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Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression
Nature Genetics  (IF38.33),  Pub Date : 2021-09-02, DOI: 10.1038/s41588-021-00913-z
Urmo Võsa, Annique Claringbould, Harm-Jan Westra, Marc Jan Bonder, Patrick Deelen, Biao Zeng, Holger Kirsten, Ashis Saha, Roman Kreuzhuber, Seyhan Yazar, Harm Brugge, Roy Oelen, Dylan H. de Vries, Monique G. P. van der Wijst, Silva Kasela, Natalia Pervjakova, Isabel Alves, Marie-Julie Favé, Mawussé Agbessi, Mark W. Christiansen, Rick Jansen, Ilkka Seppälä, Lin Tong, Alexander Teumer, Katharina Schramm, Gibran Hemani, Joost Verlouw, Hanieh Yaghootkar, Reyhan Sönmez Flitman, Andrew Brown, Viktorija Kukushkina, Anette Kalnapenkis, Sina Rüeger, Eleonora Porcu, Jaanika Kronberg, Johannes Kettunen, Bernett Lee, Futao Zhang, Ting Qi, Jose Alquicira Hernandez, Wibowo Arindrarto, Frank Beutner, Julia Dmitrieva, Mahmoud Elansary, Benjamin P. Fairfax, Michel Georges, Bastiaan T. Heijmans, Alex W. Hewitt, Mika Kähönen, Yungil Kim, Julian C. Knight, Peter Kovacs, Knut Krohn, Shuang Li, Markus Loeffler, Urko M. Marigorta, Hailang Mei, Yukihide Momozawa, Martina Müller-Nurasyid, Matthias Nauck, Michel G. Nivard, Brenda W. J. H. Penninx, Jonathan K. Pritchard, Olli T. Raitakari, Olaf Rotzschke, Eline P. Slagboom, Coen D. A. Stehouwer, Michael Stumvoll, Patrick Sullivan, Peter A. C. ’t Hoen, Joachim Thiery, Anke Tönjes, Jenny van Dongen, Maarten van Iterson, Jan H. Veldink, Uwe Völker, Robert Warmerdam, Cisca Wijmenga, Morris Swertz, Anand Andiappan, Grant W. Montgomery, Samuli Ripatti, Markus Perola, Zoltan Kutalik, Emmanouil Dermitzakis, Sven Bergmann, Timothy Frayling, Joyce van Meurs, Holger Prokisch, Habibul Ahsan, Brandon L. Pierce, Terho Lehtimäki, Dorret I. Boomsma, Bruce M. Psaty, Sina A. Gharib, Philip Awadalla, Lili Milani, Willem H. Ouwehand, Kate Downes, Oliver Stegle, Alexis Battle, Peter M. Visscher, Jian Yang, Markus Scholz, Joseph Powell, Greg Gibson, Tõnu Esko, Lude Franke

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.