Poznik, Peter A Underhill, Lachlan Coin, David Mittelman, Ruby Banerjee, Maria Cerezo, Thomas W Fitzgerald, Sandra Louzada, Andrea Massaia, Graham R Ritchie, Fengtang Yang, Divya Kalra, Walker Hale, Xu Dan, Kathleen C Barnes, Christine Beiswanger, Hongyu Cai, Hongzhi Cao, Brenna Henn, Danielle Jones, Jane S Kaye, Alastair Kent, Angeliki Kerasidou, Rasika Mathias, Pilar N Ossorio, Michael Parker, Charles N Rotimi, Charmaine D Royal, Karla Sandoval, Yeyang Su, Zhongming Tian, Sarah Tishkoff, Marc Via, Yuhong Wang, Huanming Yang, Ling Yang, Jiayong Zhu, Walter Bodmer, Gabriel Bedoya, Zhiming Cai, Yang Gao, Jiayou Chu, Leena Peltonen, Andres Garcia-Montero, Alberto Orfao, Julie Dutil, Juan C Martinez-Cruzado, Rasika A Mathias, Anselm Hennis, Harold Watson, Colin McKenzie, Firdausi Qadri, Regina LaRocque, Xiaoyan Deng, Danny Asogun, Onikepe Folarin, Christian Happi, Omonwunmi Omoniwa, Matt Stremlau, Ridhi Tariyal, Muminatou Jallow, Fatoumatta Sisay Joof, Tumani Corrah, Kirk Rockett, Dominic Kwiatkowski, Jaspal Kooner, Trân T?nh Hiên, Sarah J Dunstan, Nguyen Thuy Hang, Richard Fonnie, Robert Garry, Lansana Kanneh, Lina Moses, John Schieffelin, Donald S Grant, Carla Gallo, Giovanni Poletti, Danish Saleheen, Asif Rasheed, Lisa D Brooks, Adam L Felsenfeld, Jean E McEwen, Yekaterina Vaydylevich, Audrey Duncanson, Michael Dunn, Jeffery A Schloss, 1000 Genomes Project Consortium, Institute for Medical Engineering and Science, Broad Institute of MIT and Harvard, Lincoln Laboratory, Massachusetts Institute of Technology. Department of Biology, Gabriel, Stacey, Lander, Eric Steven, Daly, Mark J, Banks, Eric, Bhatia, Gaurav, Kashin, Seva, McCarroll, Steven A, Nemesh, James, Poplin, Ryan E., Sabeti, Pardis, Shlyakhter, Ilya, Schaffner, Stephen F, Vitti, Joseph, Gymrek, Melissa A, Hartler, Christina M., and Tariyal, Ridhi

Subjects
demography, genetic association, genotype, Human genomics, Genome-wide association study, Review, SUSCEPTIBILITY, DISEASE, polymorphism, 0302 clinical medicine, quantitative trait locus, INDEL Mutation, genetics, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), MUTATION, Exome sequencing, 0303 health sciences, public health, Sequence analysis, High-Throughput Nucleotide Sequencing, standard, Genomics, Reference Standards, Physical Chromosome Mapping, 3. Good health, priority journal, Science & Technology - Other Topics, BAYES FACTORS, Molecular Developmental Biology, Genotype, Genetics, Medical, Quantitative Trait Loci, DNA sequence, rare disease, human genetics, information processing, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, POPULATION HISTORY, human genome, Humans, retroposon, Genetic variability, human, GENOME-WIDE ASSOCIATION, 1000 Genomes Project, Demography, Science & Technology, ancestry, disease predisposition, Genetic Variation, MACULAR DEGENERATION, major clinical study, gene linkage disequilibrium, purl.org/pe-repo/ocde/ford#3.01.02 [https], Genetics, Population, 030217 neurology & neurosurgery, haplotype, Internationality, VARIANT, Datasets as Topic, Human genetic variation, COMPLEMENT FACTOR-H, single nucleotide polymorphism, genetic variability, Exome, chromosome map, Genetics, Variant Call Format, Genome, Multidisciplinary, 1000 Genomes Project Consortium, international cooperation, Multidisciplinary Sciences, standards, Disease Susceptibility, medical genetics, General Science & Technology, Population, Computational biology, Biology, gene frequency, Polymorphism, Single Nucleotide, high throughput sequencing, Rare Diseases, promoter region, MD Multidisciplinary, Genetic variation, QH426, 030304 developmental biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Genome, Human, population genetics, population structure, Sequence Analysis, DNA, gene structure, INDIVIDUALS, Haplotypes, Genome-Wide Association Study, purl.org/pe-repo/ocde/ford#1.06.07 [https]
Abstract

The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies., Wellcome Trust (London, England) (Core Award 090532/Z/09/Z), Wellcome Trust (London, England) (Senior Investigator Award 095552/Z/11/Z ), Wellcome Trust (London, England) (WT095908), Wellcome Trust (London, England) (WT109497), Wellcome Trust (London, England) (WT098051), Wellcome Trust (London, England) (WT086084/Z/08/Z), Wellcome Trust (London, England) (WT100956/Z/13/Z ), Wellcome Trust (London, England) (WT097307), Wellcome Trust (London, England) (WT0855322/Z/08/Z ), Wellcome Trust (London, England) (WT090770/Z/09/Z ), Wellcome Trust (London, England) (Major Overseas program in Vietnam grant 089276/Z.09/Z), Medical Research Council (Great Britain) (grant G0801823), Biotechnology and Biological Sciences Research Council (Great Britain) (grant BB/I02593X/1), Biotechnology and Biological Sciences Research Council (Great Britain) (grant BB/I021213/1), Zhongguo ke xue ji shu qing bao yan jiu suo. Office of 863 Programme of China (2012AA02A201), National Basic Research Program of China (2011CB809201), National Basic Research Program of China (2011CB809202), National Basic Research Program of China (2011CB809203), National Natural Science Foundation of China (31161130357), Shenzhen Municipal Government of China (grant ZYC201105170397A), Canadian Institutes of Health Research (grant 136855), Quebec Ministry of Economic Development, Innovation, and Exports (PSR-SIIRI-195), Germany. Bundesministerium für Bildung und Forschung (0315428A), Germany. Bundesministerium für Bildung und Forschung (01GS08201), Germany. Bundesministerium für Bildung und Forschung (BMBF-EPITREAT grant 0316190A), Deutsche Forschungsgemeinschaft (Emmy Noether Grant KO4037/1-1), Beatriu de Pinos Program (2006 BP-A 10144), Beatriu de Pinos Program (2009 BP-B 00274), Spanish National Institute for Health (grant PRB2 IPT13/0001-ISCIII-SGEFI/FEDER), Japan Society for the Promotion of Science (fellowship number PE13075), Marie Curie Actions Career Integration (grant 303772), Fonds National Suisse del la Recherche, SNSF, Scientifique (31003A_130342), National Center for Biotechnology Information (U.S.) (U54HG3067), National Center for Biotechnology Information (U.S.) (U54HG3273), National Center for Biotechnology Information (U.S.) (U01HG5211), National Center for Biotechnology Information (U.S.) (U54HG3079), National Center for Biotechnology Information (U.S.) (R01HG2898), National Center for Biotechnology Information (U.S.) (R01HG2385), National Center for Biotechnology Information (U.S.) (RC2HG5552), National Center for Biotechnology Information (U.S.) (U01HG6513), National Center for Biotechnology Information (U.S.) (U01HG5214), National Center for Biotechnology Information (U.S.) (U01HG5715), National Center for Biotechnology Information (U.S.) (U01HG5718), National Center for Biotechnology Information (U.S.) (U01HG5728), National Center for Biotechnology Information (U.S.) (U41HG7635), National Center for Biotechnology Information (U.S.) (U41HG7497), National Center for Biotechnology Information (U.S.) (R01HG4960), National Center for Biotechnology Information (U.S.) (R01HG5701), National Center for Biotechnology Information (U.S.) (R01HG5214), National Center for Biotechnology Information (U.S.) (R01HG6855), National Center for Biotechnology Information (U.S.) (R01HG7068), National Center for Biotechnology Information (U.S.) (R01HG7644), National Center for Biotechnology Information (U.S.) (DP2OD6514), National Center for Biotechnology Information (U.S.) (DP5OD9154), National Center for Biotechnology Information (U.S.) (R01CA166661), National Center for Biotechnology Information (U.S.) (R01CA172652), National Center for Biotechnology Information (U.S.) (P01GM99568), National Center for Biotechnology Information (U.S.) (R01GM59290), National Center for Biotechnology Information (U.S.) (R01GM104390), National Center for Biotechnology Information (U.S.) (T32GM7790), National Center for Biotechnology Information (U.S.) (R01HL87699), National Center for Biotechnology Information (U.S.) (R01HL104608), National Center for Biotechnology Information (U.S.) (T32HL94284), National Center for Biotechnology Information (U.S.) (HHSN268201100040C), National Center for Biotechnology Information (U.S.) (HHSN272201000025C), Lundbeck Foundation (grant R170-2014-1039, Simons Foundation (SFARI award SF51), National Science Foundation (U.S.) (Research Fellowship DGE-1147470)

Published
2015
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3. Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol

Author

Leslie A. Lange, Youna Hu, He Zhang, Chenyi Xue, Ellen M. Schmidt, Zheng-Zheng Tang, Chris Bizon, Ethan M. Lange, Joshua D. Smith, Emily H. Turner, Goo Jun, Hyun Min Kang, Gina Peloso, Paul Auer, Kuo-ping Li, Jason Flannick, Ji Zhang, Christian Fuchsberger, Kyle Gaulton, Cecilia Lindgren, Adam Locke, Alisa Manning, Xueling Sim, Manuel A. Rivas, Oddgeir L. Holmen, Omri Gottesman, Yingchang Lu, Douglas Ruderfer, Eli A. Stahl, Qing Duan, Yun Li, Peter Durda, Shuo Jiao, Aaron Isaacs, Albert Hofman, Joshua C. Bis, Adolfo Correa, Michael E. Griswold, Johanna Jakobsdottir, Albert V. Smith, Pamela J. Schreiner, Mary F. Feitosa, Qunyuan Zhang, Jennifer E. Huffman, Jacy Crosby, Christina L. Wassel, Ron Do, Nora Franceschini, Lisa W. Martin, Jennifer G. Robinson, Themistocles L. Assimes, David R. Crosslin, Elisabeth A. Rosenthal, Michael Tsai, Mark J. Rieder, Deborah N. Farlow, Aaron R. Folsom, Thomas Lumley, Ervin R. Fox, Christopher S. Carlson, Ulrike Peters, Rebecca D. Jackson, Cornelia M. van Duijn, André G. Uitterlinden, Daniel Levy, Jerome I. Rotter, Herman A. Taylor, Vilmundur Gudnason, David S. Siscovick, Myriam Fornage, Ingrid B. Borecki, Caroline Hayward, Igor Rudan, Y. Eugene Chen, Erwin P. Bottinger, Ruth J.F. Loos, Pål Sætrom, Kristian Hveem, Michael Boehnke, Leif Groop, Mark McCarthy, Thomas Meitinger, Christie M. Ballantyne, Stacey B. Gabriel, Christopher J. O’Donnell, Wendy S. Post, Kari E. North, Alexander P. Reiner, Eric Boerwinkle, Bruce M. Psaty, David Altshuler, Sekar Kathiresan, Dan-Yu Lin, Gail P. Jarvik, L. Adrienne Cupples, Charles Kooperberg, James G. Wilson, Deborah A. Nickerson, Goncalo R. Abecasis, Stephen S. Rich, Russell P. Tracy, Cristen J. Willer, David M. Altshuler, Gonçalo R. Abecasis, Hooman Allayee, Sharon Cresci, Mark J. Daly, Paul I.W. de Bakker, Mark A. DePristo, Peter Donnelly, Tim Fennell, Kiran Garimella, Stanley L. Hazen, Daniel M. Jordan, Adam Kiezun, Guillaume Lettre, Bingshan Li, Mingyao Li, Christopher H. Newton-Cheh, Sandosh Padmanabhan, Sara Pulit, Daniel J. Rader, David Reich, Muredach P. Reilly, Steve Schwartz, Laura Scott, John A. Spertus, Nathaniel O. Stitziel, Nina Stoletzki, Shamil R. Sunyaev, Benjamin F. Voight, Ermeg Akylbekova, Larry D. Atwood, Maja Barbalic, R. Graham Barr, Emelia J. Benjamin, Joshua Bis, Donald W. Bowden, Jennifer Brody, Matthew Budoff, Greg Burke, Sarah Buxbaum, Jeff Carr, Donna T. Chen, Ida Y. Chen, Wei-Min Chen, Pat Concannon, Ralph D’Agostino, Anita L. DeStefano, Albert Dreisbach, Josée Dupuis, J. Peter Durda, Jaclyn Ellis, Caroline S. Fox, Ervin Fox, Vincent Funari, Santhi K. Ganesh, Julius Gardin, David Goff, Ora Gordon, Wayne Grody, Myron Gross, Xiuqing Guo, Ira M. Hall, Nancy L. Heard-Costa, Susan R. Heckbert, Nicholas Heintz, David M. Herrington, DeMarc Hickson, Jie Huang, Shih-Jen Hwang, David R. Jacobs, Nancy S. Jenny, Andrew D. Johnson, Craig W. Johnson, Steven Kawut, Richard Kronmal, Raluca Kurz, Martin G. Larson, Mark Lawson, Cora E. Lewis, Dalin Li, Honghuang Lin, Chunyu Liu, Jiankang Liu, Kiang Liu, Xiaoming Liu, Yongmei Liu, William T. Longstreth, Cay Loria, Kathryn Lunetta, Aaron J. Mackey, Rachel Mackey, Ani Manichaikul, Taylor Maxwell, Barbara McKnight, James B. Meigs, Alanna C. Morrison, Solomon K. Musani, Josyf C. Mychaleckyj, Jennifer A. Nettleton, Kari North, Daniel O’Leary, Frank Ong, Walter Palmas, James S. Pankow, Nathan D. Pankratz, Shom Paul, Marco Perez, Sharina D. Person, Joseph Polak, Aaron R. Quinlan, Leslie J. Raffel, Vasan S. Ramachandran, Kenneth Rice, Jill P. Sanders, Pamela Schreiner, Sudha Seshadri, Steve Shea, Stephen Sidney, Kevin Silverstein, Nicholas L. Smith, Nona Sotoodehnia, Asoke Srinivasan, Kent Taylor, Fridtjof Thomas, Michael Y. Tsai, Kelly A. Volcik, Chrstina L. Wassel, Karol Watson, Gina Wei, Wendy White, Kerri L. Wiggins, Jemma B. Wilk, O. Dale Williams, Gregory Wilson, Phillip Wolf, Neil A. Zakai, John Hardy, James F. Meschia, Michael Nalls, Andrew Singleton, Brad Worrall, Michael J. Bamshad, Kathleen C. Barnes, Ibrahim Abdulhamid, Frank Accurso, Ran Anbar, Terri Beaty, Abigail Bigham, Phillip Black, Eugene Bleecker, Kati Buckingham, Anne Marie Cairns, Daniel Caplan, Barbara Chatfield, Aaron Chidekel, Michael Cho, David C. Christiani, James D. Crapo, Julia Crouch, Denise Daley, Anthony Dang, Hong Dang, Alicia De Paula, Joan DeCelie-Germana, Allen DozorMitch Drumm, Maynard Dyson, Julia Emerson, Mary J. Emond, Thomas Ferkol, Robert Fink, Cassandra Foster, Deborah Froh, Li Gao, William Gershan, Ronald L. Gibson, Elizabeth Godwin, Magdalen Gondor, Hector Gutierrez, Nadia N. Hansel, Paul M. Hassoun, Peter Hiatt, John E. Hokanson, Michelle Howenstine, Laura K. Hummer, Jamshed Kanga, Yoonhee Kim, Michael R. Knowles, Michael Konstan, Thomas Lahiri, Nan Laird, Christoph Lange, Lin Lin, Xihong Lin, Tin L. Louie, David Lynch, Barry Make, Thomas R. Martin, Steve C. Mathai, Rasika A. Mathias, John McNamara, Sharon McNamara, Deborah Meyers, Susan Millard, Peter Mogayzel, Richard Moss, Tanda Murray, Dennis Nielson, Blakeslee Noyes, Wanda O’Neal, David Orenstein, Brian O’Sullivan, Rhonda Pace, Peter Pare, H. Worth Parker, Mary Ann Passero, Elizabeth Perkett, Adrienne Prestridge, Nicholas M. Rafaels, Bonnie Ramsey, Elizabeth Regan, Clement Ren, George Retsch-Bogart, Michael Rock, Antony Rosen, Margaret Rosenfeld, Ingo Ruczinski, Andrew Sanford, David Schaeffer, Cindy Sell, Daniel Sheehan, Edwin K. Silverman, Don Sin, Terry Spencer, Jackie Stonebraker, Holly K. Tabor, Laurie Varlotta, Candelaria I. Vergara, Robert Weiss, Fred Wigley, Robert A. Wise, Fred A. Wright, Mark M. Wurfel, Robert Zanni, Fei Zou, Phil Green, Jay Shendure, Joshua M. Akey, Carlos D. Bustamante, Evan E. Eichler, P. Keolu Fox, Wenqing Fu, Adam Gordon, Simon Gravel, Jill M. Johnsen, Mengyuan Kan, Eimear E. Kenny, Jeffrey M. Kidd, Fremiet Lara-Garduno, Suzanne M. Leal, Dajiang J. Liu, Sean McGee, Timothy D. O’Connor, Bryan Paeper, Peggy D. Robertson, Jeffrey C. Staples, Jacob A. Tennessen, Gao Wang, Qian Yi, Rebecca Jackson, Garnet Anderson, Hoda Anton-Culver, Paul L. Auer, Shirley Beresford, Henry Black, Robert Brunner, Robert Brzyski, Dale Burwen, Bette Caan, Cara L. Carty, Rowan Chlebowski, Steven Cummings, J. David Curb, Charles B. Eaton, Leslie Ford, Stephanie M. Fullerton, Margery Gass, Nancy Geller, Gerardo Heiss, Barbara V. Howard, Li Hsu, Carolyn M. Hutter, John Ioannidis, Karen C. Johnson, Lewis Kuller, Andrea LaCroix, Kamakshi Lakshminarayan, Dorothy Lane, Norman Lasser, Erin LeBlanc, Kuo-Ping Li, Marian Limacher, Benjamin A. Logsdon, Shari Ludlam, JoAnn E. Manson, Karen Margolis, Lisa Martin, Joan McGowan, Keri L. Monda, Jane Morley Kotchen, Lauren Nathan, Judith Ockene, Mary Jo O’Sullivan, Lawrence S. Phillips, Ross L. Prentice, John Robbins, Jacques E. Rossouw, Haleh Sangi-Haghpeykar, Gloria E. Sarto, Sally Shumaker, Michael S. Simon, Marcia L. Stefanick, Evan Stein, Hua Tang, Kira C. Taylor, Cynthia A. Thomson, Timothy A. Thornton, Linda Van Horn, Mara Vitolins, Jean Wactawski-Wende, Robert Wallace, Sylvia Wassertheil-Smoller, Donglin Zeng, Deborah Applebaum-Bowden, Michael Feolo, Weiniu Gan, Dina N. Paltoo, Phyliss Sholinsky, Anne Sturcke, Epidemiology, and Internal Medicine

Subjects
Male, Genome-wide association study, 030204 cardiovascular system & hematology, Cohort Studies, 0302 clinical medicine, Gene Frequency, Receptors, Genotype, Dyslipidemias/blood, Receptors, LDL/genetics, Genetics(clinical), Exome, Genetics (clinical), Exome sequencing, Genetics, 0303 health sciences, Serine Endopeptidases, Single Nucleotide, Middle Aged, 3. Good health, Cholesterol, Phenotype, Genetic Code, Cholesterol, LDL/genetics, Female, lipids (amino acids, peptides, and proteins), Proprotein Convertases, Proprotein Convertase 9, Sequence Analysis, Adult, Apolipoproteins E/blood, LDL/genetics, Serine Endopeptidases/genetics, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Apolipoproteins E, SDG 3 - Good Health and Well-being, Humans, Polymorphism, Allele frequency, 030304 developmental biology, Genetic association, Aged, Dyslipidemias, PCSK9, DNA, Cholesterol, LDL, Lipase, Sequence Analysis, DNA, Receptors, LDL, Lipase/genetics, Proprotein Convertases/genetics, Follow-Up Studies, Genome-Wide Association Study
Abstract

Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or

Published
2014

4. Correction: Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer

Author

Mia M. Gaudet, Tomas Kirchhoff, Todd Green, Joseph Vijai, Joshua M. Korn, Candace Guiducci, Ayellet V. Segrè, Kate McGee, Lesley McGuffog, Christiana Kartsonaki, Jonathan Morrison, Sue Healey, Olga M. Sinilnikova, Dominique Stoppa-Lyonnet, Sylvie Mazoyer, Marion Gauthier-Villars, Hagay Sobol, Michel Longy, Marc Frenay, GEMO Study Collaborators, Frans B. L. Hogervorst, Matti A. Rookus, J. Margriet Collée, Nicoline Hoogerbrugge, Kees E. P. van Roozendaal, HEBON Study Collaborators, Marion Piedmonte, Wendy Rubinstein, Stacy Nerenstone, Linda Van Le, Stephanie V. Blank, Trinidad Caldés, Miguel de la Hoya, Heli Nevanlinna, Kristiina Aittomäki, Conxi Lazaro, Ignacio Blanco, Adalgeir Arason, Oskar T. Johannsson, Rosa B. Barkardottir, Peter Devilee, Olofunmilayo I. Olopade, Susan L. Neuhausen, Xianshu Wang, Zachary S. Fredericksen, Paolo Peterlongo, Siranoush Manoukian, Monica Barile, Alessandra Viel, Paolo Radice, Catherine M. Phelan, Steven Narod, Gad Rennert, Flavio Lejbkowicz, Anath Flugelman, Irene L. Andrulis, Gord Glendon, Hilmi Ozcelik, OCGN, Amanda E. Toland, Marco Montagna, Emma D'Andrea, Eitan Friedman, Yael Laitman, Ake Borg, Mary Beattie, Susan J. Ramus, Susan M. Domchek, Katherine L. Nathanson, Tim Rebbeck, Amanda B. Spurdle, Xiaoqing Chen, Helene Holland, kConFab, Esther M. John, John L. Hopper, Saundra S. Buys, Mary B. Daly, Melissa C. Southey, Mary Beth Terry, Nadine Tung, Thomas V. Overeem Hansen, Finn C. Nielsen, Mark H. Greene, Phuong L. Mai, Ana Osorio, Mercedes Durán, Raquel Andres, Javier Benítez, Jeffrey N. Weitzel, Judy Garber, Ute Hamann, Susan Peock, Margaret Cook, Clare Oliver, Debra Frost, Radka Platte, D. Gareth Evans, Fiona Lalloo, Ros Eeles, Louise Izatt, Lisa Walker, Jacqueline Eason, Julian Barwell, Andrew K. Godwin, Rita K. Schmutzler, Barbara Wappenschmidt, Stefanie Engert, Norbert Arnold, Dorothea Gadzicki, Michael Dean, Bert Gold, Robert J. Klein, Fergus J. Couch, Georgia Chenevix-Trench, Douglas F. Easton, Mark J. Daly, Antonis C. Antoniou, David M. Altshuler, and Kenneth Offit

Subjects
Genetics, QH426-470
Published
2010

5. Common genetic variants and modification of penetrance of BRCA2-Associated breast cancer

Author

Mia M Gaudet, Tomas Kirchhoff, Todd Green, Joseph Vijai, Joshua M Korn, Candace Guiducci, Ayellet V Segrè, Kate McGee, Lesley McGuffog, Christiana Kartsonaki, Jonathan Morrison, Sue Healey, Olga M Sinilnikova, Dominique Stoppa-Lyonnet, Sylvie Mazoyer, Marion Gauthier-Villars, Hagay Sobol, Michel Longy, Marc Frenay, GEMO Study Collaborators, Frans B L Hogervorst, Matti A Rookus, J Margriet Collée, Nicoline Hoogerbrugge, Kees E P van Roozendaal, HEBON Study Collaborators, Marion Piedmonte, Wendy Rubinstein, Stacy Nerenstone, Linda Van Le, Stephanie V Blank, Trinidad Caldés, Miguel de la Hoya, Heli Nevanlinna, Kristiina Aittomäki, Conxi Lazaro, Ignacio Blanco, Adalgeir Arason, Oskar T Johannsson, Rosa B Barkardottir, Peter Devilee, Olofunmilayo I Olopade, Susan L Neuhausen, Xianshu Wang, Zachary S Fredericksen, Paolo Peterlongo, Siranoush Manoukian, Monica Barile, Alessandra Viel, Paolo Radice, Catherine M Phelan, Steven Narod, Gad Rennert, Flavio Lejbkowicz, Anath Flugelman, Irene L Andrulis, Gord Glendon, Hilmi Ozcelik, OCGN, Amanda E Toland, Marco Montagna, Emma D'Andrea, Eitan Friedman, Yael Laitman, Ake Borg, Mary Beattie, Susan J Ramus, Susan M Domchek, Katherine L Nathanson, Tim Rebbeck, Amanda B Spurdle, Xiaoqing Chen, Helene Holland, kConFab, Esther M John, John L Hopper, Saundra S Buys, Mary B Daly, Melissa C Southey, Mary Beth Terry, Nadine Tung, Thomas V Overeem Hansen, Finn C Nielsen, Mark H Greene, Phuong L Mai, Ana Osorio, Mercedes Durán, Raquel Andres, Javier Benítez, Jeffrey N Weitzel, Judy Garber, Ute Hamann, EMBRACE, Susan Peock, Margaret Cook, Clare Oliver, Debra Frost, Radka Platte, D Gareth Evans, Fiona Lalloo, Ros Eeles, Louise Izatt, Lisa Walker, Jacqueline Eason, Julian Barwell, Andrew K Godwin, Rita K Schmutzler, Barbara Wappenschmidt, Stefanie Engert, Norbert Arnold, Dorothea Gadzicki, Michael Dean, Bert Gold, Robert J Klein, Fergus J Couch, Georgia Chenevix-Trench, Douglas F Easton, Mark J Daly, Antonis C Antoniou, David M Altshuler, Kenneth Offit, Broad Institute of MIT and Harvard, Korn, Joshua Marc, Korn, Joshua M., Green, Todd, Guiducci, Candace, Segre, Ayellet V., Daly, Mark J., Altshuler, David, Clinical Genetics, Internal Medicine, Pediatric Surgery, Department of Obstetrics and Gynecology, Department of Medical and Clinical Genetics, Genome-Scale Biology (GSB) Research Program, Human genetics, EMGO - Quality of care, MUMC+: DA KG Lab Centraal Lab (9), Klinische Genetica, Genetica & Celbiologie, RS: GROW - School for Oncology and Reproduction, and Universitat de Barcelona

Subjects
Cancer Research, Linkage disequilibrium, Chromosomes, Human, Pair 20, Genome-wide association study, Penetrance, RECURRENT BRCA1, 312 Clinical medicine, QH426-470, PHENOTYPE, Linkage Disequilibrium, 0302 clinical medicine, Breast cancer, Gene Frequency, Risk Factors, BRCA2 MUTATION CARRIERS, POPULATION, Genetics (clinical), Genetics and Genomics/Genetics of Disease, RISK, Genetics, Genetics and Genomics/Medical Genetics, 0303 health sciences, Genetics and Genomics/Functional Genomics, ASSOCIATION, Middle Aged, 3. Good health, DNA-Binding Proteins, Genetics and Genomics/Gene Function, SUSCEPTIBILITY GENES, 030220 oncology & carcinogenesis, Female, Genetics and Genomics/Gene Discovery, Research Article, Adult, Heterozygote, education, BRCA2 MUTATION CARRIERS, SUSCEPTIBILITY GENES, RECURRENT BRCA1, RISK, POPULATION, MODEL, PREDISPOSITION, ASSOCIATION, PHENOTYPE, FREQUENCY, Single-nucleotide polymorphism, Breast Neoplasms, Biology, FREQUENCY, Polymorphism, Single Nucleotide, White People, Càncer de mama, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, Humans, Genetic Predisposition to Disease, Receptor, Fibroblast Growth Factor, Type 2, Genetics and Genomics/Genomics, Molecular Biology, Allele frequency, Genetics and Genomics/Cancer Genetics, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, BRCA2 Protein, brca2 mutation carriers susceptibility genes recurrent brca1 risk population model predisposition association phenotype frequency, Chromosomes, Human, Pair 10, Haplotype, Genetics and Genomics, medicine.disease, PREDISPOSITION, MODEL, Minor allele frequency, Haplotypes, Cancer and Oncology, Mutation, Genome-Wide Association Study, Transcription Factors
Abstract

The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors.1 To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (, National Breast Cancer Foundation (U.S.), Starr Cancer Consortium, National Institutes of Health (U.S.) (NCI: P20CA103694-3 ), Lymphoma Foundation

Published
2010
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