Large-scale <em>cis</em>- and <em>trans</em>-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression
Vosa, Urmo; Claringbould, Annique; Westra, Harm-Jan; Bonder, Marc Jan; Deelen, Patrick; Zeng, Biao; Kirsten, Holger; Saha, Ashis; Kreuzhuber, Roman; Yazar, Seyhan; Brugge, Harm; Oelen, Roy; de Vries, Dylan H.; van der Wijst, Monique G. P.; Kasela, Silva; Pervjakova, Natalia; Alves, Isabel; Fave, Marie-Julie; Agbessi, Mawusse; Christiansen, Mark W.; Jansen, Rick; Seppala, Ilkka; Tong, Lin; Teumer, Alexander; Schramm, Katharina; Hemani, Gibran; Verlouw, Joost; Yaghootkar, Hanieh; Flitman, Reyhan Sonmez; Brown, Andrew; Kukushkina, Viktorija; Kalnapenkis, Anette; Rueger, Sina; Porcu, Eleonora; Kronberg, Jaanika; Kettunen, Johannes; Lee, Bernett; Zhang, Futao; Qi, Ting; Hernandez, Jose Alquicira; Arindrarto, Wibowo; Beutner, Frank; Dmitrieva, Julia; Elansary, Mahmoud; Fairfax, Benjamin P.; Georges, Michel; Heijmans, Bastiaan T.; Hewitt, Alex W.; Kahonen, Mika; Kim, Yungil; Knight, Julian C.; Kovacs, Peter; Krohn, Knut; Li, Shuang; Loeffler, Markus; Marigorta, Urko M.; Mei, Hailang; Momozawa, Yukihide; Mueller-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; Thiery, Joachim; Tonjes, Anke; van Dongen, Jenny; van Iterson, Maarten; Veldink, Jan H.; Voelker, Uwe; Warmerdam, Robert; Wijmenga, Cisca; Swertz, Morris; Andiappan, Anand; Montgomery, Grant W.; Ripatti, Samuli; Perola, Markus; Kutalik, Zoltan; Dermitzakis, Emmanouil; Bergmann, Sven; Frayling, Timothy; van Meurs, Joyce; Prokisch, Holger; Ahsan, Habibul; Pierce, Brandon L.; Lehtimaki, Terho; Boomsma, Dorret, I; Psaty, Bruce M.; Gharib, Sina A.; Awadalla, Philip; Milani, Lili; Ouwehand, Willem H.; Downes, Kate; Stegle, Oliver; Battle, Alexis; Visscher, Peter M.; Yang, Jian; Scholz, Markus; Powell, Joseph; Gibson, Greg; Esko, Tonu; Franke, Lude (2021-09-02)
Võsa, U., Claringbould, A., Westra, HJ. et al. Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression. Nat Genet 53, 1300–1310 (2021). https://doi.org/10.1038/s41588-021-00913-z
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2021. This is a post-peer-review, pre-copyedit version of an article published in Nat Genet. The final authenticated version is available online at https://doi.org/10.1038/s41588-021-00913-z.
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https://urn.fi/URN:NBN:fi-fe2022030422046
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Abstract
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.
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