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

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

http://urn.fi/urn:nbn:fi-fe2022030422046
Teksti
Vosa, U. (Urmo) ; Claringbould, A. (Annique) ; Westra, H.-J. (Harm-Jan) ; Bonder, M. J. (Marc Jan) ; Deelen, P. (Patrick) ; Zeng, B. (Biao) ; Kirsten, H. (Holger) ; Saha, A. (Ashis) ; Kreuzhuber, R. (Roman) ; Yazar, S. (Seyhan) ; Brugge, H. (Harm) ; Oelen, R. (Roy) ; de Vries, D. H. (Dylan H.) ; van der Wijst, M. G. (Monique G. P.) ; Kasela, S. (Silva) ; Pervjakova, N. (Natalia) ; Alves, I. (Isabel) ; Fave, M.-J. (Marie-Julie) ; Agbessi, M. (Mawusse) ; Christiansen, M. W. (Mark W.) ; Jansen, R. (Rick) ; Seppala, I. (Ilkka) ; Tong, L. (Lin) ; Teumer, A. (Alexander) ; Schramm, K. (Katharina) ; Hemani, G. (Gibran) ; Verlouw, J. (Joost) ; Yaghootkar, H. (Hanieh) ; Flitman, R. S. (Reyhan Sonmez) ; Brown, A. (Andrew) ; Kukushkina, V. (Viktorija) ; Kalnapenkis, A. (Anette) ; Rueger, S. (Sina) ; Porcu, E. (Eleonora) ; Kronberg, J. (Jaanika) ; Kettunen, J. (Johannes) ; Lee, B. (Bernett) ; Zhang, F. (Futao) ; Qi, T. (Ting) ; Hernandez, J. A. (Jose Alquicira) ; Arindrarto, W. (Wibowo) ; Beutner, F. (Frank) ; Dmitrieva, J. (Julia) ; Elansary, M. (Mahmoud) ; Fairfax, B. P. (Benjamin P.) ; Georges, M. (Michel) ; Heijmans, B. T. (Bastiaan T.) ; Hewitt, A. W. (Alex W.) ; Kahonen, M. (Mika) ; Kim, Y. (Yungil) ; Knight, J. C. (Julian C.) ; Kovacs, P. (Peter) ; Krohn, K. (Knut) ; Li, S. (Shuang) ; Loeffler, M. (Markus) ; Marigorta, U. M. (Urko M.) ; Mei, H. (Hailang) ; Momozawa, Y. (Yukihide) ; Mueller-Nurasyid, M. (Martina) ; Nauck, M. (Matthias) ; Nivard, M. G. (Michel G.) ; Penninx, B. W. (Brenda W. J. H.) ; Pritchard, J. K. (Jonathan K.) ; Raitakari, O. T. (Olli T.) ; Rotzschke, O. (Olaf) ; Slagboom, E. P. (Eline P.) ; Stehouwer, C. D. (Coen D. A.) ; Stumvoll, M. (Michael) ; Sullivan, P. (Patrick) ; Thiery, J. (Joachim) ; Tonjes, A. (Anke) ; van Dongen, J. (Jenny) ; van Iterson, M. (Maarten) ; Veldink, J. H. (Jan H.) ; Voelker, U. (Uwe) ; Warmerdam, R. (Robert) ; Wijmenga, C. (Cisca) ; Swertz, M. (Morris) ; Andiappan, A. (Anand) ; Montgomery, G. W. (Grant W.) ; Ripatti, S. (Samuli) ; Perola, M. (Markus) ; Kutalik, Z. (Zoltan) ; Dermitzakis, E. (Emmanouil) ; Bergmann, S. (Sven) ; Frayling, T. (Timothy) ; van Meurs, J. (Joyce) ; Prokisch, H. (Holger) ; Ahsan, H. (Habibul) ; Pierce, B. L. (Brandon L.) ; Lehtimaki, T. (Terho) ; Boomsma, D. I. (Dorret, I) ; Psaty, B. M. (Bruce M.) ; Gharib, S. A. (Sina A.) ; Awadalla, P. (Philip) ; Milani, L. (Lili) ; Ouwehand, W. H. (Willem H.) ; Downes, K. (Kate) ; Stegle, O. (Oliver) ; Battle, A. (Alexis) ; Visscher, P. M. (Peter M.) ; Yang, J. (Jian) ; Scholz, M. (Markus) ; Powell, J. (Joseph) ; Gibson, G. (Greg) ; Esko, T. (Tonu) ; Franke, L. (Lude)
Springer Nature

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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