ArticleScience (New York, N.Y.)2015
Human genomics. Effect of predicted protein-truncating genetic variants on the human transcriptome.
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In one paragraph
Article in Science (New York, N.Y.), 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 201 papers, 5 of them syntheses that pooled it.
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201citing papers in PubMed, 5 pooled it
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
201 citing papers in PubMed, 5 syntheses or guidelines pooled it.
- Ciliopathies are responsible for short stature and insulin resistance: A systematic review of this clinical association regarding SOFT syndrome.Reviews in endocrine & metabolic disorders · 2024Pooled it
- A resource for integrated genomic analysis of the human liver.Scientific reports · 2022Pooled it
- Endoplasmic stress-inducing variants in CPB1 and CPA1 and risk of pancreatic cancer: A case-control study and meta-analysis.International journal of cancer · 2022Pooled it
- What genes are differentially expressed in individuals with schizophrenia? A systematic review.Molecular psychiatry · 2022Pooled it
- Meta-analysis of gene-environment-wide association scans accounting for education level identifies additional loci for refractive error.Nature communications · 2016Pooled it
- Mutations in the pancreatic secretory enzymesProceedings of the National Academy of Sciences of the United States of America · 2018Trial
- Signatures of nonsense-mediated mRNA decay but no evidence for transcriptional adaptation associated with protein-truncating variants in wild yeast diploids.Molecular biology and evolution · 2026Article
- Tools and tactics for studying alternative splicing.Nature reviews. Genetics · 2026Review
- predNMD: prediction of nonsense-mediated mRNA decay for improved clinical variant pathogenicity classification.bioRxiv : the preprint server for biology · 2026Article
- Dynamics of Gene and Allelic Expression During Modern Hybrid Maize Breeding.Plant biotechnology journal · 2026Article
- RNA Sequencing Resolves Cryptic Pathogenic Variants in Mitochondrial Disease.Annals of clinical and translational neurology · 2026Article
- Targeted long-read RNA sequencing for rare disease diagnosis and variant interpretation.Science advances · 2026Article
- A loss-of-function variant in GFRAL associates with increased alcohol consumption in humans.bioRxiv : the preprint server for biology · 2026Article
- A transcriptomic dimension of neuronal and immune gene programs within the subgenual anterior cingulate cortex in schizophrenia.Translational psychiatry · 2026Article
- Clinical Variant Databases and Machine Learning Prediction Supporting Genomic Medicine.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Cellular Functional Analyses ofHuman mutation · 2026Article
- Synonymous and non-synonymous variants at splice junctions can disrupt splicing and are frequently linked to disease associated loss of function genes.BMC genomics · 2025Article
- Genomic stop codon scanning reveals quantitative principles of nonsense-mediated mRNA decay.bioRxiv : the preprint server for biology · 2025Article
- Integrative and accurate annotations enhance current nonsense-mediated mRNA decay rules.Nucleic acids research · 2025Article
- Analysis and Interpretation of Somatic NMD-Escaping Variants in Oncogenes and Dual-Function Genes across Adult and Pediatric Cancer Cohorts.medRxiv : the preprint server for health sciences · 2025Article
141 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
39 authors.
Manuel A RivasWellcome Trust Centre for Human Genetics, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. rivas@well.ox.ac.uk tlappalainen@nygenome.org macarthur@atgu.mgh.harvard.edu.
Matti PirinenFInstitute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Donald F ConradWashington University in St. Louis, St. Louis, MO, USA.
Monkol LekBroad Institute of MIT and Harvard, Cambridge, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Emily K TsangDepartment of Genetics, Stanford University, Stanford, CA, USA. Department of Pathology, Stanford University, Stanford, CA, USA. Biomedical Informatics Program, Stanford University, Stanford, CA, USA.
Konrad J KarczewskiBroad Institute of MIT and Harvard, Cambridge, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Julian B MallerBroad Institute of MIT and Harvard, Cambridge, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Kimberly R KukurbaDepartment of Genetics, Stanford University, Stanford, CA, USA. Department of Pathology, Stanford University, Stanford, CA, USA.
David S DeLucaBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Menachem FromerBroad Institute of MIT and Harvard, Cambridge, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. Department of Psychiatry, Mt. Sinai Hospital, NY, USA.
Pedro G FerreiraDepartment of Genetic Medicine and Development,University of Geneva, Geneva, Switzerland. Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland. Swiss Institute of Bioinformatics, Geneva, Switzerland.
Kevin S SmithDepartment of Genetics, Stanford University, Stanford, CA, USA. Department of Pathology, Stanford University, Stanford, CA, USA.
Rui ZhangDepartment of Genetics, Stanford University, Stanford, CA, USA.
Fengmei ZhaoBroad Institute of MIT and Harvard, Cambridge, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Eric BanksBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Ryan PoplinBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Douglas M RuderferDepartment of Psychiatry, Mt. Sinai Hospital, NY, USA. Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, NY, USA.
Shaun M PurcellBroad Institute of MIT and Harvard, Cambridge, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. Department of Psychiatry, Mt. Sinai Hospital, NY, USA. Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, NY, USA.
Taru TukiainenBroad Institute of MIT and Harvard, Cambridge, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Eric V MinikelBroad Institute of MIT and Harvard, Cambridge, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Peter D StensonInstitute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, UK.
David N CooperInstitute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, UK.
Katharine H HuangBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Timothy J SullivanBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Jared NedzelBroad Institute of MIT and Harvard, Cambridge, MA, USA.
GTEx Consortium
Geuvadis Consortium
Carlos D BustamanteDepartment of Genetics, Stanford University, Stanford, CA, USA.
Jin Billy LiDepartment of Genetics, Stanford University, Stanford, CA, USA.
Mark J DalyBroad Institute of MIT and Harvard, Cambridge, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Roderic GuigoCenter for Genomic Regulation (CRG), Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain.
Peter DonnellyWellcome Trust Centre for Human Genetics, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. Department of Statistics, University of Oxford, Oxford, UK.
Kristin ArdlieBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Michael SammethCenter for Genomic Regulation (CRG), Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain. National Institute for Scientific Computing (LNCC), Petropolis, Rio de Janeiro, Brazil.
Emmanouil T DermitzakisDepartment of Genetic Medicine and Development,University of Geneva, Geneva, Switzerland. Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland. Swiss Institute of Bioinformatics, Geneva, Switzerland.
Mark I McCarthyWellcome Trust Centre for Human Genetics, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. Oxford Center for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK.
Stephen B MontgomeryDepartment of Genetics, Stanford University, Stanford, CA, USA. Department of Pathology, Stanford University, Stanford, CA, USA.
Tuuli LappalainenDepartment of Genetics, Stanford University, Stanford, CA, USA. Department of Genetic Medicine and Development,University of Geneva, Geneva, Switzerland. Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland. Swiss Institute of Bioinformatics, Geneva, Switzerland. New York Genome Center, New York, NY, USA. Department of Systems Biology, Columbia University, New York, NY, USA. rivas@well.ox.ac.uk tlappalainen@nygenome.org macarthur@atgu.mgh.harvard.edu.
Daniel G MacArthurBroad Institute of MIT and Harvard, Cambridge, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. Department of Medicine, Harvard Medical School, Boston, MA, USA. rivas@well.ox.ac.uk tlappalainen@nygenome.org macarthur@atgu.mgh.harvard.edu.
Funding
Two-Spirit Films in Indigenous Cancer HealthP30CA016056 · NCI · ROSWELL PARK CANCER INSTITUTE CORP · PI MARK G FRATTINI · 1985 to 2026
$116.6MPOSTDOCTORAL TRAINING IN MEDICAL INFORMATION SCIENCEST15LM007033 · NLM · STANFORD UNIVERSITY · PI SYLVIA KATINA PLEVRITIS · 1985 to 2026
$25.5MPilot and Feasibility ProgramP30DK020595 · NIDDK · UNIVERSITY OF CHICAGO · PI Matthew J Brady · 2013 to 2026
$20.9MGENETICS TRAINING PROGRAM FOR PHD CANDIDATEST32GM007790 · NIGMS · STANFORD UNIVERSITY · PI BRUNET, ANNE, KINGSLEY, DAVID M · 1985 to 2020
$12.8MLIMBIC &MEDULLARY MECH. IN COCAINE-RELATED SUDDEN DEATHR01DA006227 · NIDA · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · PI MASH, DEBORAH C. · 1990 to 2012
$3.7MEpigenomic variation atlas across human tissues and individuals in GTExU01HG007610 · NHGRI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI KELLIS, MANOLIS · 2014 to 2016
$3.0MMethods for high-resolution analysis of genetic effects on gene expressionR01MH101814 · NIMH · UNIVERSITY OF GENEVA · PI BUSTAMANTE, CARLOS DANIEL, DERMITZAKIS, EMMANOUIL · 2013 to 2016
$2.3MHarnessing GTEx to Create Transcriptome Knowledge and Inform Disease BiologyR01MH101820 · NIMH · UNIVERSITY OF CHICAGO · PI COX, NANCY J, NICOLAE, DAN LIVIU · 2013 to 2015
$2.3MAnnotation and interpretation of loss-of-function polymorphisms in human genomesR01GM104371 · NIGMS · MASSACHUSETTS GENERAL HOSPITAL · PI MACARTHUR, DANIEL G · 2013 to 2016
$1.3MMODELING THE EFFECTS OF STRUCTURAL VARIATION IN GTEX DATA AND MENDELIAN DISEASER01MH101810 · NIMH · WASHINGTON UNIVERSITY · PI CONRAD, DONALD F. · 2013 to 2016
$1.3MHIGH RESOLUTION ALLELE SPECIFIC EXPRESSION ASSAYSU01HG007593 · NHGRI · STANFORD UNIVERSITY · PI LI, JIN BILLY · 2014 to 2016
$1.3MSystems approaches to link tissue-specific expression to diseaseR01MH101819 · NIMH · NORTH CAROLINA STATE UNIVERSITY RALEIGH · PI NOBEL, ANDREW B, WRIGHT, FRED A. · 2013 to 2015
$1.3MCCR NIH HHS HHSN261200800001CNCI NIH HHS HHSN261200800001ENCI NIH HHS P30 CA016056NHGRI NIH HHS U01 HG007593NHGRI NIH HHS U01HG007593NHGRI NIH HHS U01 HG007610NHLBI NIH HHS HHSN268201000029CNIDA NIH HHS DA006227NIDA NIH HHS R01 DA006227NIDDK NIH HHS P30 DK020595NIGMS NIH HHS R01 GM104371NIGMS NIH HHS R01GM104371NIMH NIH HHS MH090936NIMH NIH HHS MH090937NIMH NIH HHS MH090941NIMH NIH HHS MH090948NIMH NIH HHS MH090951NIMH NIH HHS R01 MH090936NIMH NIH HHS R01 MH090937NIMH NIH HHS R01 MH090941NIMH NIH HHS R01MH090941NIMH NIH HHS R01 MH090948NIMH NIH HHS R01 MH090951NIMH NIH HHS R01 MH101810NIMH NIH HHS R01MH101810NIMH NIH HHS R01 MH101814NIMH NIH HHS R01MH101814NIMH NIH HHS R01 MH101819NIMH NIH HHS R01 MH101820NLM NIH HHS T15 LM007033Wellcome Trust 090532Wellcome Trust 090532/Z/09/ZWellcome Trust 095552Wellcome Trust 095552/Z/11/ZWellcome Trust 098381
Abstract
Accurate prediction of the functional effect of genetic variation is critical for clinical genome interpretation. We systematically characterized the transcriptome effects of protein-truncating variants, a class of variants expected to have profound effects on gene function, using data from the Genotype-Tissue Expression (GTEx) and Geuvadis projects. We quantitated tissue-specific and positional effects on nonsense-mediated transcript decay and present an improved predictive model for this decay. We directly measured the effect of variants both proximal and distal to splice junctions. Furthermore, we found that robustness to heterozygous gene inactivation is not due to dosage compensation. Our results illustrate the value of transcriptome data in the functional interpretation of genetic variants.
Indexed as
Gene Expression RegulationGenetic VariationTranscriptomeAlternative SplicingGene Expression ProfilingGene SilencingGenome, HumanHeterozygoteHumansNonsense Mediated mRNA DecayPhenotypeProteinsProteins
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