@article{839838cd5da746bbac0ee59ecc7db5cd,
title = "Transcriptomic signatures across human tissues identify functional rare genetic variation",
abstract = "Rare genetic variants are abundant across the human genome, and identifying their function and phenotypic impact is a major challenge. Measuring aberrant gene expression has aided in identifying functional, large-effect rare variants (RVs). Here, we expanded detection of genetically driven transcriptome abnormalities by analyzing gene expression, allele-specific expression, and alternative splicing from multitissue RNA-sequencing data, and demonstrate that each signal informs unique classes of RVs. We developed Watershed, a probabilistic model that integrates multiple genomic and transcriptomic signals to predict variant function, validated these predictions in additional cohorts and through experimental assays, and used them to assess RVs in the UK Biobank, the Million Veterans Program, and the Jackson Heart Study. Our results link thousands of RVs to diverse molecular effects and provide evidence to associate RVs affecting the transcriptome with human traits.",
author = "Ferraro, {Nicole M.} and Strober, {Benjamin J.} and Jonah Einson and Abell, {Nathan S.} and Francois Aguet and Barbeira, {Alvaro N.} and Margot Brandt and Maja Bucan and Castel, {Stephane E.} and Davis, {Joe R.} and Emily Greenwald and Hess, {Gaelen T.} and Hilliard, {Austin T.} and Kember, {Rachel L.} and Bence Kotis and Park, {Yo Son} and Gina Peloso and Shweta Ramdas and Scott, {Alexandra J.} and Craig Smail and Tsang, {Emily K.} and Zekavat, {Seyedeh M.} and Marcello Ziosi and Aradhana and Ardlie, {Kristin G.} and Assimes, {Themistocles L.} and Bassik, {Michael C.} and Brown, {Christopher D.} and Adolfo Correa and Ira Hall and Im, {Hae Kyung} and Xin Li and Pradeep Natarajan and {GTEx Consortium} and Tuuli Lappalainen and Pejman Mohammadi and Montgomery, {Stephen B.} and Alexis Battle and Shankara Anand and Stacey Gabriel and Getz, {Gad A.} and Aaron Graubert and Kane Hadley and Handsaker, {Robert E.} and Huang, {Katherine H.} and Seva Kashin and Xiao Li and MacArthur, {Daniel G.} and Andrew Brown and Li, {Jin Billy} and Moore, {Helen M.}",
note = "Funding Information: supported by the Common Fund of the Office of the Director, U.S. National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, NIA, NIAID, and NINDS through NIH contracts HHSN261200800001E (Leidos Prime contract with NCI: A.M.S., D.E.T., N.V.R., J.A.M., L.S., M.E.B., L.Q., T.K., D.B., K.R., A.U.), 10XS170 (NDRI: W.F.L., J.A.T., G.K., A.M., S.S., R.H., G.Wa., M.J., M.Wa., L.E.B., C.J., J.W., B.R., M.Hu., K.M., L.A.S., H.M.G., M.Mo., L.K.B.), 10XS171 (Roswell Park Cancer Institute: B.A.F., M.T.M., E.K., B.M.G., K.D.R., J.B.), 10X172 (Science Care, Inc.), 12ST1039 (IDOX), 10ST1035 (Van Andel Institute: S.D.J., D.C.R., D.R.V.), HHSN268201000029C (Broad Institute: F.A., G.G., K.G.A., A.V.S., X.Li., E.T., S.G., A.G., S.A., K.H.H., D.T.N., K.H., S.R.M., J.L.N.), 5U41HG009494 (F.A., G.G., K.G.A.) and through NIH grants R01 DA006227-17 (Univ. of Miami Brain Bank: D.C.M., D.A.D.), Supplement to University of Miami grant DA006227 (D.C.M., D.A.D.), R01 MH090941 (Univ. of Geneva), R01 MH090951 and R01 MH090937 (Univ. of Chicago), R01 MH090936 (Univ. of North Carolina?Chapel Hill), R01MH101814 (M.M-A., V.W., S.B.M., R.G., E.T.D., D.G-M., A.V., A.B.), U01HG007593 (S.B.M.), R01MH101822 (C.D.B.), U01HG007598 (M.O., B.E.S.), U01MH104393 (A.P.F.), extension H002371 to 5U41HG002371 (W.J.K.) as well as other funding sources: R01MH106842 (T.L., P.M., E.F., P.J.H.), R01HL142028 (T.L., Si.Ka., P.J.H.), R01GM122924 (T.L., S.E.C.), R01MH107666 (H.K.I.), P30DK020595 (H.K.I.), UM1HG008901 (T.L.), R01GM124486 (T.L.), R01HG010067 (Y.Pa.), R01HG002585 (G.Wa., M.St.), Gordon and Betty Moore Foundation GBMF 4559 (G.Wa., M.St.), 1K99HG009916-01 (S.E.C.), R01HG006855 (Se.Ka., R.E.H.), BIO2015-70777-P, Ministerio de Economia y Competitividad and FEDER funds (M.M-A., V.W., R.G., D.G-M.), la Caixa Foundation ID 100010434 under agreement LCF/BQ/SO15/52260001 (D.G-M.), NIH CTSA grant UL1TR002550-01 (P.M.), Marie-Sk?odowska Curie fellowship H2020 Grant 706636 (S.K-H.), R35HG010718 (E.R.G.), FPU15/03635, Ministerio de Educaci?n, Cultura y Deporte (M.M-A.), R01MH109905, 1R01HG010480 (A.B.), Searle Scholar Program (A.B.), R01HG008150 (S.B.M., A.B.), 5T32HG000044-22, NHGRI Institutional Training Grant in Genome Science (N.R.G.), EU IMI program (UE7-DIRECT-115317-1) (E.T.D., A.V.), FNS funded project RNA1 (31003A_149984) (E.T.D., A.V.), DK110919 (F.H.), F32HG009987 (F.H.), Massachusetts Lions Eye Research Fund Grant (A.R.H.), Mr. and Mrs. Spencer T. Olin Fellowship for Women in Graduate Study (A.J.S.), P30DK20595 (H.K.I.), UL1 TR001114 (P.M.), R01AG066490 (S.B.M.), R01HL142015 (S.B.M.), U01HG009431 (S.B.M.), U01HG009080 (S.B.M.), NIMH 1R01MH109905 (A.B.), National Science Foundation Graduate Research Fellowship, grant no. DGE ? 1656518 (N.M.F.), graduate fellowship from the Stanford Center for Computational, Evolutionary and Human Genomics (N.M.F.), New York Center for Collaborative Research in Common Disease Genomics grant UM1HG008901 (J.E.), National Science Foundation of China grant 31970554 (X.L.), Shanghai Science and Technology Major Project IHPC 2017SHZDZX01 (X.L.), NIH T32 LM012409 (C.S.), Hewlett-Packard Stanford Graduate Fellowship and a doctoral scholarship from the Natural Science and Engineering Council of Canada (E.K.T.), Lucille P. Markey Stanford Graduate Fellowship (J.R.D.). We used data from the MVP, Office of Research and Development, Veterans Health Administration, supported by award no. MVP000. This publication does not represent the views of the Department of Veterans Affairs, the U.S. Food and Drug Administration, or the U.S. Government. Molecular Data for the TOPMed program was supported by the National Heart, Lung and Blood Institute (NHLBI). Genome sequencing for ?NHLBI TOPMed: The Jackson Heart Study? (phs000964.v1.p1) was performed at the Northwest Genomics Center (HHSN268201100037C). Core support including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Core support including phenotype harmonization, data management, sample-identity QC, and general program coordination were provided by the TOPMed Data Coordinating Center (R01HL-120393; U01HL-120393; contract HHSN268201800001I). This research was also supported by funding from: the Department of Veterans Affairs awards nos. I01-BX03340 and I01-BX003362 (T.L.A.). P.N. and G.M.P. are supported by R01HL142711 from the National Heart, Lung, and Blood Institute (NHLBI). The JHS is supported and conducted in collaboration with Jackson State University (HHSN268201800013I), Tougaloo College (HHSN268201800014I), the Mississippi State Department of Health (HHSN268201800015I) and the University of Mississippi Medical Center (HHSN268201800010I, HHSN268201800011I and HHSN268201800012I) contracts from the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute on Minority Health and Health Disparities Publisher Copyright: {\textcopyright} 2020 American Association for the Advancement of Science. All rights reserved. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",
year = "2020",
month = sep,
day = "11",
doi = "10.1126/science.aaz5900",
language = "English",
volume = "369",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6509",
}