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1. Sequencing by avidity enables high accuracy with low reagent consumption

Author

Sinan Arslan, Francisco J. Garcia, Minghao Guo, Matthew W. Kellinger, Semyon Kruglyak, Jake A. LeVieux, Adeline H. Mah, Haosen Wang, Junhua Zhao, Chunhong Zhou, Andrew Altomare, John Bailey, Matthew B. Byrne, Chiting Chang, Steve X. Chen, Claudia N. Dennler, Vivian T. Dien, Derek Fuller, Ryan Kelley, Omid Khandan, Michael G. Klein, Michael Kim, Bryan R. Lajoie, Bill Lin, Yu Liu, Tyler Lopez, Peter T. Mains, Andrew D. Price, Samantha R. Robertson, Hermes Taylor-Weiner, Ramreddy Tippana, Austin B. Tomaney, Su Zhang, Mark R. Ambroso, Rosita Bajari, Ava M. Bellizzi, Chris B. Benitez, Daniel R. Berard, Lorenzo Berti, Kelly N. Blease, Angela P. Blum, Andrew M. Boddicker, Leo Bondar, Chris Brown, Chris A. Bui, Juan Calleja-Aguirre, Kevin Cappa, Joshua Chan, Victor W. Chang, Katherine Charov, Xiyi Chen, Rodger M. Constandse, Ryan Costello, Weston Damron, Mariam Dawood, Nicole DeBuono, John D. Dimalanta, Laure Edoli, Keerthana Elango, Nikka Faustino, Chao Feng, Mathhew Ferrari, Keith Frankie, Adam Fries, Anne Galloway, Vlad Gavrila, Gregory J. Gemmen, James Ghadiali, Arash Ghorbani, Logan A. Goddard, Adriana R. Guetter, Garren L. Hendricks, Jendrik Hentschel, Daniel J. Honigfort, Yun-Ting Hsieh, Yu-Hsien Hwang Fu, Scott K. Im, Chaoyi Jin, Shradha Kabu, Daniel E. Kincade, Shawn Levy, Yu Li, Vincent K. Liang, William H. Light, Jonathan B. Lipsher, Tsung-li Liu, Grace Long, Rui Ma, John M. Mailloux, Kyle A. Mandla, Anyssa R. Martinez, Max Mass, Daniel T. McKean, Michael Meron, Celyne S. Moh, Rachel K. Moore, Juan Moreno, Jordan M. Neysmith, Cassandra S. Niman, Jesus M. Nunez, Micah T. Ojeda, Sara Espinosa Ortiz, Jenna Owens, Geoffrey Piland, Daniel J. Proctor, Josua B. Purba, Michael Ray, Daisong Rong, Virginia M. Saade, Sanchari Saha, Gustav Santo Tomas, Nicholas Scheidler, Luqmanal H. Sirajudeen, Samantha Snow, Gudrun Stengel, Ryan Stinson, Michael J. Stone, Keoni J. Sundseth, Eileen Thai, Connor J. Thompson, Marco Tjioe, Christy L. Trejo, Greg Trieger, Diane Ni Truong, Ben Tse, Benjamin Voiles, Henry Vuong, Jennifer C. Wong, Chiung-Ting Wu, Hua Yu, Yingxian Yu, Ming Yu, Xi Zhang, Da Zhao, Genhua Zheng, Molly He, and Michael Previte

Abstract

We present avidity sequencing - a novel sequencing chemistry that separately optimizes the process of stepping along a DNA template and the process of identifying each nucleotide within the template. Nucleotide identification uses multivalent nucleotide ligands on dye-labeled cores to form polymerase-polymer nucleotide complexes bound to clonal copies of DNA targets. These polymer-nucleotide substrates, termed avidites, decrease the required concentration of reporting nucleotides from micromolar to nanomolar, and yield negligible dissociation rates. We demonstrate the use of avidites as a key component of a sequencing technology that surpasses Q40 accuracy and enables a diversity of applications that include single cell RNA-seq and whole human genome sequencing. We also show the advantages of this technology in sequencing through long homopolymers.

Published
2022
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2. Origin and dynamics of Mycobacterium tuberculosis subpopulations that predictably generate drug tolerance and resistance

Author

Jees Sebastian, Anooja Thomas, Carly Levine, Riju Shrestha, Shawn Levy, Hassan Safi, Sri Ram Pentakota, Pradeep Kumar, and David Alland

Subjects
Virology, Microbiology
Abstract

Initial responses to tuberculosis treatment are poor predictors of final therapeutic outcomes in drug-susceptible disease suggesting that treatment success depends on features that are hidden within a small minority of the overall infecting Mycobacterium tuberculosis (Mtb) population. We developed a multi-transwell robotic system to perform numerous parallel cultures of genetically barcoded Mtb exposed to steady-state concentrations of rifampicin to uncover these difficult to eliminate minority populations. We found that tolerance repeatedly emerged from at least two subpopulations of barcoded cells, one that could not grow on solid agar media and a second that could form colonies, but whose kill curves diverged from the general bacterial population within 4 and 16 days of drug exposure, respectively. These tolerant subpopulations reproducibly passed through a phase characterized by multiple unfixed resistance mutations followed by emergent drug resistance in some cultures. Barcodes associated with drug resistance identified an especially privileged subpopulation that was rarely eliminated despite 20 days of drug treatment even in cultures that did not contain any drug resistant mutants. The association of this evolutionary scenario with a defined subset of barcodes across multiple independent cultures suggested a transiently heritable phenotype, and indeed glpK phase variation mutants were associated with up to 16 % of the resistant cultures. Drug tolerance and resistance were eliminated in ΔruvA mutant consistent with the importance of bacterial stress responses. This work provides a window into the origin and dynamics of bacterial drug tolerant subpopulations whose elimination may be critical to developing rapid and resistance free cures.ImportanceTuberculosis is unusual among bacterial diseases in that treatments which can rapidly resolve symptoms do not predictably lead to a durable cure unless treatment is continued for months after all clinical and microbiological signs of disease have been eradicated. Using a novel steady-state antibiotic exposure system combined with chromosomal barcoding, we identified small hidden Mycobacterium tuberculosis subpopulations that repeatedly enter into a state of drug tolerance with a predisposition to develop fixed drug resistance after first developing a cloud of unfixed resistance mutations. The existence of these difficult to eradicate subpopulations may explain the need for extended treatment regimen for tuberculosis. Their identification provides opportunities to test genetic and therapeutic approaches that may result in shorter and more effective TB treatments.

Published
2022
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3. Combinatorial transcription factor profiles predict mature and functional human islet α and β cells

Author

Stephen C. J. Parker, Patrick E. MacDonald, Rachana Haliyur, Greg Poffenberger, John T. Walker, Jean-Philippe Cartailler, Shristi Shrestha, Diane C. Saunders, Rita Bottino, Roland Stein, Xiao-Qing Dai, Alvin C. Powers, Nripesh Prasad, Marcela Brissova, Joan Camunas-Soler, Radhika Aramandla, and Shawn Levy

Subjects
geography, geography.geographical_feature_category, Chemistry, Cell, Islet, Cell biology, Electrophysiology, medicine.anatomical_structure, MAFB, medicine, Secretion, Transcription factor, Function (biology), Hormone
Abstract

Islet-enriched transcription factors (TFs) exert broad control over cellular processes in pancreatic α and β cells and changes in their expression are associated with developmental state and diabetes. However, the implications of heterogeneity in TF expression across islet cell populations are not well understood. To define this TF heterogeneity and its consequences for cellular function, we profiled >40,000 cells from normal human islets by scRNA-seq and stratified α and β cells based on combinatorial TF expression. Subpopulations of islet cells co-expressingARX/MAFB(α cells) andMAFA/MAFB(β cells) exhibited greater expression of key genes related to glucose sensing and hormone secretion relative to subpopulations expressing only one or neither TF. Moreover, all subpopulations were identified in native pancreatic tissue from multiple donors. By Patch-seq,MAFA/MAFBco-expressing β cells showed enhanced electrophysiological activity. Thus, these results indicate combinatorial TF expression in islet α and β cells predicts highly functional, mature subpopulations.

Published
2021
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4. Quality Control Metrics for Whole Blood Transcriptome Analysis in the Parkinson’s Progression Markers Initiative (PPMI)

Author

Arthur W. Toga, Alyssa Reimer, Parkinson Progression Marker Initiative, Elizabeth Hutchins, J. Raphael Gibbs, Shawn Levy, Samantha J. Hutten, Karen Crawford, Nripesh Prasad, Bradford Casey, Kendall Van Keuren-Jensen, Eric Alsop, Madison Robinson, Mark R. Cookson, Ivo Violich, David Craig, and Timothy G. Whitsett

Subjects
Oncology, Transcriptome, medicine.medical_specialty, business.industry, Internal medicine, Whole Transcriptome Sequencing, medicine, Observational study, Disease, Longitudinal cohort, business, Whole blood
Abstract

The Michael J. Fox Foundation’s Parkinson’s Progression Markers Initiative (PPMI) is an observational study to comprehensively evaluate Parkinson’s disease (PD) patients using imaging, biologic sampling, clinical and behavioural assessments to identify biomarkers of PD progression. As part of this study, we obtained 4,756 whole blood samples from 1,570 subjects at baseline, 0.5, 1, 2, and 3 years from enrollment in the study. We isolated RNA and performed whole transcriptome sequencing in this longitudinal cohort. Here, we describe and quantify technical variability associated with this dataset through the use of pooled reference samples, including plate distribution, RNA quality, and outliers. This large, uniformly processed dataset is available to researchers at https://www.ppmi-info.org.

Published
2021
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5. Multi-Platform Assessment of DNA Sequencing Performance using Human and Bacterial Reference Genomes in the ABRF Next-Generation Sequencing Study

Author

Fritz J. Sedlazeck, Gary P. Schroth, Zachary T. Herbert, Christopher E. Mason, Scott Tighe, Jin Jen, Michael M. Khayat, George Grills, Phoebe K. Laaguiby, Charles M Nicolet, Don A. Baldwin, Justin M. Zook, Giuseppe Narzisi, Alicia Alonso, Medhat Mahmoud, Shawn Levy, Jonathan Foox, Derek Warner, William G. Farmerie, Jenny Xiang, Wayne E. Clarke, and Marta Byrska-Bishop

Subjects
Computer science, Genomics, Nanopore sequencing, Computational biology, Ion semiconductor sequencing, Pacific biosciences, Genome, Multi platform, DNA sequencing
Abstract

Massively parallel DNA sequencing is a critical tool for genomics research and clinical diagnostics. Here, we describe the Association of Biomolecular Resource Facilities (ABRF) Next-Generation Sequencing Phase II Study to measure quality and reproducibility of DNA sequencing. Replicates of human and bacterial reference DNA samples were generated across multiple sequencing platforms, including well-established technologies such as Illumina, ThermoFisher Ion Torrent, and Pacific Biosciences, as well as emerging technologies such as BGI, Genapsys, and Oxford Nanopore. A total of 202 datasets were generated to investigate the performance of a total of 16 sequencing platforms, including mappability of reads, coverage and error rates in difficult genomic regions, and detection of small-scale polymorphisms and large-scale structural variants. This study provides a comprehensive baseline resource for continual benchmarking as chemistries, methods, and platforms evolve for DNA sequencing.

Published
2020
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6. Shotgun Transcriptome and Isothermal Profiling of SARS-CoV-2 Infection Reveals Unique Host Responses, Viral Diversification, and Drug Interactions

Author

David Danko, Ari Melnick, Fritz J. Sedlazeck, Matthew MacKay, Melissa M. Cushing, Lin Cong, Robert E. Schwartz, Massimo Loda, Lars F. Westblade, Daniela Bezdan, Jonathan Foox, Diana Pohle, Peter A D Steel, Craig Westover, Nicholas P. Tatonetti, John Sipley, Arryn Craney, Amos J Shemesh, Danielle Thierry-Mieg, Iman Hajirasouliha, Shawn Levy, Alon Shaiber, Daniel Butler, Vijendra Ramlall, Undina Gisladottir, Krista Ryon, Dong Xu, Chandrima Bhattacharya, Michael Zietz, Joel Rosiene, Shixiu Wu, Hanna Rennert, Jenny Xiang, Maria A. Sierra, Nikolay A. Ivanov, Bradley W. Langhorst, Nathan A. Tanner, P. Ruggiero, Mirella Salvatore, Priya Velu, Justyna Gawrys, Cem Meydan, Benjamin Young, Ebrahim Afshinnekoo, Stacy M. Horner, Dmitry Meleshko, Christopher Mozsary, Thomas Iftner, Angelika Iftner, Christopher E. Mason, Jean Thierry-Mieg, and Marcin Imielinski

Subjects
Drug, 0303 health sciences, media_common.quotation_subject, Outbreak, Diseases, Subclade, Shotgun, RNA-Seq, Biology, Virology, Article, Computational biology and bioinformatics, 3. Good health, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Interferon, Pandemic, medicine, 030217 neurology & neurosurgery, 030304 developmental biology, medicine.drug, media_common
Abstract

In less than nine months, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) killed over a million people, including >25,000 in New York City (NYC) alone. The COVID-19 pandemic caused by SARS-CoV-2 highlights clinical needs to detect infection, track strain evolution, and identify biomarkers of disease course. To address these challenges, we designed a fast (30-minute) colorimetric test (LAMP) for SARS-CoV-2 infection from naso/oropharyngeal swabs and a large-scale shotgun metatranscriptomics platform (total-RNA-seq) for host, viral, and microbial profiling. We applied these methods to clinical specimens gathered from 669 patients in New York City during the first two months of the outbreak, yielding a broad molecular portrait of the emerging COVID-19 disease. We find significant enrichment of a NYC-distinctive clade of the virus (20C), as well as host responses in interferon, ACE, hematological, and olfaction pathways. In addition, we use 50,821 patient records to find that renin–angiotensin–aldosterone system inhibitors have a protective effect for severe COVID-19 outcomes, unlike similar drugs. Finally, spatial transcriptomic data from COVID-19 patient autopsy tissues reveal distinct ACE2 expression loci, with macrophage and neutrophil infiltration in the lungs. These findings can inform public health and may help develop and drive SARS-CoV-2 diagnostic, prevention, and treatment strategies., Here, using clinical samples and autopsy tissues, the authors combine fast-colorimetric test (LAMP) for SARS-CoV-2 infection and large-scale shotgun metatranscriptomics for host, viral, and microbial profiling and provide a map of the viral genetic features of the New York City outbreak and associate specific host responses and gene expression perturbations with SARS-CoV-2 infection.

Published
2020
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7. Single-Cell, Human Sperm Transcriptomes and Variants from Fathers of Autistic and Healthy Children

Author

Paul Feinstein, Christopher E. Mason, Shristi Shrestha, Aguiar-Pulido, Delia Tomoiaga, Jeffrey A. Rosenfeld, and Shawn Levy

Subjects
Genetics, 0303 health sciences, Mutation rate, 030219 obstetrics & reproductive medicine, urogenital system, Cell, RNA, Biology, medicine.disease, Sperm, 3. Good health, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Single cell sequencing, medicine, Autism, Stem cell, 030304 developmental biology
Abstract

The human sperm is one of the smallest cells in the body, but also one of the most important, as it serves as the entire paternal genetic contribution to a child. This is especially relevant for diseases such as Autism Spectrum Disorders (ASD), which have been correlated with advance paternal age. Historically, most studies of sperm have focused on the assessment of a bulk sperm, wherein millions of individual sperm are present and only high-frequency variants can be detected. Using 10X Chromium single cell sequencing technology, we have assessed the RNA from >65,000 single sperm cells across 6 donors (scsperm-RNA-seq), including two of whom have autistic children and four that do not. Using multiple RNA-seq methods for differential expression and variant analysis, we found clusters of sperm mutations in each donor that are indicative of the sperm being produced by different stem cell pools. Moreover, by comparing the two groups, we have found expression changes that can separate out the two sets of donors. Finally, through our novel variant calling from single-cell RNA-seq methods, we have shown that we can detect mutation rates in sperm from ASD donors that is distinct from the controls, highlighting this method as a new means to characterize ASD risk.

Published
2019
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8. Transcriptomic Imputation of Bipolar Disorder and Bipolar subtypes reveals 29 novel associated genes

Author

Thomas G. Schulze, Eduard Vieta, Melissa J. Green, Jakob Grove, Ingrid Melle, Preben Bo Mortensen, Nicholas J. Schork, Thorgeir E. Thorgeirsson, Jonas Bybjerg-Grauholm, Margit Burmeister, Peter R. Schofield, Szabolcs Szelinger, Fermín Mayoral, Katherine Gordon-Smith, Qingqin S. Li, Claire O'Donovan, Josep Antoni Ramos-Quiroga, Derek W. Morris, Douglas M. Ruderfer, Stefan Herms, Huckins Lm, Martin Hautzinger, Eline J. Regeer, Sebastian Zöllner, Gustavo Turecki, Christine Søholm Hansen, Helena Medeiros, Laura J. Scott, Annelie Nordin Adolfsson, Helmut Vedder, Thomas W. Weickert, Nelson B. Freimer, Céline S. Reinbold, James McKay, Cathryn M. Lewis, Eric R. Gamazon, Frank Bellivier, Marie B¾kvad-Hansen, Srdjan Djurovic, Chun Chieh Fan, Ole A. Andreassen, Solveig K. Sieberts, Jack D. Barchas, David Curtis, Elaine K. Green, Tatiana Foroud, Shaun Purcell, Mette A. Peters, Joanna M. Biernacka, Fabian Streit, Alan F. Schatzberg, James L. Kennedy, Tiffany A. Greenwood, Bertram Müller-Myhsok, Robin Kramer, Swapnil Awasthi, Jordan W. Smoller, Cristina Sánchez-Mora, George Kirov, Ulrik Fredrik Malt, Gabriel E. Hoffman, Liz Forty, Pablo Cervantes, Jose Guzman Parra, Nicholas G. Martin, William Byerley, J. Raymond DePaulo, Martin Alda, Anil P.S. Ori, Menachem Fromer, William E. Bunney, Valentina Escott-Price, Judith A. Badner, Danielle Posthuma, Judith Allardyce, M. Ribasés, Manolis Kogevinas, Stephanie H. Witt, Anne T. Spijker, James A. Knowles, Simon Xi, Jun Li, Francis J. McMahon, Nancy J. Cox, Marcella Rietschel, Markus Leber, Laura M. Huckins, John I. Nurnberger, M. Casas, Marco P. Boks, Maria Hipolito, Evaristus A. Nwulia, Gerome Breen, Franziska Degenhardt, Janice M. Fullerton, Carlos N. Pato, Urs Heilbronner, Piotr M. Czerski, Michael Steffens, Monika Budde, Nicholas John Craddock, Katrin Gade, Bernie Devlin, Sarah Kittel-Schneider, Enrico Domenci, Weihua Guan, Sarah E. Bergen, Fan Meng, Eystein Stordal, Janet L. Sobell, Naomi R. Wray, Engilbert Sigurdsson, Marion Leboyer, Sven Cichon, Pamela Sklar, Bruno Etain, Richard M. Myers, Melvin G. McInnis, Steve McCarroll, Nicholas Bass, Christine Fraser, Thomas W. Mühleisen, Anna Maaser, Patrick F. Sullivan, Mark A. Frye, Amanda Dobbyn, John P. Rice, Amy Perry, Wei Xu, Thomas Damm Als, Anders D. Børglum, Anna C. Koller, Michael Conlon O'Donovan, Pamela B. Mahon, Sara A. Paciga, Douglas Blackwood, Michael Bauer, Fernando S. Goes, Susanne Lucae, Markus M. Nöthen, Josef Frank, Grant W. Montgomery, Scott D. Gordon, Philip B. Mitchell, Hoang T. Nguyen, Huda Akil, Chunyu Liu, Stanley J. Watson, Allan H. Young, Roel A. Ophoff, Caroline M. Nievergelt, John B. Vincent, Robert Karlsson, Kari Stefansson, Thomas Werge, Niamh Mullins, William A. Scheftner, Elliot S. Gershon, Peter McGuffin, Ralph Kupka, Mikael Landén, Matthew Flickinger, Claudia Giambartolomei, Carsten Bøcker Pedersen, Michael John Owen, Diego Albani, Hae Kyung Im, Andres Metspalu, Gunnar Morken, Panos Roussos, Tõnu Esko, Andrew M. McIntosh, Vishwajit L. Nimgaonkar, Per Hoffmann, Olav B. Smeland, Stéphane Jamain, Ole Mors, Vahram Haroutunian, Anders Juréus, Shawn Levy, Roy H. Perlis, Whitney McFadden, James Boocock, Ney Alliey-Rodriguez, Stacy Steinberg, Paul D. Shilling, Arne E. Vaaler, David Craig, Sarah E. Medland, Donald J. MacIntyre, William Coryell, Jens Treutlein, Joanna Hauser, Cynthia Shannon Weickert, Jana Strohmaier, Guy A. Rouleau, Michele T. Pato, John R. Kelsoe, Arianna Di Florio, Radhika Kandaswamy, David M. Hougaard, Toni-Kim Clarke, Susan L. McElroy, Ian Jones, Sarah Knott, Tatyana Shehktman, Wade H. Berrettini, John Strauss, Anders M. Dale, Peter P. Zandi, Andreas Reif, Claire Slaney, Julie Garnham, Margarita Rivera, Michael Gill, Lisa Jones, Cristiana Cruceanu, Sascha B. Fischer, Marian L. Hamshere, Lilijana Oruc, Weiqing Wang, Eli A. Stahl, Wolfgang Maier, Peng Zhang, Hreinn Stefansson, Ingrid Agartz, Bernhard T. Baune, Esben Agerbo, Alessandro Serretti, Robert C. Thompson, Ketil J. Oedegaard, William Lawson, Merete Nordentoft, Jacob Lawrence, Fabio Rivas, James B. Potash, Aiden Corvin, Christina M. Hultman, Maria Grigoroiu-Serbanescu, Marianne Giørtz Pedersen, Michael Boehnke, René S. Kahn, Lili Milani, Jurgen Del-Favero, Veera M. Rajagopal, Jolanta Lissowska, Howard J. Edenberg, Udo Dannlowski, Rolf Adolfsson, Andrea Pfennig, Adebayo Anjorin, and Torbjørn Elvsåshagen

Subjects
Genotype, Expression quantitative trait loci, medicine, Genome-wide association study, Locus (genetics), Bipolar disorder, Computational biology, Biology, medicine.disease, Phenotype, Genetic architecture, Imputation (genetics)
Abstract

Bipolar disorder is a complex neuropsychiatric disorder presenting with episodic mood disturbances. In this study we use a transcriptomic imputation approach to identify novel genes and pathways associated with bipolar disorder, as well as three diagnostically and genetically distinct subtypes. Transcriptomic imputation approaches leverage well-curated and publicly available eQTL reference panels to create gene-expression prediction models, which may then be applied to “impute” genetically regulated gene expression (GREX) in large GWAS datasets. By testing for association between phenotype and GREX, rather than genotype, we hope to identify more biologically interpretable associations, and thus elucidate more of the genetic architecture of bipolar disorder.We applied GREX prediction models for 13 brain regions (derived from CommonMind Consortium and GTEx eQTL reference panels) to 21,488 bipolar cases and 54,303 matched controls, constituting the largest transcriptomic imputation study of bipolar disorder (BPD) to date. Additionally, we analyzed three specific BPD subtypes, including 14,938 individuals with subtype 1 (BD-I), 3,543 individuals with subtype 2 (BD-II), and 1,500 individuals with schizoaffective subtype (SAB).We identified 125 gene-tissue associations with BPD, of which 53 represent independent associations after FINEMAP analysis. 29/53 associations were novel; i.e., did not lie within 1Mb of a locus identified in the recent PGC-BD GWAS. We identified 37 independent BD-I gene-tissue associations (10 novel), 2 BD-II associations, and 2 SAB associations. Our BPD, BD-I and BD-II associations were significantly more likely to be differentially expressed in post-mortem brain tissue of BPD, BD-I and BD-II cases than we might expect by chance. Together with our pathway analysis, our results support long-standing hypotheses about bipolar disorder risk, including a role for oxidative stress and mitochondrial dysfunction, the post-synaptic density, and an enrichment of circadian rhythm and clock genes within our results.

Published
2017
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9. A reference panel of 64,976 haplotypes for genotype imputation

Author

Steven A. McCarroll, Gerome Breen, Nicole Soranzo, Sayantan Das, Ilaria Gandin, Lukas Forer, David Schlessinger, Jonathan Marchini, Francesco Cucca, Anand Swaroop, Seppo Koskinen, Aliki-Eleni Farmaki, Alan Kwong, Gonçalo R. Abecasis, Marcus Dörr, Yang Luo, Andrew T. Chan, Andrea Angius, P. Eline Slagboom, Petr Danecek, Cinzia Sala, Ulrike Peters, Marcus A. Tuke, D.I. Boomsma, Jan H. Veldink, Nicholas J. Timpson, Scott I. Vrieze, Aarno Palotie, Matt McGue, Wouter van Rheenen, Melvin G. McInnis, Shawn Levy, George Dedoussis, Richard Durbin, Matthias Kretzler, Ross M. Fraser, C Sidore, David Melzer, Eleftheria Zeggini, Andrew R. Wood, Veikko Salomaa, Oddgeir L. Holmen, Alexander Teumer, Hyun Min Kang, James F. Wilson, Cristen J. Willer, Laura J. Scott, Richard M. Myers, George Davey Smith, Andrew T. Hattersley, Matthias Nauck, Matthew G. Sampson, Christian Fuchsberger, Josine L. Min, Leonard H. van den Berg, Thomas Meitinger, David Altshuler, John B. Vincent, Kevin Sharp, Jaakko Tuomilehto, Daniela Toniolo, Cornelia M. van Duijn, Samuli Ripatti, Stacey Gabriel, Michael Boehnke, Annelot M. Dekker, Francis S. Collins, He Zhang, Klaudia Walter, Deborah A. Nickerson, Nicola Pirastu, Morris A. Swertz, Kari Branham, Luigi Ferrucci, Sai Chen, Fabio Busonero, Paul I.W. de Bakker, Kristian Hveem, Charles Kooperberg, Michela Traglia, Warren W. Kretzschmar, Leif Groop, Tabitha A. Harrison, Sebastian Schoenherr, J. Brent Richards, Uwe Völker, Shane A. McCarthy, Harry Campbell, Massimo Mezzavilla, Chad M. Brummett, Mark I. McCarthy, Tim D. Spector, Dwight Stambolian, Massimiliano Cocca, Emily Y. Chew, Carlos N. Pato, Jeffrey C. Barrett, Christopher E. Gillies, William G. Iacono, Karen L. Mohlke, Olivier Delaneau, Laura J Corbin, Cisca Wijmenga, Anubha Mahajan, Timothy M. Frayling, James Lee, Michele T. Pato, Carl A. Anderson, Arthur Gilly, Kerrin S. Small, Paolo Gasparini, Biological Psychology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, McCarthy, Shane [0000-0002-2715-4187], Das, Sayantan [0000-0001-6346-1590], Kretzschmar, Warren [0000-0002-2575-0807], Durbin, Richard [0000-0002-9130-1006], Apollo - University of Cambridge Repository, Epidemiology, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Mccarthy, Shane, Das, Sayantan, Kretzschmar, Warren, Delaneau, Olivier, Wood, Andrew R, Teumer, Alexander, Kang, Hyun Min, Fuchsberger, Christian, Danecek, Petr, Sharp, Kevin, Luo, Yang, Sidore, Carlo, Kwong, Alan, Timpson, Nichola, Koskinen, Seppo, Vrieze, Scott, Scott, Laura J, Zhang, He, Mahajan, Anubha, Veldink, Jan, Peters, Ulrike, Pato, Carlo, van Duijn, Cornelia M, Gillies, Christopher E, Gandin, Ilaria, Mezzavilla, Massimo, Gilly, Arthur, Cocca, Massimiliano, Traglia, Michela, Angius, Andrea, Barrett, Jeffrey C, Boomsma, Dorrett, Branham, Kari, Breen, Gerome, Brummett, Chad M, Busonero, Fabio, Campbell, Harry, Chan, Andrew, Chen, Sai, Chew, Emily, Collins, Francis S, Corbin, Laura J, Smith, George Davey, Dedoussis, George, Dorr, Marcu, Farmaki, Aliki Eleni, Ferrucci, Luigi, Forer, Luka, Fraser, Ross M, Gabriel, Stacey, Levy, Shawn, Groop, Leif, Harrison, Tabitha, Hattersley, Andrew, Holmen, Oddgeir L, Hveem, Kristian, Kretzler, Matthia, Lee, James C, Mcgue, Matt, Meitinger, Thoma, Melzer, David, Min, Josine L, Mohlke, Karen L, Vincent, John B, Nauck, Matthia, Nickerson, Deborah, Palotie, Aarno, Pato, Michele, Pirastu, Nicola, Mcinnis, Melvin, Richards, J. Brent, Sala, Cinzia, Salomaa, Veikko, Schlessinger, David, Schoenherr, Sebastian, Slagboom, P. Eline, Small, Kerrin, Spector, Timothy, Stambolian, Dwight, Tuke, Marcu, Tuomilehto, Jaakko, van den Berg, Leonard H, van Rheenen, Wouter, Volker, Uwe, Wijmenga, Cisca, Toniolo, Daniela, Zeggini, Eleftheria, Gasparini, Paolo, Sampson, Matthew G, Wilson, James F, Frayling, Timothy, de Bakker, Paul I. W, Swertz, Morris A, Mccarroll, Steven, Kooperberg, Charle, Dekker, Annelot, Altshuler, David, Willer, Cristen, Iacono, William, Ripatti, Samuli, Soranzo, Nicole, Walter, Klaudia, Swaroop, Anand, Cucca, Francesco, Anderson, Carl A, Myers, Richard M, Boehnke, Michael, Mccarthy, Mark I, and Durbin, Richard

Subjects
0301 basic medicine, Netherlands Twin Register (NTR), Genotype, Population, Genome-wide association study, Single-nucleotide polymorphism, Computational biology, Biology, Polymorphism, Single Nucleotide, SEQUENCE, Article, 03 medical and health sciences, 0302 clinical medicine, Reference Values, Journal Article, Genetics, Humans, GENOME-WIDE ASSOCIATION, education, Alleles, POPULATION, 030304 developmental biology, Genetic association, Whole genome sequencing, education.field_of_study, Internet, 0303 health sciences, Genotype imputation, Medicine (all), Haplotype, ALSPAC, Minor allele frequency, 030104 developmental biology, Genetic Techniques, Haplotypes, RARE VARIANTS, 030217 neurology & neurosurgery, Imputation (genetics), Genome-Wide Association Study
Abstract

We describe a reference panel of 64,976 human haplotypes at 39,235,157 SNPs constructed using whole genome sequence data from 20 studies of predominantly European ancestry. Using this resource leads to accurate genotype imputation at minor allele frequencies as low as 0.1%, a large increase in the number of SNPs tested in association studies and can help to discover and refine causal loci. We describe remote server resources that allow researchers to carry out imputation and phasing consistently and efficiently.

Published
2015
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