@article{36880dcba9194b7fa00ea3e2f93b39b8,
title = "The impact of rare variation on gene expression across tissues",
abstract = "Rare genetic variants are abundant in humans and are expected to contribute to individual disease risk1-4. While genetic association studies have successfully identified common genetic variants associated with susceptibility, these studies are not practical for identifying rare variants1,5. Efforts to distinguish pathogenic variants from benign rare variants have leveraged the genetic code to identify deleterious protein-coding alleles1,6,7, but no analogous code exists for non-coding variants. Therefore, ascertaining which rare variants have phenotypic effects remains a major challenge. Rare non-coding variants have been associated with extreme gene expression in studies using single tissues8-11, but their effects across tissues are unknown. Here we identify gene expression outliers, or individuals showing extreme expression levels for a particular gene, across 44 human tissues by using combined analyses of whole genomes and multi-tissue RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project v6p release12. We find that 58% of underexpression and 28% of overexpression outliers have nearby conserved rare variants compared to 8% of non-outliers. Additionally, we developed RIVER (RNA-informed variant effect on regulation), a Bayesian statistical model that incorporates expression data to predict a regulatory effect for rare variants with higher accuracy than models using genomic annotations alone. Overall, we demonstrate that rare variants contribute to large gene expression changes across tissues and provide an integrative method for interpretation of rare variants in individual genomes.",
author = "{GTEx Consortium} and Xin Li and Yungil Kim and Tsang, {Emily K.} and Davis, {Joe R.} and Damani, {Farhan N.} and Colby Chiang and Hess, {Gaelen T.} and Zachary Zappala and Strober, {Benjamin J.} and Scott, {Alexandra J.} and Amy Li and Andrea Ganna and Bassik, {Michael C.} and Merker, {Jason D.} and Fran{\c c}ois Aguet and Ardlie, {Kristin G.} and Cummings, {Beryl B.} and Gelfand, {Ellen T.} and Gad Getz and Kane Hadley and Handsaker, {Robert E.} and Huang, {Katherine H.} and Seva Kashin and Karczewski, {Konrad J.} and Monkol Lek and Xiao Li and MacArthur, {Daniel G.} and Nedzel, {Jared L.} and Nguyen, {Duyen T.} and Noble, {Michael S.} and Segr{\`e}, {Ayellet V.} and Trowbridge, {Casandra A.} and Taru Tukiainen and Abell, {Nathan S.} and Brunilda Balliu and Ruth Barshir and Omer Basha and Bogu, {Gireesh K.} and Andrew Brown and Brown, {Christopher D.} and Castel, {Stephane E.} and Chen, {Lin S.} and Conrad, {Donald F.} and Cox, {Nancy J.} and Olivier Delaneau and Dermitzakis, {Emmanouil T.} and Engelhardt, {Barbara E.} and Eleazar Eskin and Ferreira, {Pedro G.} and Hall, {Ira M.}",
note = "Funding Information: Acknowledgements We thank members of the MacArthur laboratory and the Laboratory, Data Analysis, and Coordinating Center (LDACC) for performing the quality control of the whole genome sequencing data, D. Conrad for help with the structural variant calls, D. A. Knowles for code review, J. T. Leek and C. D. Brown for feedback on the manuscript, and the artists of the graphics that we modified in Fig. 1 (https://pixabay.com/en/man-silhouette-stand-straight-308387/ and http://www.allvectors.com/human-organs/). The Genotype-Tissue Expression (GTEx) project was supported by the Common Fund of the Office of the Director of the National Institutes of Health (NIH). Additional funds were provided by the National Cancer Institute; National Human Genome Research Institute (NHGRI); National Heart, Lung, and Blood Institute; National Institute on Drug Abuse; National Institute of Mental Health; and National Institute of Neurological Disorders and Stroke. Donors were enrolled at the Biospecimen Source Sites funded by Leidos Biomedical, Inc. (Leidos) subcontracts to the National Disease Research Interchange (10XS170) and Roswell Park Cancer Institute (10XS171). The LDACC was funded through a contract (HHSN268201000029C) to The Broad Institute. Biorepository operations were funded through a Leidos subcontract to the Van Andel Institute (10ST1035). Additional data repository and project management were provided by Leidos (HHSN261200800001E). The Brain Bank was supported by a supplement to University of Miami grant DA006227. We are grateful for support from a Hewlett-Packard Stanford Graduate Fellowship (E.K.T.), a doctoral scholarship from the Natural Science and Engineering Council of Canada (E.K.T.), a Lucille P. Markey Biomedical Research Stanford Graduate Fellowship (J.R.D.), the Stanford Genome Training Program (SGTP; NHGRI T32HG000044) (J.R.D., Z.Z.), the National Science Foundation GRFP (DGE-114747) (Z.Z.), the Joseph C. Pistritto Research Fellowship (F.N.D.), NIH training grant T32 GM007057 (B.J.S.), a Mr and Mrs Spencer T. Olin Fellowship for Women in Graduate Study (A.J.S.), the Searle Scholars Program (A.B.), NIH grants 1R01MH109905-01 (A.B.), R01MH101814 (NIH Common Fund; GTEx Program) (A.B. and S.B.M.), R01HG008150 (NHGRI; Non-Coding Variants Program) (A.B., S.B.M.), and NHGRI grants U01HG007436 and U01HG009080 (S.B.M.). Publisher Copyright: {\textcopyright} 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.",
year = "2017",
month = oct,
day = "11",
doi = "10.1038/nature24267",
language = "English",
volume = "550",
pages = "239--243",
journal = "Nature",
issn = "0028-0836",
number = "7675",
}