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Nature. 2017 Oct 11;550(7675):239-243. doi: 10.1038/nature24267.

The impact of rare variation on gene expression across tissues.

Collaborators (248)

Aguet F, Ardlie KG, Cummings BB, Gelfand ET, Getz G, Hadley K, Handsaker RE, Huang KH, Kashin S, Karczewski KJ, Lek M, Li X, MacArthur DG, Nedzel JL, Nguyen DT, Noble MS, Segrè AV, Trowbridge CA, Tukiainen T, Abell NS, Balliu B, Barshir R, Basha O, Battle A, Bogu GK, Brown A, Brown CD, Castel SE, Chen LS, Chiang C, Conrad DF, Cox NJ, Damani FN, Davis JR, Delaneau O, Dermitzakis ET, Engelhardt BE, Eskin E, Ferreira PG, Frésard L, Gamazon ER, Garrido-Martín D, Gewirtz ADH, Gliner G, Gloudemans MJ, Guigo R, Hall IM, Han B, He Y, Hormozdiari F, Howald C, Kyung Im H, Jo B, Yong Kang E, Kim Y, Kim-Hellmuth S, Lappalainen T, Li G, Li X, Liu B, Mangul S, McCarthy MI, McDowell IC, Mohammadi P, Monlong J, Montgomery SB, Muñoz-Aguirre M, Ndungu AW, Nicolae DL, Nobel AB, Oliva M, Ongen H, Palowitch JJ, Panousis N, Papasaikas P, Park Y, Parsana P, Payne AJ, Peterson CB, Quan J, Reverter F, Sabatti C, Saha A, Sammeth M, Scott AJ, Shabalin AA, Sodaei R, Stephens M, Stranger BE, Strober BJ, Sul JH, Tsang EK, Urbut S, van de Bunt M, Wang G, Wen X, Wright FA, Xi HS, Yeger-Lotem E, Zappala Z, Zaugg JB, Zhou YH, Akey JM, Bates D, Chan J, Chen LS, Claussnitzer M, Demanelis K, Diegel M, Doherty JA, Feinberg AP, Fernando MS, Halow J, Hansen KD, Haugen E, Hickey PF, Hou L, Jasmine F, Jian R, Jiang L, Johnson A, Kaul R, Kellis M, Kibriya MG, Lee K, Billy Li J, Li Q, Li X, Lin J, Lin S, Linder S, Linke C, Liu Y, Maurano MT, Molinie B, Montgomery SB, Nelson J, Neri FJ, Oliva M, Park Y, Pierce BL, Rinaldi NJ, Rizzardi LF, Sandstrom R, Skol A, Smith KS, Snyder MP, Stamatoyannopoulos J, Stranger BE, Tang H, Tsang EK, Wang L, Wang M, Van Wittenberghe N, Wu F, Zhang R, Nierras CR, Branton PA, Carithers LJ, Guan P, Moore HM, Rao A, Vaught JB, Gould SE, Lockart NC, Martin C, Struewing JP, Volpi S, Addington AM, Koester SE, Little AR, Brigham LE, Hasz R, Hunter M, Johns C, Johnson M, Kopen G, Leinweber WF, Lonsdale JT, McDonald A, Mestichelli B, Myer K, Roe B, Salvatore M, Shad S, Thomas JA, Walters G, Washington M, Wheeler J, Bridge J, Foster BA, Gillard BM, Karasik E, Kumar R, Miklos M, Moser MT, Jewell SD, Montroy RG, Rohrer DC, Valley DR, Davis DA, Mash DC, Undale AH, Smith AM, Tabor DE, Roche NV, McLean JA, Vatanian N, Robinson KL, Sobin L, Barcus ME, Valentino KM, Qi L, Hunter S, Hariharan P, Singh S, Um KS, Matose T, Tomaszewski MM, Barker LK, Mosavel M, Siminoff LA, Traino HM, Flicek P, Juettemann T, Ruffier M, Sheppard D, Taylor K, Trevanion SJ, Zerbino DR, Craft B, Goldman M, Haeussler M, Kent WJ, Lee CM, Paten B, Rosenbloom KR, Vivian J, Zhu J, Craft B, Goldman M, Haeussler M, Kent WJ, Lee CM, Paten B, Rosenbloom KR, Vivian J, Zhu J.

Author information

1
Department of Pathology, Stanford University, Stanford, California 94305, USA.
2
Department of Computer Science, Johns Hopkins University, Baltimore 21218, Maryland, USA.
3
Biomedical Informatics Program, Stanford University, Stanford, California 94305, USA.
4
Department of Genetics, Stanford University, Stanford, California 94305, USA.
5
McDonnell Genome Institute, Washington University School of Medicine, St Louis, Missouri 63108, USA.
6
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland 21218, USA.
7
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
8
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
9
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
10
Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA.
11
Department of Genetics, Washington University School of Medicine, St Louis, Missouri 63110, USA.

Abstract

Rare genetic variants are abundant in humans and are expected to contribute to individual disease risk. While genetic association studies have successfully identified common genetic variants associated with susceptibility, these studies are not practical for identifying rare variants. Efforts to distinguish pathogenic variants from benign rare variants have leveraged the genetic code to identify deleterious protein-coding alleles, 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 tissues, 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 release. 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.

PMID:
29022581
PMCID:
PMC5877409
DOI:
10.1038/nature24267
[Indexed for MEDLINE]
Free PMC Article

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