718 results on '"Eric S. Lander"'
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2. Prioritizing disease and trait causal variants at the TNFAIP3 locus using functional and genomic features
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John P. Ray, Carl G. de Boer, Charles P. Fulco, Caleb A. Lareau, Masahiro Kanai, Jacob C. Ulirsch, Ryan Tewhey, Leif S. Ludwig, Steven K. Reilly, Drew T. Bergman, Jesse M. Engreitz, Robbyn Issner, Hilary K. Finucane, Eric S. Lander, Aviv Regev, and Nir Hacohen
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Science - Abstract
While genome-wide association studies have yielded thousands of trait-associated loci, identifying causal variants remains challenging. Here, the authors perform seven genomics assays in various cell types to prioritize genetic variants in the TNFAIP3 locus, and report high-priority variants within disease-associated haplotypes.
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- 2020
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3. Gain-of-Function Claims for Type-2-Diabetes-Associated Coding Variants in SLC16A11 Are Not Supported by the Experimental Data
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Eitan Hoch, Jose C. Florez, Eric S. Lander, and Suzanne B.R. Jacobs
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Biology (General) ,QH301-705.5 - Abstract
Summary: Human genetic variants in SLC16A11 are associated with increased risk of type 2 diabetes (T2D). We previously identified two distinct mechanisms through which co-inherited T2D-risk coding and non-coding variants disrupt SLC16A11 expression and activity, thus implicating reduced SLC16A11 function as the disease-relevant direction of effect. In a recent publication, Zhao et al. (2019a) argue that human SLC16A11 coding variants confer gain of function, basing their conclusions on phenotypic changes observed following overexpression of mutant murine Slc16a11. However, data necessary to demonstrate gain-of-function activity are not reported. Furthermore, several fundamental flaws in their experimental system—including inaccurate modeling of the human variant haplotype and expression conditions that are not physiologically relevant—prevent conclusions about T2D-risk variant effects on human physiology. This Matters Arising paper is in response to Zhao et al. (2019a), published in Cell Reports. See also the response by Zhao et al. (2019b) in this issue of Cell Reports. : Hoch et al. discuss the analysis of coding variants of SLC16A11 in mice and humans in light of a recent Cell Reports publication. This Matters Arising paper is in response to Zhao et al. (2019a), published in Cell Reports. See also the response by Zhao et al. (2019b), published in this issue. Keywords: SLC16A11, type 2 diabetes, T2D
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- 2019
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4. Deep-coverage whole genome sequences and blood lipids among 16,324 individuals
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Pradeep Natarajan, Gina M. Peloso, Seyedeh Maryam Zekavat, May Montasser, Andrea Ganna, Mark Chaffin, Amit V. Khera, Wei Zhou, Jonathan M. Bloom, Jesse M. Engreitz, Jason Ernst, Jeffrey R. O’Connell, Sanni E. Ruotsalainen, Maris Alver, Ani Manichaikul, W. Craig Johnson, James A. Perry, Timothy Poterba, Cotton Seed, Ida L. Surakka, Tonu Esko, Samuli Ripatti, Veikko Salomaa, Adolfo Correa, Ramachandran S. Vasan, Manolis Kellis, Benjamin M. Neale, Eric S. Lander, Goncalo Abecasis, Braxton Mitchell, Stephen S. Rich, James G. Wilson, L. Adrienne Cupples, Jerome I. Rotter, Cristen J. Willer, Sekar Kathiresan, and NHLBI TOPMed Lipids Working Group
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Science - Abstract
Common genetic variants associated with plasma lipids have been extensively studied for a better understanding of common diseases. Here, the authors use whole-genome sequencing of 16,324 individuals to analyze rare variant associations and to determine their monogenic and polygenic contribution to lipid traits.
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- 2018
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5. A novel Ruminococcus gnavus clade enriched in inflammatory bowel disease patients
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Andrew Brantley Hall, Moran Yassour, Jenny Sauk, Ashley Garner, Xiaofang Jiang, Timothy Arthur, Georgia K. Lagoudas, Tommi Vatanen, Nadine Fornelos, Robin Wilson, Madeline Bertha, Melissa Cohen, John Garber, Hamed Khalili, Dirk Gevers, Ashwin N. Ananthakrishnan, Subra Kugathasan, Eric S. Lander, Paul Blainey, Hera Vlamakis, Ramnik J. Xavier, and Curtis Huttenhower
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Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract that is associated with changes in the gut microbiome. Here, we sought to identify strain-specific functional correlates with IBD outcomes. Methods We performed metagenomic sequencing of monthly stool samples from 20 IBD patients and 12 controls (266 total samples). These were taxonomically profiled with MetaPhlAn2 and functionally profiled using HUMAnN2. Differentially abundant species were identified using MaAsLin and strain-specific pangenome haplotypes were analyzed using PanPhlAn. Results We found a significantly higher abundance in patients of facultative anaerobes that can tolerate the increased oxidative stress of the IBD gut. We also detected dramatic, yet transient, blooms of Ruminococcus gnavus in IBD patients, often co-occurring with increased disease activity. We identified two distinct clades of R. gnavus strains, one of which is enriched in IBD patients. To study functional differences between these two clades, we augmented the R. gnavus pangenome by sequencing nine isolates from IBD patients. We identified 199 IBD-specific, strain-specific genes involved in oxidative stress responses, adhesion, iron-acquisition, and mucus utilization, potentially conferring an adaptive advantage for this R. gnavus clade in the IBD gut. Conclusions This study adds further evidence to the hypothesis that increased oxidative stress may be a major factor shaping the dysbiosis of the microbiome observed in IBD and suggests that R. gnavus may be an important member of the altered gut community in IBD.
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- 2017
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6. Genomic Correlates of Immune-Cell Infiltrates in Colorectal Carcinoma
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Marios Giannakis, Xinmeng Jasmine Mu, Sachet A. Shukla, Zhi Rong Qian, Ofir Cohen, Reiko Nishihara, Samira Bahl, Yin Cao, Ali Amin-Mansour, Mai Yamauchi, Yasutaka Sukawa, Chip Stewart, Mara Rosenberg, Kosuke Mima, Kentaro Inamura, Katsuhiko Nosho, Jonathan A. Nowak, Michael S. Lawrence, Edward L. Giovannucci, Andrew T. Chan, Kimmie Ng, Jeffrey A. Meyerhardt, Eliezer M. Van Allen, Gad Getz, Stacey B. Gabriel, Eric S. Lander, Catherine J. Wu, Charles S. Fuchs, Shuji Ogino, and Levi A. Garraway
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Biology (General) ,QH301-705.5 - Abstract
Large-scale genomic characterization of tumors from prospective cohort studies may yield new insights into cancer pathogenesis. We performed whole-exome sequencing of 619 incident colorectal cancers (CRCs) and integrated the results with tumor immunity, pathology, and survival data. We identified recurrently mutated genes in CRC, such as BCL9L, RBM10, CTCF, and KLF5, that were not previously appreciated in this disease. Furthermore, we investigated the genomic correlates of immune-cell infiltration and found that higher neoantigen load was positively associated with overall lymphocytic infiltration, tumor-infiltrating lymphocytes (TILs), memory T cells, and CRC-specific survival. The association with TILs was evident even within microsatellite-stable tumors. We also found positive selection of mutations in HLA genes and other components of the antigen-processing machinery in TIL-rich tumors. These results may inform immunotherapeutic approaches in CRC. More generally, this study demonstrates a framework for future integrative molecular epidemiology research in colorectal and other malignancies.
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- 2016
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7. Perturbation of m6A Writers Reveals Two Distinct Classes of mRNA Methylation at Internal and 5′ Sites
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Schraga Schwartz, Maxwell R. Mumbach, Marko Jovanovic, Tim Wang, Karolina Maciag, G. Guy Bushkin, Philipp Mertins, Dmitry Ter-Ovanesyan, Naomi Habib, Davide Cacchiarelli, Neville E. Sanjana, Elizaveta Freinkman, Michael E. Pacold, Rahul Satija, Tarjei S. Mikkelsen, Nir Hacohen, Feng Zhang, Steven A. Carr, Eric S. Lander, and Aviv Regev
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Biology (General) ,QH301-705.5 - Abstract
N6-methyladenosine (m6A) is a common modification of mRNA with potential roles in fine-tuning the RNA life cycle. Here, we identify a dense network of proteins interacting with METTL3, a component of the methyltransferase complex, and show that three of them (WTAP, METTL14, and KIAA1429) are required for methylation. Monitoring m6A levels upon WTAP depletion allowed the definition of accurate and near single-nucleotide resolution methylation maps and their classification into WTAP-dependent and -independent sites. WTAP-dependent sites are located at internal positions in transcripts, topologically static across a variety of systems we surveyed, and inversely correlated with mRNA stability, consistent with a role in establishing “basal” degradation rates. WTAP-independent sites form at the first transcribed base as part of the cap structure and are present at thousands of sites, forming a previously unappreciated layer of transcriptome complexity. Our data shed light on the proteomic and transcriptional underpinnings of this RNA modification.
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- 2014
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8. Neurocognitive trajectory and proteomic signature of inherited risk for Alzheimer's disease.
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Manish D Paranjpe, Mark Chaffin, Sohail Zahid, Scott Ritchie, Jerome I Rotter, Stephen S Rich, Robert Gerszten, Xiuqing Guo, Susan Heckbert, Russ Tracy, John Danesh, Eric S Lander, Michael Inouye, Sekar Kathiresan, Adam S Butterworth, and Amit V Khera
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Genetics ,QH426-470 - Abstract
For Alzheimer's disease-a leading cause of dementia and global morbidity-improved identification of presymptomatic high-risk individuals and identification of new circulating biomarkers are key public health needs. Here, we tested the hypothesis that a polygenic predictor of risk for Alzheimer's disease would identify a subset of the population with increased risk of clinically diagnosed dementia, subclinical neurocognitive dysfunction, and a differing circulating proteomic profile. Using summary association statistics from a recent genome-wide association study, we first developed a polygenic predictor of Alzheimer's disease comprised of 7.1 million common DNA variants. We noted a 7.3-fold (95% CI 4.8 to 11.0; p < 0.001) gradient in risk across deciles of the score among 288,289 middle-aged participants of the UK Biobank study. In cross-sectional analyses stratified by age, minimal differences in risk of Alzheimer's disease and performance on a digit recall test were present according to polygenic score decile at age 50 years, but significant gradients emerged by age 65. Similarly, among 30,541 participants of the Mass General Brigham Biobank, we again noted no significant differences in Alzheimer's disease diagnosis at younger ages across deciles of the score, but for those over 65 years we noted an odds ratio of 2.0 (95% CI 1.3 to 3.2; p = 0.002) in the top versus bottom decile of the polygenic score. To understand the proteomic signature of inherited risk, we performed aptamer-based profiling in 636 blood donors (mean age 43 years) with very high or low polygenic scores. In addition to the well-known apolipoprotein E biomarker, this analysis identified 27 additional proteins, several of which have known roles related to disease pathogenesis. Differences in protein concentrations were consistent even among the youngest subset of blood donors (mean age 33 years). Of these 28 proteins, 7 of the 8 proteins with concentrations available were similarly associated with the polygenic score in participants of the Multi-Ethnic Study of Atherosclerosis. These data highlight the potential for a DNA-based score to identify high-risk individuals during the prolonged presymptomatic phase of Alzheimer's disease and to enable biomarker discovery based on profiling of young individuals in the extremes of the score distribution.
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- 2022
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9. A structural variation reference for medical and population genetics.
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Ryan L. Collins, Harrison Brand, Konrad J. Karczewski, Xuefang Zhao, Jessica Alföldi, Laurent C. Francioli, Amit V. Khera, Chelsea Lowther, Laura D. Gauthier, Harold Wang, Nicholas A. Watts, Matthew Solomonson, Alexander Baumann, Ruchi Munshi, Mark Walker, Christopher W. Whelan, Yongqing Huang, Ted Brookings, Ted Sharpe, Matthew R. Stone, Elise Valkanas, Jack Fu, Grace Tiao, Kristen M. Laricchia, Valentín Ruano-Rubio, Christine Stevens, Namrata Gupta, Caroline Cusick, Lauren Margolin, Irina M. Armean, Eric Banks, Louis Bergelson, Kristian Cibulskis, Kristen M. Connolly, Miguel Covarrubias, Beryl B. Cummings, Mark J. Daly, Stacey Donnelly, Yossi Farjoun, Steven Ferriera, Stacey Gabriel, Jeff Gentry, Thibault Jeandet, Diane Kaplan, Christopher Llanwarne, Eric V. Minikel, Benjamin M. Neale, Sam Novod, Anne H. O'Donnell-Luria, Nikelle Petrillo, Timothy Poterba, David Roazen, Andrea Saltzman, Kaitlin E. Samocha, Molly Schleicher, Cotton Seed, José Soto, Kathleen Tibbetts, Charlotte Tolonen, Christopher Vittal, Gordon Wade, Arcturus Wang, Qingbo Wang, James S. Ware, Ben Weisburd, Nicola Whiffin, Carlos A. Aguilar Salinas, Tariq Ahmad 0003, Christine M. Albert, Diego Ardissino, Gil Atzmon, John Barnard, Laurent Beaugerie, Emelia J. Benjamin, Michael Boehnke, Lori L. Bonnycastle, Erwin P. Bottinger, Donald W. Bowden, Matthew J. Bown, John C. Chambers, Juliana C. Chan, Daniel Chasman, Judy Cho, Mina K. Chung, Bruce Cohen, Adolfo Correa, Dana Dabelea, Dawood Darbar, Ravindranath Duggirala, Josée Dupuis, Patrick T. Ellinor, Roberto Elosua, Jeanette Erdmann, Tõnu Esko, Martti Färkkilä, Jose Florez, Andre Franke, Gad Getz, Benjamin Glaser, Stephen J. Glatt, David Goldstein, Clicerio Gonzalez, Leif Groop, Christopher A. Haiman, Craig Hanis, Matthew Harms, Mikko Hiltunen, Matti M. Holi, Christina M. Hultman, Mikko Kallela, Jaakko Kaprio, Sekar Kathiresan, Bong-Jo Kim, Young Jin Kim, George Kirov, Jaspal Kooner, Seppo Koskinen, Harlan M. Krumholz, Subra Kugathasan, Soo Heon Kwak, Markku Laakso, Terho Lehtimäki, Ruth J. F. Loos, Steven A. Lubitz, Ronald C. W. Ma, Daniel G. MacArthur, Jaume Marrugat, Kari M. Mattila, Steven A. McCarroll, Mark I. McCarthy, Dermot McGovern, Ruth McPherson, James B. Meigs, Olle Melander, Andres Metspalu, Peter M. Nilsson, Michael C. O'Donovan, Dost öngür, Lorena Orozco, Michael J. Owen, Colin N. A. Palmer, Aarno Palotie, Kyong Soo Park, Carlos Pato, Ann E. Pulver, Nazneen Rahman, Anne M. Remes, John D. Rioux, Samuli Ripatti, Dan M. Roden, Danish Saleheen, Veikko Salomaa, Nilesh J. Samani, Jeremiah Scharf, Heribert Schunkert, Moore B. Shoemaker, Pamela Sklar, Hilkka Soininen, Harry Sokol, Tim Spector, Patrick F. Sullivan, Jaana Suvisaari, E. Shyong Tai, Yik Ying Teo, Tuomi Tiinamaija, Ming Tsuang, Dan Turner, Teresa Tusie-Luna, Erkki Vartiainen, Hugh Watkins, Rinse K. Weersma, Maija Wessman, James G. Wilson, Ramnik J. Xavier, Kent D. Taylor, Henry J. Lin, Stephen S. Rich, Wendy S. Post, Yii-Der Ida Chen, Jerome I. Rotter, Chad Nusbaum, Anthony A. Philippakis, Eric S. Lander, and Michael E. Talkowski
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- 2020
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10. Supp. Table S22 from Genetic Mechanisms of Immune Evasion in Colorectal Cancer
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Ulrike Peters, Shuji Ogino, Antoni Ribas, Charles S. Fuchs, Thomas J. Hudson, Levi A. Garraway, Eric S. Lander, Stacey B. Gabriel, Jesse M. Zaretsky, Syed H. Zaidi, Ming Yu, Catherine J. Wu, David A. Wheeler, Alexander Upfill-Brown, Jennifer Tsoi, Wei Sun, Janet L. Stanford, Sachet Shukla, Brian Shirts, Eve Shinbrot, Daniel Sanghoon Shin, Stephen J. Salipante, Ben J. Raphael, Elleanor H. Quist, Cristina Puig-Saus, Colin C. Pritchard, Matteo Pellegrini, Brian B. Nadel, Dennis J. Montoya, Mark D.M. Leiserson, Paige Krystofinski, Yeon Joo Kim, Jeroen R. Huyghe, Siwen Hu-Lieskovan, Li Hsu, William M. Grady, Milan S. Geybels, Helena Escuin-Ordinas, Charles Connolly, Gabriel Abril-Rodriguez, Katsuhiko Nosho, Teppei Morikawa, Kentaro Inamura, Zhi Rong Qian, Reiko Nishihara, Jonathan A. Nowak, Michael Quist, Xinmeng Jasmine Mu, Tsuyoshi Hamada, Daniel K. Wells, Marios Giannakis, and Catherine S. Grasso
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Supplementary Table S22: Segmented b-allele deficits
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- 2023
11. Supplementary Table 4 from Activating mTOR Mutations in a Patient with an Extraordinary Response on a Phase I Trial of Everolimus and Pazopanib
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Jonathan E. Rosenberg, Levi A. Garraway, Philip W. Kantoff, Stacey B. Gabriel, Eric S. Lander, David M. Sabatini, Geoffrey I. Shapiro, Massimo Loda, Sabina Signoretti, Edward C. Stack, Mary Ellen Taplin, Aymen A. Elfiky, James M. Cleary, Leena Gandhi, Toni K. Choueiri, Michelle Stewart, Jeffrey G. Supko, Susanna Jacobus, Eran Hodis, Eliezer M. Van Allen, Brian C. Grabiner, and Nikhil Wagle
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XLSX file 451K, Somatic mutations identified by whole exome sequencing
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- 2023
12. Supp. Tables S16-S19 from Genetic Mechanisms of Immune Evasion in Colorectal Cancer
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Ulrike Peters, Shuji Ogino, Antoni Ribas, Charles S. Fuchs, Thomas J. Hudson, Levi A. Garraway, Eric S. Lander, Stacey B. Gabriel, Jesse M. Zaretsky, Syed H. Zaidi, Ming Yu, Catherine J. Wu, David A. Wheeler, Alexander Upfill-Brown, Jennifer Tsoi, Wei Sun, Janet L. Stanford, Sachet Shukla, Brian Shirts, Eve Shinbrot, Daniel Sanghoon Shin, Stephen J. Salipante, Ben J. Raphael, Elleanor H. Quist, Cristina Puig-Saus, Colin C. Pritchard, Matteo Pellegrini, Brian B. Nadel, Dennis J. Montoya, Mark D.M. Leiserson, Paige Krystofinski, Yeon Joo Kim, Jeroen R. Huyghe, Siwen Hu-Lieskovan, Li Hsu, William M. Grady, Milan S. Geybels, Helena Escuin-Ordinas, Charles Connolly, Gabriel Abril-Rodriguez, Katsuhiko Nosho, Teppei Morikawa, Kentaro Inamura, Zhi Rong Qian, Reiko Nishihara, Jonathan A. Nowak, Michael Quist, Xinmeng Jasmine Mu, Tsuyoshi Hamada, Daniel K. Wells, Marios Giannakis, and Catherine S. Grasso
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Supplementary Tables S16-S19, describing IHC results on NHS/HPFS data
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- 2023
13. Supplementary Table S3 from Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets
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William C. Hahn, Gad Getz, David N. Louis, José Baselga, Tracy T. Batchelor, Rameen Beroukhim, Eric S. Lander, Stacey Gabriel, Levi Garraway, Matthew Meyerson, Anat Stemmer-Rachamimov, Eric P. Winer, Nancy U. Lin, Michael S. Rabin, Carrie Sougnez, Sabina Signoretti, Toni K. Choueiri, Mai P. Hoang, Bruce E. Johnson, Aaron R. Thorner, Paul Van Hummelen, Corey M. Gill, Frederick G. Barker, Mara Rosenberg, Aaron Chevalier, Aaron McKenna, Sung-Hye Park, Sun Ha Paek, Ian F. Dunn, William T. Curry, Elena Martinez-Saez, Joan Seoane, Josep Tabernero, Keith L. Ligon, Kristian Cibulskis, Peleg M. Horowitz, Michael S. Lawrence, Eliezer M. Van Allen, Robert T. Jones, Amaro Taylor-Weiner, Daniel P. Cahill, Sandro Santagata, Scott L. Carter, and Priscilla K. Brastianos
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Summary of clinically informative (TARGET) genes.
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- 2023
14. Supplementary Methods, Figures S1 - S20 from Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets
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William C. Hahn, Gad Getz, David N. Louis, José Baselga, Tracy T. Batchelor, Rameen Beroukhim, Eric S. Lander, Stacey Gabriel, Levi Garraway, Matthew Meyerson, Anat Stemmer-Rachamimov, Eric P. Winer, Nancy U. Lin, Michael S. Rabin, Carrie Sougnez, Sabina Signoretti, Toni K. Choueiri, Mai P. Hoang, Bruce E. Johnson, Aaron R. Thorner, Paul Van Hummelen, Corey M. Gill, Frederick G. Barker, Mara Rosenberg, Aaron Chevalier, Aaron McKenna, Sung-Hye Park, Sun Ha Paek, Ian F. Dunn, William T. Curry, Elena Martinez-Saez, Joan Seoane, Josep Tabernero, Keith L. Ligon, Kristian Cibulskis, Peleg M. Horowitz, Michael S. Lawrence, Eliezer M. Van Allen, Robert T. Jones, Amaro Taylor-Weiner, Daniel P. Cahill, Sandro Santagata, Scott L. Carter, and Priscilla K. Brastianos
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Supplementary Methods, Figures S1 - S20. Figure S1. Branched evolution leads to tissue-sampling bias in primary tumor samples. Figure S2. Results of ABSOLUTE on samples from patient 418. Figure S3. 2D Bayesian clustering analysis of point-mutation CCF distributions in case 418. Figure S4. Bayesian clustering of private point-mutation CCF distributions in all sequenced tissue samples from case 418. Figure S5. Genetic alterations supporting phylogeny construction in case 418. Figure S6. Phylogenetic tree for case 418 Figure S7. Evolutionary relationships between primary tumor-samples and brain metastasis samples Figure S8. Detection of homozygous deletion in CDKN2A in the brain metastasis of case 24. Figure S9. Amplification of FGFR1 and MYC detected in the brain metastasis of case 331. Figure S10. Additional alterations under investigation for association with various targeted therapies. Figure S11. Power for paired-detection of somatic mutations. Figure S12. Amplification of CCNE1 detected in the brain metastasis of case 314. Figure S13. Amplification of EGFR detected in the brain metastasis of case 314. Figure S14. Amplification of MYC detected in the brain metastasis of case 308. Figure S15. Amplification of MYC detected in the brain metastasis of case 138. Figure S16. Amplifications of CDK6 and MET detected in the brain metastasis of case 138. Figure S17. Amplifications of CCNE1 and AKT2 detected in the brain metastasis of case 138. Figure S18. Amplification of EGFR detected in a regional lymph node from case 296. Figure S19. Power for somatic mutation detection in 86 matched primary-tumor and brain-metastasis samples. Figure S20. Calling of amplifications in primary-tumor samples and paired brain metastases.
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- 2023
15. Supplementary File 1 from Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets
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William C. Hahn, Gad Getz, David N. Louis, José Baselga, Tracy T. Batchelor, Rameen Beroukhim, Eric S. Lander, Stacey Gabriel, Levi Garraway, Matthew Meyerson, Anat Stemmer-Rachamimov, Eric P. Winer, Nancy U. Lin, Michael S. Rabin, Carrie Sougnez, Sabina Signoretti, Toni K. Choueiri, Mai P. Hoang, Bruce E. Johnson, Aaron R. Thorner, Paul Van Hummelen, Corey M. Gill, Frederick G. Barker, Mara Rosenberg, Aaron Chevalier, Aaron McKenna, Sung-Hye Park, Sun Ha Paek, Ian F. Dunn, William T. Curry, Elena Martinez-Saez, Joan Seoane, Josep Tabernero, Keith L. Ligon, Kristian Cibulskis, Peleg M. Horowitz, Michael S. Lawrence, Eliezer M. Van Allen, Robert T. Jones, Amaro Taylor-Weiner, Daniel P. Cahill, Sandro Santagata, Scott L. Carter, and Priscilla K. Brastianos
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Supplementary File 1. Power for detection of somatic point mutations in coding exons of TARGET genes. The description for the plots in Supplementary File 1 can be found in the Legend of Supplementary Figure S1.
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- 2023
16. Data Supplement from Activating mTOR Mutations in a Patient with an Extraordinary Response on a Phase I Trial of Everolimus and Pazopanib
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Jonathan E. Rosenberg, Levi A. Garraway, Philip W. Kantoff, Stacey B. Gabriel, Eric S. Lander, David M. Sabatini, Geoffrey I. Shapiro, Massimo Loda, Sabina Signoretti, Edward C. Stack, Mary Ellen Taplin, Aymen A. Elfiky, James M. Cleary, Leena Gandhi, Toni K. Choueiri, Michelle Stewart, Jeffrey G. Supko, Susanna Jacobus, Eran Hodis, Eliezer M. Van Allen, Brian C. Grabiner, and Nikhil Wagle
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PDF file 196K, The Data Supplement contains Supplementary Tables 1-3, which provide additional detail about the clinical trial as well as Supplementary Methods and References
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- 2023
17. Supp. Tables S1, S3-S15, S20, and S23 from Genetic Mechanisms of Immune Evasion in Colorectal Cancer
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Ulrike Peters, Shuji Ogino, Antoni Ribas, Charles S. Fuchs, Thomas J. Hudson, Levi A. Garraway, Eric S. Lander, Stacey B. Gabriel, Jesse M. Zaretsky, Syed H. Zaidi, Ming Yu, Catherine J. Wu, David A. Wheeler, Alexander Upfill-Brown, Jennifer Tsoi, Wei Sun, Janet L. Stanford, Sachet Shukla, Brian Shirts, Eve Shinbrot, Daniel Sanghoon Shin, Stephen J. Salipante, Ben J. Raphael, Elleanor H. Quist, Cristina Puig-Saus, Colin C. Pritchard, Matteo Pellegrini, Brian B. Nadel, Dennis J. Montoya, Mark D.M. Leiserson, Paige Krystofinski, Yeon Joo Kim, Jeroen R. Huyghe, Siwen Hu-Lieskovan, Li Hsu, William M. Grady, Milan S. Geybels, Helena Escuin-Ordinas, Charles Connolly, Gabriel Abril-Rodriguez, Katsuhiko Nosho, Teppei Morikawa, Kentaro Inamura, Zhi Rong Qian, Reiko Nishihara, Jonathan A. Nowak, Michael Quist, Xinmeng Jasmine Mu, Tsuyoshi Hamada, Daniel K. Wells, Marios Giannakis, and Catherine S. Grasso
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Supplementary Tables S1, S3 through S15, S20, and S23
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- 2023
18. Data from Genetic Mechanisms of Immune Evasion in Colorectal Cancer
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Ulrike Peters, Shuji Ogino, Antoni Ribas, Charles S. Fuchs, Thomas J. Hudson, Levi A. Garraway, Eric S. Lander, Stacey B. Gabriel, Jesse M. Zaretsky, Syed H. Zaidi, Ming Yu, Catherine J. Wu, David A. Wheeler, Alexander Upfill-Brown, Jennifer Tsoi, Wei Sun, Janet L. Stanford, Sachet Shukla, Brian Shirts, Eve Shinbrot, Daniel Sanghoon Shin, Stephen J. Salipante, Ben J. Raphael, Elleanor H. Quist, Cristina Puig-Saus, Colin C. Pritchard, Matteo Pellegrini, Brian B. Nadel, Dennis J. Montoya, Mark D.M. Leiserson, Paige Krystofinski, Yeon Joo Kim, Jeroen R. Huyghe, Siwen Hu-Lieskovan, Li Hsu, William M. Grady, Milan S. Geybels, Helena Escuin-Ordinas, Charles Connolly, Gabriel Abril-Rodriguez, Katsuhiko Nosho, Teppei Morikawa, Kentaro Inamura, Zhi Rong Qian, Reiko Nishihara, Jonathan A. Nowak, Michael Quist, Xinmeng Jasmine Mu, Tsuyoshi Hamada, Daniel K. Wells, Marios Giannakis, and Catherine S. Grasso
- Abstract
To understand the genetic drivers of immune recognition and evasion in colorectal cancer, we analyzed 1,211 colorectal cancer primary tumor samples, including 179 classified as microsatellite instability–high (MSI-high). This set includes The Cancer Genome Atlas colorectal cancer cohort of 592 samples, completed and analyzed here. MSI-high, a hypermutated, immunogenic subtype of colorectal cancer, had a high rate of significantly mutated genes in important immune-modulating pathways and in the antigen presentation machinery, including biallelic losses of B2M and HLA genes due to copy-number alterations and copy-neutral loss of heterozygosity. WNT/β-catenin signaling genes were significantly mutated in all colorectal cancer subtypes, and activated WNT/β-catenin signaling was correlated with the absence of T-cell infiltration. This large-scale genomic analysis of colorectal cancer demonstrates that MSI-high cases frequently undergo an immunoediting process that provides them with genetic events allowing immune escape despite high mutational load and frequent lymphocytic infiltration and, furthermore, that colorectal cancer tumors have genetic and methylation events associated with activated WNT signaling and T-cell exclusion.Significance: This multi-omic analysis of 1,211 colorectal cancer primary tumors reveals that it should be possible to better monitor resistance in the 15% of cases that respond to immune blockade therapy and also to use WNT signaling inhibitors to reverse immune exclusion in the 85% of cases that currently do not. Cancer Discov; 8(6); 730–49. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 663
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- 2023
19. Supplementary File 3 from Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets
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William C. Hahn, Gad Getz, David N. Louis, José Baselga, Tracy T. Batchelor, Rameen Beroukhim, Eric S. Lander, Stacey Gabriel, Levi Garraway, Matthew Meyerson, Anat Stemmer-Rachamimov, Eric P. Winer, Nancy U. Lin, Michael S. Rabin, Carrie Sougnez, Sabina Signoretti, Toni K. Choueiri, Mai P. Hoang, Bruce E. Johnson, Aaron R. Thorner, Paul Van Hummelen, Corey M. Gill, Frederick G. Barker, Mara Rosenberg, Aaron Chevalier, Aaron McKenna, Sung-Hye Park, Sun Ha Paek, Ian F. Dunn, William T. Curry, Elena Martinez-Saez, Joan Seoane, Josep Tabernero, Keith L. Ligon, Kristian Cibulskis, Peleg M. Horowitz, Michael S. Lawrence, Eliezer M. Van Allen, Robert T. Jones, Amaro Taylor-Weiner, Daniel P. Cahill, Sandro Santagata, Scott L. Carter, and Priscilla K. Brastianos
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Supplementary File 3. Detailed plots of the data used for phylogenetic inference in each case. The description for the plots in Supplementary File 3 can be found in the Legend of Supplementary Figure S13-S17.
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- 2023
20. Supplementary Figure 1 from Activating mTOR Mutations in a Patient with an Extraordinary Response on a Phase I Trial of Everolimus and Pazopanib
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Jonathan E. Rosenberg, Levi A. Garraway, Philip W. Kantoff, Stacey B. Gabriel, Eric S. Lander, David M. Sabatini, Geoffrey I. Shapiro, Massimo Loda, Sabina Signoretti, Edward C. Stack, Mary Ellen Taplin, Aymen A. Elfiky, James M. Cleary, Leena Gandhi, Toni K. Choueiri, Michelle Stewart, Jeffrey G. Supko, Susanna Jacobus, Eran Hodis, Eliezer M. Van Allen, Brian C. Grabiner, and Nikhil Wagle
- Abstract
PDF file 249K, Effect of pazopanib on S6K1 phosphorylation in cells expressing activating MTOR mutations
- Published
- 2023
21. Supplementary File 2 from Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets
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William C. Hahn, Gad Getz, David N. Louis, José Baselga, Tracy T. Batchelor, Rameen Beroukhim, Eric S. Lander, Stacey Gabriel, Levi Garraway, Matthew Meyerson, Anat Stemmer-Rachamimov, Eric P. Winer, Nancy U. Lin, Michael S. Rabin, Carrie Sougnez, Sabina Signoretti, Toni K. Choueiri, Mai P. Hoang, Bruce E. Johnson, Aaron R. Thorner, Paul Van Hummelen, Corey M. Gill, Frederick G. Barker, Mara Rosenberg, Aaron Chevalier, Aaron McKenna, Sung-Hye Park, Sun Ha Paek, Ian F. Dunn, William T. Curry, Elena Martinez-Saez, Joan Seoane, Josep Tabernero, Keith L. Ligon, Kristian Cibulskis, Peleg M. Horowitz, Michael S. Lawrence, Eliezer M. Van Allen, Robert T. Jones, Amaro Taylor-Weiner, Daniel P. Cahill, Sandro Santagata, Scott L. Carter, and Priscilla K. Brastianos
- Abstract
Supplementary File 2. Detailed plots of SCNA calls in TARGET genes. The description for the plots in Supplementary File 2 can be found in the Legend of Supplementary Figure S3.
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- 2023
22. Supplementary Table 2 from Loss of E-Cadherin Promotes Metastasis via Multiple Downstream Transcriptional Pathways
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Robert A. Weinberg, Eric S. Lander, Jing Yang, Sendurai A. Mani, Piyush B. Gupta, and Tamer T. Onder
- Abstract
Supplementary Table 2 from Loss of E-Cadherin Promotes Metastasis via Multiple Downstream Transcriptional Pathways
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- 2023
23. Supplementary Table 4 from Loss of E-Cadherin Promotes Metastasis via Multiple Downstream Transcriptional Pathways
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Robert A. Weinberg, Eric S. Lander, Jing Yang, Sendurai A. Mani, Piyush B. Gupta, and Tamer T. Onder
- Abstract
Supplementary Table 4 from Loss of E-Cadherin Promotes Metastasis via Multiple Downstream Transcriptional Pathways
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- 2023
24. Supplementary Table 3 from Loss of E-Cadherin Promotes Metastasis via Multiple Downstream Transcriptional Pathways
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Robert A. Weinberg, Eric S. Lander, Jing Yang, Sendurai A. Mani, Piyush B. Gupta, and Tamer T. Onder
- Abstract
Supplementary Table 3 from Loss of E-Cadherin Promotes Metastasis via Multiple Downstream Transcriptional Pathways
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- 2023
25. Supplementary Figure Legends 1-6 from Loss of E-Cadherin Promotes Metastasis via Multiple Downstream Transcriptional Pathways
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Robert A. Weinberg, Eric S. Lander, Jing Yang, Sendurai A. Mani, Piyush B. Gupta, and Tamer T. Onder
- Abstract
Supplementary Figure Legends 1-6 from Loss of E-Cadherin Promotes Metastasis via Multiple Downstream Transcriptional Pathways
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- 2023
26. Supplementary Figures 1-6 from Loss of E-Cadherin Promotes Metastasis via Multiple Downstream Transcriptional Pathways
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Robert A. Weinberg, Eric S. Lander, Jing Yang, Sendurai A. Mani, Piyush B. Gupta, and Tamer T. Onder
- Abstract
Supplementary Figures 1-6 from Loss of E-Cadherin Promotes Metastasis via Multiple Downstream Transcriptional Pathways
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- 2023
27. Data from Loss of E-Cadherin Promotes Metastasis via Multiple Downstream Transcriptional Pathways
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Robert A. Weinberg, Eric S. Lander, Jing Yang, Sendurai A. Mani, Piyush B. Gupta, and Tamer T. Onder
- Abstract
Loss of the epithelial adhesion molecule E-cadherin is thought to enable metastasis by disrupting intercellular contacts—an early step in metastatic dissemination. To further investigate the molecular basis of this notion, we use two methods to inhibit E-cadherin function that distinguish between E-cadherin's cell-cell adhesion and intracellular signaling functions. Whereas the disruption of cell-cell contacts alone does not enable metastasis, the loss of E-cadherin protein does, through induction of an epithelial-to-mesenchymal transition, invasiveness, and anoikis resistance. We find the E-cadherin binding partner β-catenin to be necessary, but not sufficient, for induction of these phenotypes. In addition, gene expression analysis shows that E-cadherin loss results in the induction of multiple transcription factors, at least one of which, Twist, is necessary for E-cadherin loss–induced metastasis. These findings indicate that E-cadherin loss in tumors contributes to metastatic dissemination by inducing wide-ranging transcriptional and functional changes. [Cancer Res 2008;68(10):3645–53]
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- 2023
28. Supplementary Table 1 from Loss of E-Cadherin Promotes Metastasis via Multiple Downstream Transcriptional Pathways
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Robert A. Weinberg, Eric S. Lander, Jing Yang, Sendurai A. Mani, Piyush B. Gupta, and Tamer T. Onder
- Abstract
Supplementary Table 1 from Loss of E-Cadherin Promotes Metastasis via Multiple Downstream Transcriptional Pathways
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- 2023
29. Mapping the convergence of genes for coronary artery disease onto endothelial cell programs
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Gavin R. Schnitzler, Helen Kang, Vivian S. Lee-Kim, X. Rosa Ma, Tony Zeng, Ramcharan S. Angom, Shi Fang, Shamsudheen Karuthedath Vellarikkal, Ronghao Zhou, Katherine Guo, Oscar Sias-Garcia, Alex Bloemendal, Glen Munson, Philine Guckelberger, Tung H. Nguyen, Drew T. Bergman, Nathan Cheng, Brian Cleary, Krishna Aragam, Debabrata Mukhopadhyay, Eric S. Lander, Hilary K. Finucane, Rajat M. Gupta, and Jesse M. Engreitz
- Abstract
Genome-wide association studies (GWAS) have discovered thousands of risk loci for common, complex diseases, each of which could point to genes and gene programs that influence disease. For some diseases, it has been observed that GWAS signals converge on a smaller number of biological programs, and that this convergence can help to identify causal genes1–6. However, identifying such convergence remains challenging: each GWAS locus can have many candidate genes, each gene might act in one or more possible programs, and it remains unclear which programs might influence disease risk. Here, we developed a new approach to address this challenge, by creating unbiased maps to link disease variants to genes to programs (V2G2P) in a given cell type. We applied this approach to study the role of endothelial cells in the genetics of coronary artery disease (CAD). To link variants to genes, we constructed enhancer-gene maps using the Activity-by-Contact model7,8. To link genes to programs, we applied CRISPRi-Perturb-seq9–12to knock down all expressed genes within ±500 Kb of 306 CAD GWAS signals13,14and identify their effects on gene expression programs using single-cell RNA-sequencing. By combining these variant-to-gene and gene-to-program maps, we find that 43 of 306 CAD GWAS signals converge onto 5 gene programs linked to the cerebral cavernous malformations (CCM) pathway—which is known to coordinate transcriptional responses in endothelial cells15, but has not been previously linked to CAD risk. The strongest regulator of these programs isTLNRD1, which we show is a new CAD gene and novel regulator of the CCM pathway.TLNRD1loss-of-function alters actin organization and barrier function in endothelial cellsin vitro, and heart development in zebrafishin vivo. Together, our study identifies convergence of CAD risk loci into prioritized gene programs in endothelial cells, nominates new genes of potential therapeutic relevance for CAD, and demonstrates a generalizable strategy to connect disease variants to functions.
- Published
- 2022
30. Gene Sequencing Identifies Perturbation in Nitric Oxide Signaling as a Nonlipid Molecular Subtype of Coronary Artery Disease
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Amit V. Khera, Minxian Wang, Mark Chaffin, Connor A. Emdin, Nilesh J. Samani, Heribert Schunkert, Hugh Watkins, Ruth McPherson, Jeanette Erdmann, Roberto Elosua, Eric Boerwinkle, Diego Ardissino, Adam S. Butterworth, Emanuele Di Angelantonio, Aliya Naheed, John Danesh, Rajiv Chowdhury, Harlan M. Krumholz, Wayne H.-H. Sheu, Stephen S. Rich, Jerome I. Rotter, Yii-der Ida Chen, Stacey Gabriel, Eric S. Lander, Danish Saleheen, and Sekar Kathiresan
- Subjects
General Medicine - Abstract
Background: A key goal of precision medicine is to disaggregate common, complex diseases into discrete molecular subtypes. Rare coding variants in the low-density lipoprotein receptor gene ( LDLR ) are identified in 1% to 2% of coronary artery disease (CAD) patients, defining a molecular subtype with risk driven by hypercholesterolemia. Methods: To search for additional subtypes, we compared the frequency of rare, predicted loss-of-function and damaging missense variants aggregated within a given gene in 41 081 CAD cases versus 217 115 controls. Results: Rare variants in LDLR were most strongly associated with CAD, present in 1% of cases and associated with 4.4-fold increased CAD risk. A second subtype was characterized by variants in endothelial nitric oxide synthase gene ( NOS3 ), a key enzyme regulating vascular tone, endothelial function, and platelet aggregation. A rare predicted loss-of-function or damaging missense variants in NOS3 was present in 0.6% of cases and associated with 2.42-fold increased risk of CAD (95% CI, 1.80–3.26; P =5.50×10 −9 ). These variants were associated with higher systolic blood pressure (+3.25 mm Hg; [95% CI, 1.86–4.65]; P =5.00×10 −6 ) and increased risk of hypertension (adjusted odds ratio 1.31; [95% CI, 1.14–1.51]; P =2.00×10 −4 ) but not circulating cholesterol concentrations, suggesting that, beyond lipid pathways, nitric oxide synthesis is a key nonlipid driver of CAD risk. Conclusions: Beyond LDLR , we identified an additional nonlipid molecular subtype of CAD characterized by rare variants in the NOS3 gene.
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- 2022
31. A patient-driven clinicogenomic partnership for metastatic prostate cancer
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Jett Crowdis, Sara Balch, Lauren Sterlin, Beena S. Thomas, Sabrina Y. Camp, Michael Dunphy, Elana Anastasio, Shahrayz Shah, Alyssa L. Damon, Rafael Ramos, Delia M. Sosa, Ilan K. Small, Brett N. Tomson, Colleen M. Nguyen, Mary McGillicuddy, Parker S. Chastain, Meng Xiao He, Alexander T.M. Cheung, Stephanie Wankowicz, Alok K. Tewari, Dewey Kim, Saud H. AlDubayan, Ayanah Dowdye, Benjamin Zola, Joel Nowak, Jan Manarite, Idola Henry Gunn, Bryce Olson, Eric S. Lander, Corrie A. Painter, Nikhil Wagle, and Eliezer M. Van Allen
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Genetics ,Biochemistry, Genetics and Molecular Biology (miscellaneous) - Abstract
Molecular profiling studies have enabled discoveries for metastatic prostate cancer (MPC) but have predominantly occurred in academic medical institutions and involved non-representative patient populations. We established the Metastatic Prostate Cancer Project (MPCproject, mpcproject.org), a patient-partnered initiative to involve patients with MPC living anywhere in the US and Canada in molecular research. Here, we present results from our partnership with the first 706 MPCproject participants. While 41% of patient partners live in rural, physician-shortage, or medically underserved areas, the MPCproject has not yet achieved racial diversity, a disparity that demands new initiatives detailed herein. Among molecular data from 333 patient partners (572 samples), exome sequencing of 63 tumor and 19 cell-free DNA (cfDNA) samples recapitulated known findings in MPC, while inexpensive ultra-low-coverage sequencing of 318 cfDNA samples revealed clinically relevant
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- 2022
32. Extremely sparse models of linkage disequilibrium in ancestrally diverse association studies
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Pouria Salehi Nowbandegani, Anthony Wilder Wohns, Jenna L. Ballard, Eric S. Lander, Alex Bloemendal, Benjamin M. Neale, and Luke J. O’Connor
- Abstract
Linkage disequilibrium (LD) is the correlation among nearby genetic variants. In genetic association studies, LD is often modeled using massive local correlation matrices, but this approach is slow, especially in ancestrally diverse studies. Here, we introduce LD graphical models (LDGMs), which are an extremely sparse and efficient representation of LD. LDGMs are derived from genome-wide genealogies; statistical relationships among alleles in the LDGM correspond to genealogical relationships among haplotypes. We publish LDGMs and ancestry specific LDGM precision matrices for 18 million common SNPs (MAF>1%) in five ancestry groups, validate their accuracy, and demonstrate order-of-magnitude improvements in runtime for commonly used LD matrix computations. We implement an extremely fast multi-ancestry polygenic prediction method, BLUPx-ldgm, which performs better than a similar method based on the reference LD correlation matrix. LDGMs will enable sophisticated methods that scale to ancestrally genetic association data across millions of variants and individuals.
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- 2022
33. Inferring gene regulation from stochastic transcriptional variation across single cells at steady state
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Anika Gupta, Jorge D. Martin-Rufino, Thouis R. Jones, Vidya Subramanian, Xiaojie Qiu, Emanuelle I. Grody, Alex Bloemendal, Chen Weng, Sheng-Yong Niu, Kyung Hoi Min, Arnav Mehta, Kaite Zhang, Layla Siraj, Aziz Al' Khafaji, Vijay G. Sankaran, Soumya Raychaudhuri, Brian Cleary, Sharon Grossman, and Eric S. Lander
- Subjects
Multidisciplinary ,Gene Expression Regulation ,Computer Simulation ,Gene Regulatory Networks ,Models, Biological ,Transcription Factors - Abstract
Regulatory relationships between transcription factors (TFs) and their target genes lie at the heart of cellular identity and function; however, uncovering these relationships is often labor-intensive and requires perturbations. Here, we propose a principled framework to systematically infer gene regulation for all TFs simultaneously in cells at steady state by leveraging the intrinsic variation in the transcriptional abundance across single cells. Through modeling and simulations, we characterize how transcriptional bursts of a TF gene are propagated to its target genes, including the expected ranges of time delay and magnitude of maximum covariation. We distinguish these temporal trends from the time-invariant covariation arising from cell states, and we delineate the experimental and technical requirements for leveraging these small but meaningful cofluctuations in the presence of measurement noise. While current technology does not yet allow adequate power for definitively detecting regulatory relationships for all TFs simultaneously in cells at steady state, we investigate a small-scale dataset to inform future experimental design. This study supports the potential value of mapping regulatory connections through stochastic variation, and it motivates further technological development to achieve its full potential.
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- 2022
34. Massively parallel base editing to map variant effects in human hematopoiesis
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Jorge D. Martin-Rufino, Nicole Castano, Michael Pang, Emanuelle I. Grody, Samantha Joubran, Alexis Caulier, Lara Wahlster, Tongqing Li, Xiaojie Qiu, Anna Maria Riera-Escandell, Gregory A. Newby, Aziz Al’Khafaji, Santosh Chaudhary, Susan Black, Chen Weng, Glen Munson, David R. Liu, Marcin W. Wlodarski, Kacie Sims, Jamie H. Oakley, Ross M. Fasano, Ramnik J. Xavier, Eric S. Lander, Daryl E. Klein, and Vijay G. Sankaran
- Subjects
General Biochemistry, Genetics and Molecular Biology - Published
- 2023
35. Compressed sensing for highly efficient imaging transcriptomics
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Ehsan Habibi, Fei Chen, Evan Murray, Aviv Regev, Brian Cleary, Anubhav Sinha, Jamie L. Marshall, Jon Bezney, Eric S. Lander, Shahul Alam, and Brooke Simonton
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In situ ,0303 health sciences ,Computer science ,Spatially resolved ,Systems biology ,Resolution (electron density) ,Biomedical Engineering ,Magnification ,Bioengineering ,Computational biology ,Applied Microbiology and Biotechnology ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,Compressed sensing ,Gene Modules ,Molecular Medicine ,030217 neurology & neurosurgery ,030304 developmental biology ,Biotechnology - Abstract
Recent methods for spatial imaging of tissue samples can identify up to ~100 individual proteins1–3 or RNAs4–10 at single-cell resolution. However, the number of proteins or genes that can be studied in these approaches is limited by long imaging times. Here we introduce Composite In Situ Imaging (CISI), a method that leverages structure in gene expression across both cells and tissues to limit the number of imaging cycles needed to obtain spatially resolved gene expression maps. CISI defines gene modules that can be detected using composite measurements from imaging probes for subsets of genes. The data are then decompressed to recover expression values for individual genes. CISI further reduces imaging time by not relying on spot-level resolution, enabling lower magnification acquisition, and is overall about 500-fold more efficient than current methods. Applying CISI to 12 mouse brain sections, we accurately recovered the spatial abundance of 37 individual genes from 11 composite measurements covering 180 mm2 and 476,276 cells. Spatial transcriptomics is enhanced by using imaging probes for subsets of genes.
- Published
- 2021
36. Compatibility rules of human enhancer and promoter sequences
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Drew T. Bergman, Thouis R. Jones, Vincent Liu, Judhajeet Ray, Evelyn Jagoda, Layla Siraj, Helen Y. Kang, Joseph Nasser, Michael Kane, Antonio Rios, Tung H. Nguyen, Sharon R. Grossman, Charles P. Fulco, Eric S. Lander, and Jesse M. Engreitz
- Subjects
Multidisciplinary ,Enhancer Elements, Genetic ,Promoter Regions, Genetic ,Article - Abstract
Gene regulation in the human genome is controlled by distal enhancers that activate specific nearby promoters(1). One model for this specificity is that promoters might have sequence-encoded preferences for certain enhancers, for example mediated by interacting sets of transcription factors or cofactors(2). This “biochemical compatibility” model has been supported by observations at individual human promoters and by genome-wide measurements in Drosophila(3-9). However, the degree to which human enhancers and promoters are intrinsically compatible has not been systematically measured, and how their activities combine to control RNA expression remains unclear. Here we designed a high-throughput reporter assay called ExP STARR-seq (enhancer x promoter self-transcribing active regulatory region sequencing) and applied it to examine the combinatorial compatibilities of 1,000 enhancer and 1,000 promoter sequences in human K562 cells. We identify simple rules for enhancer-promoter compatibility: most enhancers activated all promoters by similar amounts, and intrinsic enhancer and promoter activities combine multiplicatively to determine RNA output (R(2)=0.82). In addition, two classes of enhancers and promoters showed subtle preferential effects. Promoters of housekeeping genes contained built-in activating motifs for factors such as GABPA and YY1, which decreased the responsiveness of promoters to distal enhancers. Promoters of variably expressed genes lacked these motifs and showed stronger responsiveness to enhancers. Together, this systematic assessment of enhancer-promoter compatibility suggests a multiplicative model tuned by enhancer and promoter class to control gene transcription in the human genome.
- Published
- 2022
37. Human Molecular Genetics and Genomics — Important Advances and Exciting Possibilities
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Eric S. Lander, Jennifer A. Doudna, Francis S. Collins, and Charles N. Rotimi
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medicine.medical_specialty ,Genetics, Medical ,Genomic research ,MEDLINE ,Genomics ,030204 cardiovascular system & hematology ,History, 21st Century ,Code (semiotics) ,03 medical and health sciences ,0302 clinical medicine ,Molecular genetics ,Human Genome Project ,medicine ,Humans ,Clustered Regularly Interspaced Short Palindromic Repeats ,030212 general & internal medicine ,Molecular Biology ,National Academies of Science, Engineering, and Medicine, U.S., Health and Medicine Division ,business.industry ,Genetic Diseases, Inborn ,Historical Article ,General Medicine ,History, 20th Century ,Genetic code ,Data science ,United States ,business - Abstract
Human Molecular Genetics and Genomics Genomic research has evolved from seeking to understand the fundamentals of the human genetic code to examining the ways in which this code varies among people...
- Published
- 2021
38. Phylogenetically and spatially conserved word pairs associated with gene expression changes in yeasts.
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Derek Y. Chiang, Alan M. Moses, Manolis Kamvysselis, Eric S. Lander, and Michael B. Eisen
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- 2003
- Full Text
- View/download PDF
39. ARPA-H: Accelerating biomedical breakthroughs
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Tara A. Schwetz, Lawrence A. Tabak, Francis S. Collins, and Eric S. Lander
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2019-20 coronavirus outbreak ,Multidisciplinary ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Political science ,fungi ,food and beverages ,Virology - Abstract
A DARPA-like culture at NIH can drive biomedical and health advances
- Published
- 2021
40. HyPR-seq: Single-cell quantification of chosen RNAs via hybridization and sequencing of DNA probes
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Drew T. Bergman, Philine Guckelberger, Eric S. Lander, Jesse M. Engreitz, Qingbo Wang, Vidya Subramanian, Anna Greka, Linlin M. Chen, Benjamin R. Doughty, Joseph Nasser, Sarah Mangiameli, Jamie L. Marshall, Teia Noel, K. Zhang, Fei Chen, Charles P. Fulco, Elizabeth J. Grinkevich, and Samuel G. Rodriques
- Subjects
Time Factors ,THP-1 Cells ,Gene Expression ,Genomics ,Computational biology ,Biology ,Kidney ,Polyadenylation ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Gene expression ,Animals ,Humans ,RNA, Messenger ,Gene ,030304 developmental biology ,Regulation of gene expression ,0303 health sciences ,Multidisciplinary ,Hybridization probe ,Intron ,High-Throughput Nucleotide Sequencing ,Nucleic Acid Hybridization ,RNA ,Biological Sciences ,Amplicon ,Introns ,CRISPR-Cas Systems ,Single-Cell Analysis ,DNA Probes ,K562 Cells ,030217 neurology & neurosurgery - Abstract
Single-cell quantification of RNAs is important for understanding cellular heterogeneity and gene regulation, yet current approaches suffer from low sensitivity for individual transcripts, limiting their utility for many applications. Here we present Hybridization of Probes to RNA for sequencing (HyPR-seq), a method to sensitively quantify the expression of hundreds of chosen genes in single cells. HyPR-seq involves hybridizing DNA probes to RNA, distributing cells into nanoliter droplets, amplifying the probes with PCR, and sequencing the amplicons to quantify the expression of chosen genes. HyPR-seq achieves high sensitivity for individual transcripts, detects nonpolyadenylated and low-abundance transcripts, and can profile more than 100,000 single cells. We demonstrate how HyPR-seq can profile the effects of CRISPR perturbations in pooled screens, detect time-resolved changes in gene expression via measurements of gene introns, and detect rare transcripts and quantify cell-type frequencies in tissue using low-abundance marker genes. By directing sequencing power to genes of interest and sensitively quantifying individual transcripts, HyPR-seq reduces costs by up to 100-fold compared to whole-transcriptome single-cell RNA-sequencing, making HyPR-seq a powerful method for targeted RNA profiling in single cells.
- Published
- 2020
41. The SARS-CoV-2 RNA–protein interactome in infected human cells
- Author
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Jens Ade, Yuanjie Wei, Eric S. Lander, Utz Fischer, Jörg Vogel, Simone Werner, Jochen Bodem, Randy Melanson, C. Schneider, Hasmik Keshishian, Lars Dölken, Sebastian Zielinski, Caleb A. Lareau, Sabina Ganskih, Neva Caliskan, Steven A. Carr, Mathias Munschauer, Luisa Kirschner, Nora Schmidt, Thomas Hennig, Matthias Zimmer, and HIRI, Helmholtz-Institut für RNA-basierte Infektionsforschung, Josef-Shneider Strasse 2, 97080 Würzburg, Germany.
- Subjects
Microbiology (medical) ,Proteomics ,Proteome ,viruses ,Immunology ,RNA-binding protein ,Biology ,Virus Replication ,Interactome ,Applied Microbiology and Biotechnology ,Microbiology ,Autoantigens ,Article ,Cell Line ,03 medical and health sciences ,0302 clinical medicine ,Virology ,Genetics ,Humans ,Protein Interaction Maps ,skin and connective tissue diseases ,030304 developmental biology ,Ribonucleoprotein ,RNA metabolism ,0303 health sciences ,Innate immune system ,SARS-CoV-2 ,fungi ,RNA ,COVID-19 ,RNA-Binding Proteins ,Cell Biology ,Cell biology ,Viral replication ,Ribonucleoproteins ,Host-Pathogen Interactions ,Nucleic acid ,RNA, Viral ,030217 neurology & neurosurgery - Abstract
Characterizing the interactions that SARS-CoV-2 viral RNAs make with host cell proteins during infection can improve our understanding of viral RNA functions and the host innate immune response. Using RNA antisense purification and mass spectrometry, we identified up to 104 human proteins that directly and specifically bind to SARS-CoV-2 RNAs in infected human cells. We integrated the SARS-CoV-2 RNA interactome with changes in proteome abundance induced by viral infection and linked interactome proteins to cellular pathways relevant to SARS-CoV-2 infections. We demonstrated by genetic perturbation that cellular nucleic acid-binding protein (CNBP) and La-related protein 1 (LARP1), two of the most strongly enriched viral RNA binders, restrict SARS-CoV-2 replication in infected cells and provide a global map of their direct RNA contact sites. Pharmacological inhibition of three other RNA interactome members, PPIA, ATP1A1, and the ARP2/3 complex, reduced viral replication in two human cell lines. The identification of host dependency factors and defence strategies as presented in this work will improve the design of targeted therapeutics against SARS-CoV-2., Interactions between SARS-CoV-2 viral RNAs and host cell proteins during infection are evaluated to improve our understanding of viral RNA functions and the host innate immune response.
- Published
- 2020
42. Molecular classification of multiple tumor types.
- Author
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Chen-Hsiang Yeang, Sridhar Ramaswamy, Pablo Tamayo, Sayan Mukherjee 0001, Ryan M. Rifkin, Michael Angelo, Michael Reich, Eric S. Lander, Jill P. Mesirov, and Todd R. Golub
- Published
- 2001
43. Class prediction and discovery using gene expression data.
- Author
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Donna K. Slonim, Pablo Tamayo, Jill P. Mesirov, Todd R. Golub, and Eric S. Lander
- Published
- 2000
- Full Text
- View/download PDF
44. Human and mouse gene structure: comparative analysis and application to exon prediction.
- Author
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Serafim Batzoglou, Lior Pachter, Jill P. Mesirov, Bonnie Berger, and Eric S. Lander
- Published
- 2000
- Full Text
- View/download PDF
45. A dictionary based approach for gene annotation.
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Lior Pachter, Serafim Batzoglou, Valentin I. Spitkovsky, William S. Beebee, Eric S. Lander, Bonnie Berger, and Daniel J. Kleitman
- Published
- 1999
- Full Text
- View/download PDF
46. Mapping and characterization of structural variation in 17,795 human genomes
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Ryan M. Layer, Susan K. Dutcher, Donna M. Muzny, Krishna L. Kanchi, Eric S. Lander, David E. Larson, Colby Chiang, Nathan O. Stitziel, Michael C. Zody, Tara C. Matise, Ira M. Hall, Allison A. Regier, Catherine Reeves, Haley J. Abel, William J Salerno, Nhgri Centers for Common Disease Genomics, Steven Buyske, Indraniel Das, Benjamin M. Neale, Institute for Molecular Medicine Finland, Centre of Excellence in Complex Disease Genetics, Research Programs Unit, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, Doctoral Programme in Social Sciences, Department of Public Health, Samuli Olli Ripatti / Principal Investigator, Complex Disease Genetics, University Management, Biostatistics Helsinki, HUS Heart and Lung Center, CAMM - Research Program for Clinical and Molecular Metabolism, and Helsinki University Hospital Area
- Subjects
Male ,IMPACT ,DATABASE ,PREDICTION ,NUCLEOTIDE ,Quantitative Trait Loci ,Population ,Gene Dosage ,Computational biology ,VARIANTS ,Biology ,Genome ,Article ,Epigenesis, Genetic ,Structural variation ,03 medical and health sciences ,0302 clinical medicine ,ELEMENTS ,WIDE ASSOCIATION ,Humans ,Copy-number variation ,COMMUNITY-DRIVEN RESOURCE ,Indel ,education ,Alleles ,COPY NUMBER VARIATION ,030304 developmental biology ,Whole genome sequencing ,0303 health sciences ,education.field_of_study ,Multidisciplinary ,Whole Genome Sequencing ,Genome, Human ,Racial Groups ,Genetic Variation ,High-Throughput Nucleotide Sequencing ,Molecular Sequence Annotation ,FRAMEWORK ,Human genetics ,Genetics, Population ,Case-Control Studies ,Female ,Human genome ,3111 Biomedicine ,Software ,030217 neurology & neurosurgery - Abstract
Structural variants in more than 17,000 human genomes are mapped and characterized using whole-genome sequencing, showing how this type of variation contributes to rare deleterious coding and noncoding alleles. A key goal of whole-genome sequencing for studies of human genetics is to interrogate all forms of variation, including single-nucleotide variants, small insertion or deletion (indel) variants and structural variants. However, tools and resources for the study of structural variants have lagged behind those for smaller variants. Here we used a scalable pipeline(1)to map and characterize structural variants in 17,795 deeply sequenced human genomes. We publicly release site-frequency data to create the largest, to our knowledge, whole-genome-sequencing-based structural variant resource so far. On average, individuals carry 2.9 rare structural variants that alter coding regions; these variants affect the dosage or structure of 4.2 genes and account for 4.0-11.2% of rare high-impact coding alleles. Using a computational model, we estimate that structural variants account for 17.2% of rare alleles genome-wide, with predicted deleterious effects that are equivalent to loss-of-function coding alleles; approximately 90% of such structural variants are noncoding deletions (mean 19.1 per genome). We report 158,991 ultra-rare structural variants and show that 2% of individuals carry ultra-rare megabase-scale structural variants, nearly half of which are balanced or complex rearrangements. Finally, we infer the dosage sensitivity of genes and noncoding elements, and reveal trends that relate to element class and conservation. This work will help to guide the analysis and interpretation of structural variants in the era of whole-genome sequencing.
- Published
- 2020
47. Towards a treatment for genetic prion disease: trials and biomarkers
- Author
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Stuart L. Schreiber, Eric Vallabh Minikel, Eric S. Lander, and Sonia M Vallabh
- Subjects
0301 basic medicine ,Disease onset ,Prions ,business.industry ,Disease agent ,Neurodegenerative Diseases ,Single gene ,Disease ,Bioinformatics ,Prion Proteins ,Prion Diseases ,nervous system diseases ,Clinical trial ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Animals ,Humans ,Medicine ,Neurology (clinical) ,Prion protein ,Age of onset ,business ,Biomarkers ,030217 neurology & neurosurgery - Abstract
Prion disease is a rare, fatal, and exceptionally rapid neurodegenerative disease. Although incurable, prion disease follows a clear pathogenic mechanism, in which a single gene gives rise to a single prion protein (PrP) capable of converting into the sole causal disease agent, the misfolded prion. As efforts progress to leverage this mechanistic knowledge toward rational therapies, a principal challenge will be the design of clinical trials. Previous trials in prion disease have been done in symptomatic patients who are often profoundly debilitated at enrolment. About 15% of prion disease cases are genetic, creating an opportunity for early therapeutic intervention to delay or prevent disease. Highly variable age of onset and absence of established prodromal biomarkers might render infeasible existing models for testing drugs before disease onset. Advancement of near-term targeted therapeutics could crucially depend on thoughtful design of rigorous presymptomatic trials.
- Published
- 2020
48. Prioritizing disease and trait causal variants at the TNFAIP3 locus using functional and genomic features
- Author
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Nir Hacohen, Caleb A. Lareau, Drew T. Bergman, Leif S. Ludwig, Masahiro Kanai, Robbyn Issner, John P. Ray, Steven K. Reilly, Eric S. Lander, Jesse M. Engreitz, Carl G. de Boer, Ryan Tewhey, Jacob C. Ulirsch, Charles P. Fulco, Aviv Regev, and Hilary K. Finucane
- Subjects
0301 basic medicine ,Epigenomics ,CRISPR-Cas9 genome editing ,Linkage disequilibrium ,Multifactorial Inheritance ,Science ,General Physics and Astronomy ,Single-nucleotide polymorphism ,Locus (genetics) ,Genomics ,Biology ,Proof of Concept Study ,General Biochemistry, Genetics and Molecular Biology ,Article ,Linkage Disequilibrium ,Autoimmune Diseases ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Genetic variation ,Immunogenetics ,Humans ,Genetic Predisposition to Disease ,lcsh:Science ,Tumor Necrosis Factor alpha-Induced Protein 3 ,Genetic association ,Genetics ,Multidisciplinary ,Haplotype ,Genetic Variation ,Functional genomics ,General Chemistry ,030104 developmental biology ,Haplotypes ,Genetic Loci ,Trait ,lcsh:Q ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
Genome-wide association studies have associated thousands of genetic variants with complex traits and diseases, but pinpointing the causal variant(s) among those in tight linkage disequilibrium with each associated variant remains a major challenge. Here, we use seven experimental assays to characterize all common variants at the multiple disease-associated TNFAIP3 locus in five disease-relevant immune cell lines, based on a set of features related to regulatory potential. Trait/disease-associated variants are enriched among SNPs prioritized based on either: (1) residing within CRISPRi-sensitive regulatory regions, or (2) localizing in a chromatin accessible region while displaying allele-specific reporter activity. Of the 15 trait/disease-associated haplotypes at TNFAIP3, 9 have at least one variant meeting one or both of these criteria, 5 of which are further supported by genetic fine-mapping. Our work provides a comprehensive strategy to characterize genetic variation at important disease-associated loci, and aids in the effort to identify trait causal genetic variants., While genome-wide association studies have yielded thousands of trait-associated loci, identifying causal variants remains challenging. Here, the authors perform seven genomics assays in various cell types to prioritize genetic variants in the TNFAIP3 locus, and report high-priority variants within disease-associated haplotypes.
- Published
- 2020
49. The Angiosarcoma Project: enabling genomic and clinical discoveries in a rare cancer through patient-partnered research
- Author
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Jason L. Hornick, Jorge Gómez Tejeda Zañudo, Todd R. Golub, Priscilla Merriam, Alyssa L. Damon, Brett N. Tomson, Corrie A. Painter, Yen-Lin Chen, Eric S. Lander, Michael Dunphy, Chandrajit P. Raut, Brian A. Van Tine, Beena Thomas, Dewey Kim, George D. Demetri, Rachel Stoddard, Shahrayz Shah, Nikhil Wagle, and Esha Jain
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,Genomic data ,Germline ,General Biochemistry, Genetics and Molecular Biology ,Annual incidence ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Angiosarcoma ,neoplasms ,Exome sequencing ,business.industry ,Incidence (epidemiology) ,Medical record ,General Medicine ,medicine.disease ,Rare cancer ,Immune checkpoint ,030104 developmental biology ,030220 oncology & carcinogenesis ,Etiology ,Sarcoma ,business - Abstract
Despite rare cancers accounting for 25% of adult tumors1, they are difficult to study due to the low disease incidence and geographically dispersed patient populations, which has resulted in significant unmet clinical needs for patients with rare cancers. We assessed whether a patient-partnered research approach using online engagement can overcome these challenges, focusing on angiosarcoma, a sarcoma with an annual incidence of 300 cases in the United States. Here we describe the development of the Angiosarcoma Project (ASCproject), an initiative enabling US and Canadian patients to remotely share their clinical information and biospecimens for research. The project generates and publicly releases clinically annotated genomic data on tumor and germline specimens on an ongoing basis. Over 18 months, 338 patients registered for the ASCproject, which comprises a large proportion of all patients with angiosarcoma. Whole-exome sequencing (WES) of 47 tumors revealed recurrently mutated genes that included KDR, TP53, and PIK3CA. PIK3CA-activating mutations were observed predominantly in primary breast angiosarcoma, which suggested a therapeutic rationale. Angiosarcoma of the head, neck, face and scalp (HNFS) was associated with a high tumor mutation burden (TMB) and a dominant ultraviolet damage mutational signature, which suggested that for the subset of patients with angiosarcoma of HNFS, ultraviolet damage may be a causative factor and that immune checkpoint inhibition may be beneficial. Medical record review revealed that two patients with HNFS angiosarcoma had received off-label therapeutic use of antibody to the programmed death-1 protein (anti-PD-1) and had experienced exceptional responses, which highlights immune checkpoint inhibition as a therapeutic avenue for HNFS angiosarcoma. This patient-partnered approach has catalyzed an opportunity to discover the etiology and potential therapies for patients with angiosarcoma. Collectively, this proof-of-concept study demonstrates that empowering patients to directly participate in research can overcome barriers in rare diseases and can enable discoveries. A framework of patient-partnered research allows patients with angiosarcoma to share their samples and clinical records securely to accelerate molecular characterization of tumors and identification of therapeutic approaches.
- Published
- 2020
50. Neurocognitive trajectory and proteomic signature of inherited risk for Alzheimer's disease
- Author
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Manish D. Paranjpe, Mark Chaffin, Sohail Zahid, Scott Ritchie, Jerome I. Rotter, Stephen S. Rich, Robert Gerszten, Xiuqing Guo, Susan Heckbert, Russ Tracy, John Danesh, Eric S. Lander, Michael Inouye, Sekar Kathiresan, Adam S. Butterworth, and Amit V. Khera
- Subjects
Adult ,Proteomics ,Cancer Research ,Middle Aged ,Cross-Sectional Studies ,Alzheimer Disease ,Genetics ,Humans ,Molecular Biology ,Genetics (clinical) ,Ecology, Evolution, Behavior and Systematics ,Biomarkers ,Aged ,Genome-Wide Association Study - Abstract
For Alzheimer’s disease–a leading cause of dementia and global morbidity–improved identification of presymptomatic high-risk individuals and identification of new circulating biomarkers are key public health needs. Here, we tested the hypothesis that a polygenic predictor of risk for Alzheimer’s disease would identify a subset of the population with increased risk of clinically diagnosed dementia, subclinical neurocognitive dysfunction, and a differing circulating proteomic profile. Using summary association statistics from a recent genome-wide association study, we first developed a polygenic predictor of Alzheimer’s disease comprised of 7.1 million common DNA variants. We noted a 7.3-fold (95% CI 4.8 to 11.0; p < 0.001) gradient in risk across deciles of the score among 288,289 middle-aged participants of the UK Biobank study. In cross-sectional analyses stratified by age, minimal differences in risk of Alzheimer’s disease and performance on a digit recall test were present according to polygenic score decile at age 50 years, but significant gradients emerged by age 65. Similarly, among 30,541 participants of the Mass General Brigham Biobank, we again noted no significant differences in Alzheimer’s disease diagnosis at younger ages across deciles of the score, but for those over 65 years we noted an odds ratio of 2.0 (95% CI 1.3 to 3.2; p = 0.002) in the top versus bottom decile of the polygenic score. To understand the proteomic signature of inherited risk, we performed aptamer-based profiling in 636 blood donors (mean age 43 years) with very high or low polygenic scores. In addition to the well-known apolipoprotein E biomarker, this analysis identified 27 additional proteins, several of which have known roles related to disease pathogenesis. Differences in protein concentrations were consistent even among the youngest subset of blood donors (mean age 33 years). Of these 28 proteins, 7 of the 8 proteins with concentrations available were similarly associated with the polygenic score in participants of the Multi-Ethnic Study of Atherosclerosis. These data highlight the potential for a DNA-based score to identify high-risk individuals during the prolonged presymptomatic phase of Alzheimer’s disease and to enable biomarker discovery based on profiling of young individuals in the extremes of the score distribution.
- Published
- 2021
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