Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression

Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis - and trans -expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individua...

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Vydáno v:	Nature genetics Ročník 53; číslo 9; s. 1300 - 1310
Hlavní autoři:	Claringbould, Annique, Westra, Harm-Jan, Bonder, Marc Jan, Deelen, Patrick, Kirsten, Holger, Saha, Ashis, Yazar, Seyhan, Brugge, Harm, Oelen, Roy, de Vries, Dylan H., van der Wijst, Monique G. P., Kasela, Silva, Pervjakova, Natalia, Alves, Isabel, Favé, Marie-Julie, Agbessi, Mawussé, Christiansen, Mark W., Jansen, Rick, Seppälä, Ilkka, Tong, Lin, Teumer, Alexander, Schramm, Katharina, Hemani, Gibran, Verlouw, Joost, Yaghootkar, Hanieh, Sönmez Flitman, Reyhan, Brown, Andrew, Kukushkina, Viktorija, Kalnapenkis, Anette, Rüeger, Sina, Porcu, Eleonora, Kettunen, Johannes, Lee, Bernett, Zhang, Futao, Qi, Ting, Arindrarto, Wibowo, Beutner, Frank, Dmitrieva, Julia, Elansary, Mahmoud, Fairfax, Benjamin P., Georges, Michel, Heijmans, Bastiaan T., Hewitt, Alex W., Kähönen, Mika, Kim, Yungil, Knight, Julian C., Kovacs, Peter, Krohn, Knut, Li, Shuang, Loeffler, Markus, Marigorta, Urko M., Mei, Hailang, Momozawa, Yukihide, Müller-Nurasyid, Martina, Nauck, Matthias, Nivard, Michel G., Penninx, Brenda W. J. H., Pritchard, Jonathan K., Raitakari, Olli T., Rotzschke, Olaf, Slagboom, Eline P., Stehouwer, Coen D. A., Stumvoll, Michael, Sullivan, Patrick, ’t Hoen, Peter A. C., Thiery, Joachim, Tönjes, Anke, van Dongen, Jenny, van Iterson, Maarten, Veldink, Jan H., Völker, Uwe, Warmerdam, Robert, Wijmenga, Cisca, Swertz, Morris, Andiappan, Anand, Montgomery, Grant W., Ripatti, Samuli, Perola, Markus, Kutalik, Zoltan, Dermitzakis, Emmanouil, Bergmann, Sven, van Meurs, Joyce, Prokisch, Holger, Ahsan, Habibul, Pierce, Brandon L., Lehtimäki, Terho, Psaty, Bruce M., Gharib, Sina A., Awadalla, Philip, Milani, Lili, Ouwehand, Willem H., Downes, Kate, Stegle, Oliver, Battle, Alexis, Visscher, Peter M., Yang, Jian, Powell, Joseph, Gibson, Greg, Esko, Tõnu, Franke, Lude
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	New York Nature Publishing Group US 01.09.2021 Nature Publishing Group
Témata:	631/208/199 631/208/200 631/208/205/2138 Agriculture Animal Genetics and Genomics Biomedical and Life Sciences Biomedicine Blood Blood Proteins - genetics Cancer Research Consortia Datasets Gene expression Gene Expression Regulation - genetics Gene Function Gene mapping Gene regulation Genes Genetic analysis Genetic diversity Genetic research Genetic variance Genetic variation Genetics Genetics & genetic processes Genome-Wide Association Study Genomes Génétique & processus génétiques Human Genetics Humans Identification and classification Life sciences Medical Engineering Medicinsk teknik Meta-analysis Multifactorial Inheritance - genetics Phenotypes Polygenic inheritance Polymorphism, Single Nucleotide - genetics Quantitative trait loci Quantitative Trait Loci - genetics Regulatory mechanisms (biology) Replication Sample size Sciences du vivant Transcription factors Transcriptome - genetics Transcriptomes United Kingdom
ISSN:	1061-4036, 1546-1718, 1546-1718
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Popis
Shrnutí:	Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis - and trans -expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis -eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans -eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans -eQTL. Trans -eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes. Analyses of expression profiles from whole blood of 31,684 individuals identify cis -expression quantitative trait loci (eQTL) effects for 88% of genes and trans -eQTL effects for 37% of trait-associated variants.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 scopus-id:2-s2.0-85115732255 info:eu-repo/grantAgreement/EC/H2020/733100 These authors jointly supervised U.V. and A.C. coordinated the consortium analyses, ran the meta-analyses, interpreted the data, performed downstream analyses, drafted and revised the manuscript. H-J.W., MJ.B. and P.D. developed the software used in the analyses, did downstream analyses, participated in manuscript writing and revisions. L.F. and T.E. conceived the study. L.F. supervised the project, ran downstream analyses, participated in the manuscript writing and revisions. B.Z., H.K., A.S., S.K., N.P., I.A., M-J.F., M.A., M.W.C., R.J., I.S., L.T., A.T., K.S., J.V., H.Y., V.K., A.K., J.Ke., J.P., B.L. ran consortium analyses in their respective cohorts. A.S., R.K., S.K., G.H., R.S., A.Br. ran replication analyses in their respective cohorts. A.A., G.W.M., S.Ri., M.P., E.D., S.B., T.F., J.v.M, H.P., H.A., B.P., T.L., D.I.B., B.M.P., S.A.G., P.A., L.M., W.H.O., K.D., O.S., A.Ba., M.Sc., G.G., T.E., W.A., F.B., J.D., M.E., B.P.F, M.G., B.T.H., M.K., Y.K., J.C.K, P.K., K.K., M.L., U.M.M., H.M., Y.M., M.M-N., M.Na., M.G.N., B.WJH.P., O.T.R., O.Ro., E.P.S, C.D.A.S., M.St., P.S., P.A.C.’tH, J.T., A.Tö., J.v.D., M.v.I., J.H.V., U.Vö., C.W. provided the data used in the study. B.Z., H.K., Z.K., J.Kr., S.Rü., E.P., S.L., J.Y., F.Z., P.M.V., J.P., T.Q., R.W., H.K, M.Sc. and G.G. participated in downstream analyses. S.Y., H.B., R.O., D.d.V. and M.v.d.W. ran replication analyses in scRNA-seq cohorts. A.H., JA.H. and J.P. generated scRNA-seq replication data. H.K., A.T., M.G., M.G.N., J.P., Z.K., J.Y., P.M.V., M.Sc., G.G., J.P., S.A.G. and P.A.C.’tH. contributed to writing and revising the manuscript. J.K.P. provided Supplementary Equations for interpretation of results. H.B. and M.Sw. created the website to host the results. U.V. and A.C. contributed equally to this work. H-J.W, MJ.B. and P.D. contributed equally to this work. L.F., T.E., G.G. and J.P. jointly supervised this work. BIOS Consortium contributed with the subset of the whole blood data, used in discovery analyses. i2QTL Consortium contributed with trans-eQTL and eQTS replication analyses in iPSCs. A list of authors and their affiliations appears at the end of the paper. Full list for consortium members appears in Supplementary Note These authors contributed equally Author contributions
ISSN:	1061-4036 1546-1718 1546-1718
DOI:	10.1038/s41588-021-00913-z