Population-scale tissue transcriptomics maps long non-coding RNAs to complex disease

GTEx Consortium

doi:10.1016/j.cell.2021.03.050

Population-scale tissue transcriptomics maps long non-coding RNAs to complex disease

GTEx Consortium

Oregon National Primate Research Center

Research output: Contribution to journal › Article › peer-review

49 Scopus citations

Abstract

Long non-coding RNA (lncRNA) genes have well-established and important impacts on molecular and cellular functions. However, among the thousands of lncRNA genes, it is still a major challenge to identify the subset with disease or trait relevance. To systematically characterize these lncRNA genes, we used Genotype Tissue Expression (GTEx) project v8 genetic and multi-tissue transcriptomic data to profile the expression, genetic regulation, cellular contexts, and trait associations of 14,100 lncRNA genes across 49 tissues for 101 distinct complex genetic traits. Using these approaches, we identified 1,432 lncRNA gene-trait associations, 800 of which were not explained by stronger effects of neighboring protein-coding genes. This included associations between lncRNA quantitative trait loci and inflammatory bowel disease, type 1 and type 2 diabetes, and coronary artery disease, as well as rare variant associations to body mass index.

Original language	English (US)
Pages (from-to)	2633-2648.e19
Journal	Cell
Volume	184
Issue number	10
DOIs	https://doi.org/10.1016/j.cell.2021.03.050
State	Published - May 13 2021

Keywords

GTEx
co-expression
colocalization
complex trait
disease
eQTL
expression quantitative trait loci
lncRNA
long non-coding RNA

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.cell.2021.03.050

Cite this

@article{e92225e881844336b067290a35852847,

title = "Population-scale tissue transcriptomics maps long non-coding RNAs to complex disease",

abstract = "Long non-coding RNA (lncRNA) genes have well-established and important impacts on molecular and cellular functions. However, among the thousands of lncRNA genes, it is still a major challenge to identify the subset with disease or trait relevance. To systematically characterize these lncRNA genes, we used Genotype Tissue Expression (GTEx) project v8 genetic and multi-tissue transcriptomic data to profile the expression, genetic regulation, cellular contexts, and trait associations of 14,100 lncRNA genes across 49 tissues for 101 distinct complex genetic traits. Using these approaches, we identified 1,432 lncRNA gene-trait associations, 800 of which were not explained by stronger effects of neighboring protein-coding genes. This included associations between lncRNA quantitative trait loci and inflammatory bowel disease, type 1 and type 2 diabetes, and coronary artery disease, as well as rare variant associations to body mass index.",

keywords = "GTEx, co-expression, colocalization, complex trait, disease, eQTL, expression quantitative trait loci, lncRNA, long non-coding RNA",

author = "{GTEx Consortium} and {de Goede}, {Olivia M.} and Nachun, {Daniel C.} and Ferraro, {Nicole M.} and Gloudemans, {Michael J.} and Rao, {Abhiram S.} and Craig Smail and Eulalio, {Tiffany Y.} and Fran{\c c}ois Aguet and Bernard Ng and Jishu Xu and Barbeira, {Alvaro N.} and Castel, {Stephane E.} and Sarah Kim-Hellmuth and Park, {Yo Son} and Scott, {Alexandra J.} and Strober, {Benjamin J.} 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 Xiao Li and MacArthur, {Daniel G.} and Meier, {Samuel R.} and Nedzel, {Jared L.} and Nguyen, {Duyen T.} and Segr{\`e}, {Ayellet V.} and Ellen Todres and Brunilda Balliu and Rodrigo Bonazzola and Andrew Brown and Conrad, {Donald F.} and Cotter, {Daniel J.} and Nancy Cox and Sayantan Das and Dermitzakis, {Emmanouil T.} and Jonah Einson and Engelhardt, {Barbara E.} and Eleazar Eskin and Flynn, {Elise D.} and Laure Fresard and Gamazon, {Eric R.} and Diego Garrido-Mart{\'i}n and Gay, {Nicole R.} and Roderic Guig{\'o} and Hamel, {Andrew R.} and Yuan He and Hoffman, {Paul J.}",

note = "Funding Information: We thank the Montgomery and Kirkegaard labs for their feedback on this work. The GTEx project was supported by the Common Fund of the Office of the Director of the National Institutes of Health (NIH) and by the National Cancer Institute , the National Human Genome Research Institute (NHGRI), the National Heart, Lung, and Blood Institute (NHLBI), the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health , and the National Institute of Neurological Disorders and Stroke. We are thankful for support from a Stanford graduate fellowship and Bio-X Stanford interdisciplinary graduate fellowship (to O.M.d.G.); a National Science Foundation graduate research fellowship (to N.M.F.); NHLBI grant R01HL135313-01 (to A.S.R.); National Library of Medicine (NLM) training grant 5T15LM007033-36 (to T.Y.E.); NHLBI grant HHSN268201000029C and NHGRI grant 5U41HG009494 (to F.A. and K.G.A.); NIH grants R01GM122924 (to S.E.C. and T.L.) and 1K99HG009916-01 (to S.E.C.); Marie-Sk{\l}odowska Curie fellowship H2020 grant 706636 (to S.K.-H.); NIH grant R01HG010067 (to Y.P.); a Mr. and Mrs. Spencer T. Olin fellowship for women in graduate study (to A.J.S.); NIH grant R01MH109905 (to A.B.); the Searle Scholar Program (to A.B.); NIH grant R01MH101822 (to C.D.B.); NIH grants R01MH106842 , R01HL142028 , UM1HG008901 , and R01GM124486 (to T.L.); NIH grants R01MH107666 and P30DK020595 (H.K.I.); NIH grants R01HL109512 , R01HL134817 , R33HL120757 , and R01HL139478 (to T.Q.); the Chan Zuckerberg Foundation-Human Cell Atlas Initiative (to T.Q.); Stanford University School of Medicine (to K.K.); and NIH grants R01MH101814 (NIH Common Fund; GTEx Program) (to A.B. and S.B.M.), R01HG008150 (NHGRI; Non-Coding Variants Program) (to A.B. and S.B.M.), and R01AG066490 , R01HL142015 , U01HG009431 , and U01HG009080 (to S.B.M.). Funding Information: We thank the Montgomery and Kirkegaard labs for their feedback on this work. The GTEx project was supported by the Common Fund of the Office of the Director of the National Institutes of Health (NIH) and by the National Cancer Institute, the National Human Genome Research Institute (NHGRI), the National Heart, Lung, and Blood Institute (NHLBI), the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health, and the National Institute of Neurological Disorders and Stroke. We are thankful for support from a Stanford graduate fellowship and Bio-X Stanford interdisciplinary graduate fellowship (to O.M.d.G.); a National Science Foundation graduate research fellowship (to N.M.F.); NHLBI grant R01HL135313-01 (to A.S.R.); National Library of Medicine (NLM) training grant 5T15LM007033-36 (to T.Y.E.); NHLBI grant HHSN268201000029C and NHGRI grant 5U41HG009494 (to F.A. and K.G.A.); NIH grants R01GM122924 (to S.E.C. and T.L.) and 1K99HG009916-01 (to S.E.C.); Marie-Sk?odowska Curie fellowship H2020 grant 706636 (to S.K.-H.); NIH grant R01HG010067 (to Y.P.); a Mr. and Mrs. Spencer T. Olin fellowship for women in graduate study (to A.J.S.); NIH grant R01MH109905 (to A.B.); the Searle Scholar Program (to A.B.); NIH grant R01MH101822 (to C.D.B.); NIH grants R01MH106842, R01HL142028, UM1HG008901, and R01GM124486 (to T.L.); NIH grants R01MH107666 and P30DK020595 (H.K.I.); NIH grants R01HL109512, R01HL134817, R33HL120757, and R01HL139478 (to T.Q.); the Chan Zuckerberg Foundation-Human Cell Atlas Initiative (to T.Q.); Stanford University School of Medicine (to K.K.); and NIH grants R01MH101814 (NIH Common Fund; GTEx Program) (to A.B. and S.B.M.), R01HG008150 (NHGRI; Non-Coding Variants Program) (to A.B. and S.B.M.), and R01AG066490, R01HL142015, U01HG009431, and U01HG009080 (to S.B.M.). O.M.d.G. designed the study, conducted analyses, visualized data, and co-wrote the manuscript; D.C.N. conducted co-expression and ASE analyses. N.M.F. conducted outlier analysis and contributed to writing. M.J.G. conducted colocalization analysis. A.S.R. contributed to colocalization analysis. C.S. contributed to outlier analysis. T.Y.E. contributed to ASE analysis. F.A. generated QTL and ASE data. B.N. and J.X. contributed to QTL replication analyses. A.N.B. contributed to GWAS and colocalization analysis. S.E.C. generated ASE and tissue-sharing data. S.K.-H. generated tissue sharing data. Y.P. contributed to colocalization analysis. A.J.S. generated structural variant data. B.J.S. contributed to outlier analysis. C.D.B. and X.W. led trainees and contributed to GWAS and colocalization analysis. I.M.H. led trainees and contributed to structural variant data. A.B. contributed to outlier analysis. T.L. led trainees. H.K.I. led trainees and led the GWAS analysis team. K.G.A. generated data and provided oversight of the LDACC and pipelines. S.M. led trainees and contributed to QTL replication analyses. T.Q. and K.K. helped with data interpretation. S.B.M. designed the study, led trainees, and co-wrote the manuscript. F.A. is an inventor on a patent application related to TensorQTL; S.E.C. is a co-founder and chief technology officer at Variant Bio and owns stock in Variant Bio; T.L. is on the scientific advisory board of Variant Bio, Goldfinch Bio, and GSK and owns stock in Variant Bio; and S.B.M. is on the scientific advisory board of MyOme. All other authors report no competing interests. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",

year = "2021",

month = may,

day = "13",

doi = "10.1016/j.cell.2021.03.050",

language = "English (US)",

volume = "184",

pages = "2633--2648.e19",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "10",

}

TY - JOUR

T1 - Population-scale tissue transcriptomics maps long non-coding RNAs to complex disease

AU - GTEx Consortium

AU - de Goede, Olivia M.

AU - Nachun, Daniel C.

AU - Ferraro, Nicole M.

AU - Gloudemans, Michael J.

AU - Rao, Abhiram S.

AU - Smail, Craig

AU - Eulalio, Tiffany Y.

AU - Aguet, François

AU - Ng, Bernard

AU - Xu, Jishu

AU - Barbeira, Alvaro N.

AU - Castel, Stephane E.

AU - Kim-Hellmuth, Sarah

AU - Park, Yo Son

AU - Scott, Alexandra J.

AU - Strober, Benjamin J.

AU - Anand, Shankara

AU - Gabriel, Stacey

AU - Getz, Gad A.

AU - Graubert, Aaron

AU - Hadley, Kane

AU - Handsaker, Robert E.

AU - Huang, Katherine H.

AU - Li, Xiao

AU - MacArthur, Daniel G.

AU - Meier, Samuel R.

AU - Nedzel, Jared L.

AU - Nguyen, Duyen T.

AU - Segrè, Ayellet V.

AU - Todres, Ellen

AU - Balliu, Brunilda

AU - Bonazzola, Rodrigo

AU - Brown, Andrew

AU - Conrad, Donald F.

AU - Cotter, Daniel J.

AU - Cox, Nancy

AU - Das, Sayantan

AU - Dermitzakis, Emmanouil T.

AU - Einson, Jonah

AU - Engelhardt, Barbara E.

AU - Eskin, Eleazar

AU - Flynn, Elise D.

AU - Fresard, Laure

AU - Gamazon, Eric R.

AU - Garrido-Martín, Diego

AU - Gay, Nicole R.

AU - Guigó, Roderic

AU - Hamel, Andrew R.

AU - He, Yuan

AU - Hoffman, Paul J.

N1 - Funding Information: We thank the Montgomery and Kirkegaard labs for their feedback on this work. The GTEx project was supported by the Common Fund of the Office of the Director of the National Institutes of Health (NIH) and by the National Cancer Institute , the National Human Genome Research Institute (NHGRI), the National Heart, Lung, and Blood Institute (NHLBI), the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health , and the National Institute of Neurological Disorders and Stroke. We are thankful for support from a Stanford graduate fellowship and Bio-X Stanford interdisciplinary graduate fellowship (to O.M.d.G.); a National Science Foundation graduate research fellowship (to N.M.F.); NHLBI grant R01HL135313-01 (to A.S.R.); National Library of Medicine (NLM) training grant 5T15LM007033-36 (to T.Y.E.); NHLBI grant HHSN268201000029C and NHGRI grant 5U41HG009494 (to F.A. and K.G.A.); NIH grants R01GM122924 (to S.E.C. and T.L.) and 1K99HG009916-01 (to S.E.C.); Marie-Skłodowska Curie fellowship H2020 grant 706636 (to S.K.-H.); NIH grant R01HG010067 (to Y.P.); a Mr. and Mrs. Spencer T. Olin fellowship for women in graduate study (to A.J.S.); NIH grant R01MH109905 (to A.B.); the Searle Scholar Program (to A.B.); NIH grant R01MH101822 (to C.D.B.); NIH grants R01MH106842 , R01HL142028 , UM1HG008901 , and R01GM124486 (to T.L.); NIH grants R01MH107666 and P30DK020595 (H.K.I.); NIH grants R01HL109512 , R01HL134817 , R33HL120757 , and R01HL139478 (to T.Q.); the Chan Zuckerberg Foundation-Human Cell Atlas Initiative (to T.Q.); Stanford University School of Medicine (to K.K.); and NIH grants R01MH101814 (NIH Common Fund; GTEx Program) (to A.B. and S.B.M.), R01HG008150 (NHGRI; Non-Coding Variants Program) (to A.B. and S.B.M.), and R01AG066490 , R01HL142015 , U01HG009431 , and U01HG009080 (to S.B.M.). Funding Information: We thank the Montgomery and Kirkegaard labs for their feedback on this work. The GTEx project was supported by the Common Fund of the Office of the Director of the National Institutes of Health (NIH) and by the National Cancer Institute, the National Human Genome Research Institute (NHGRI), the National Heart, Lung, and Blood Institute (NHLBI), the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health, and the National Institute of Neurological Disorders and Stroke. We are thankful for support from a Stanford graduate fellowship and Bio-X Stanford interdisciplinary graduate fellowship (to O.M.d.G.); a National Science Foundation graduate research fellowship (to N.M.F.); NHLBI grant R01HL135313-01 (to A.S.R.); National Library of Medicine (NLM) training grant 5T15LM007033-36 (to T.Y.E.); NHLBI grant HHSN268201000029C and NHGRI grant 5U41HG009494 (to F.A. and K.G.A.); NIH grants R01GM122924 (to S.E.C. and T.L.) and 1K99HG009916-01 (to S.E.C.); Marie-Sk?odowska Curie fellowship H2020 grant 706636 (to S.K.-H.); NIH grant R01HG010067 (to Y.P.); a Mr. and Mrs. Spencer T. Olin fellowship for women in graduate study (to A.J.S.); NIH grant R01MH109905 (to A.B.); the Searle Scholar Program (to A.B.); NIH grant R01MH101822 (to C.D.B.); NIH grants R01MH106842, R01HL142028, UM1HG008901, and R01GM124486 (to T.L.); NIH grants R01MH107666 and P30DK020595 (H.K.I.); NIH grants R01HL109512, R01HL134817, R33HL120757, and R01HL139478 (to T.Q.); the Chan Zuckerberg Foundation-Human Cell Atlas Initiative (to T.Q.); Stanford University School of Medicine (to K.K.); and NIH grants R01MH101814 (NIH Common Fund; GTEx Program) (to A.B. and S.B.M.), R01HG008150 (NHGRI; Non-Coding Variants Program) (to A.B. and S.B.M.), and R01AG066490, R01HL142015, U01HG009431, and U01HG009080 (to S.B.M.). O.M.d.G. designed the study, conducted analyses, visualized data, and co-wrote the manuscript; D.C.N. conducted co-expression and ASE analyses. N.M.F. conducted outlier analysis and contributed to writing. M.J.G. conducted colocalization analysis. A.S.R. contributed to colocalization analysis. C.S. contributed to outlier analysis. T.Y.E. contributed to ASE analysis. F.A. generated QTL and ASE data. B.N. and J.X. contributed to QTL replication analyses. A.N.B. contributed to GWAS and colocalization analysis. S.E.C. generated ASE and tissue-sharing data. S.K.-H. generated tissue sharing data. Y.P. contributed to colocalization analysis. A.J.S. generated structural variant data. B.J.S. contributed to outlier analysis. C.D.B. and X.W. led trainees and contributed to GWAS and colocalization analysis. I.M.H. led trainees and contributed to structural variant data. A.B. contributed to outlier analysis. T.L. led trainees. H.K.I. led trainees and led the GWAS analysis team. K.G.A. generated data and provided oversight of the LDACC and pipelines. S.M. led trainees and contributed to QTL replication analyses. T.Q. and K.K. helped with data interpretation. S.B.M. designed the study, led trainees, and co-wrote the manuscript. F.A. is an inventor on a patent application related to TensorQTL; S.E.C. is a co-founder and chief technology officer at Variant Bio and owns stock in Variant Bio; T.L. is on the scientific advisory board of Variant Bio, Goldfinch Bio, and GSK and owns stock in Variant Bio; and S.B.M. is on the scientific advisory board of MyOme. All other authors report no competing interests. Publisher Copyright: © 2021 Elsevier Inc.

PY - 2021/5/13

Y1 - 2021/5/13

N2 - Long non-coding RNA (lncRNA) genes have well-established and important impacts on molecular and cellular functions. However, among the thousands of lncRNA genes, it is still a major challenge to identify the subset with disease or trait relevance. To systematically characterize these lncRNA genes, we used Genotype Tissue Expression (GTEx) project v8 genetic and multi-tissue transcriptomic data to profile the expression, genetic regulation, cellular contexts, and trait associations of 14,100 lncRNA genes across 49 tissues for 101 distinct complex genetic traits. Using these approaches, we identified 1,432 lncRNA gene-trait associations, 800 of which were not explained by stronger effects of neighboring protein-coding genes. This included associations between lncRNA quantitative trait loci and inflammatory bowel disease, type 1 and type 2 diabetes, and coronary artery disease, as well as rare variant associations to body mass index.

AB - Long non-coding RNA (lncRNA) genes have well-established and important impacts on molecular and cellular functions. However, among the thousands of lncRNA genes, it is still a major challenge to identify the subset with disease or trait relevance. To systematically characterize these lncRNA genes, we used Genotype Tissue Expression (GTEx) project v8 genetic and multi-tissue transcriptomic data to profile the expression, genetic regulation, cellular contexts, and trait associations of 14,100 lncRNA genes across 49 tissues for 101 distinct complex genetic traits. Using these approaches, we identified 1,432 lncRNA gene-trait associations, 800 of which were not explained by stronger effects of neighboring protein-coding genes. This included associations between lncRNA quantitative trait loci and inflammatory bowel disease, type 1 and type 2 diabetes, and coronary artery disease, as well as rare variant associations to body mass index.

KW - GTEx

KW - co-expression

KW - colocalization

KW - complex trait

KW - disease

KW - eQTL

KW - expression quantitative trait loci

KW - lncRNA

KW - long non-coding RNA

UR - http://www.scopus.com/inward/record.url?scp=85105565888&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85105565888&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2021.03.050

DO - 10.1016/j.cell.2021.03.050

M3 - Article

C2 - 33864768

AN - SCOPUS:85105565888

SN - 0092-8674

VL - 184

SP - 2633-2648.e19

JO - Cell

JF - Cell

IS - 10

ER -

Population-scale tissue transcriptomics maps long non-coding RNAs to complex disease

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