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

Vosa, U.; Claringbould, A.; Westra, H.J.; Bonder, M.J.; Deelen, P.; Zeng, B.; ... ; i2QTL Consortium (2021)

Article / Letter to editor

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.

• All authors: Vosa, U.; Claringbould, A.; Westra, H.J.; Bonder, M.J.; Deelen, P.; Zeng, B.; Kirsten, H.; Saha, A.; Kreuzhuber, R.; Yazar, S.; Brugge, H.; Oelen, R.; Vries, D.H. de; Wijst, M.G.P. van der; Kasela, S.; Pervjakova, N.; Alves, I.; Fave, M.J.; Agbessi, M.; Christiansen, M.W.; Jansen, R.; Seppala, I.; Tong, L.; Teumer, A.; Schramm, K.; Hemani, G.; Verlouw, J.; Yaghootkar, H.; Flitman, R.S.; Brown, A.; Kukushkina, V.; Kalnapenkis, A.; Rueger, S.; Porcu, E.; Kronberg, J.; Kettunen, J.; Lee, B.; Zhang, F.T.; Qi, T.; Hernandez, J.A.; Arindrarto, W.; Beutner, F.; Dmitrieva, J.; Elansary, M.; Fairfax, B.P.; Georges, M.; Heijmans, B.T.; Hewitt, A.W.; Kahonen, M.; Kim, Y.; Knight, J.C.; Kovacs, P.; Krohn, K.; Li, S.; Loeffler, M.; Marigorta, U.M.; Mei, H.L.; Momozawa, Y.; Muller-Nurasyid, M.; Nauck, M.; Nivard, M.G.; Penninx, B.W.J.H.; Pritchard, J.K.; Raitakari, O.T.; Rotzschke, O.; Slagboom, E.P.; Stehouwer, C.D.A.; Stumvoll, M.; Sullivan, P.; Hoen, P.A.C. 't; Thiery, J.; Tonjes, A.; Dongen, J. van; Iterson, M. van; Veldink, J.H.; Volker, U.; Warmerdam, R.; Wijmenga, C.; Swertz, M.; Andiappan, A.; Montgomery, G.W.; Ripatti, S.; Perola, M.; Kutalik, Z.; Dermitzakis, E.; Bergmann, S.; Frayling, T.; Meurs, J. van; Prokisch, H.; Ahsan, H.; Pierce, B.L.; Lehtimaki, T.; Boomsma, D.I.; Psaty, B.M.; Gharib, S.A.; Awadalla, P.; Milani, L.; Ouwehand, W.H.; Downes, K.; Stegle, O.; Battle, A.; Visscher, P.M.; Yang, J.; Scholz, M.; Powell, J.; Gibson, G.; Esko, T.; Franke, L.; BIOS Consortium; i2QTL Consortium
• Date: 2021-09-02
• Journal: Nature Genetics
• Volume: 53
• Issue: 9
• Pages: 1300 - 1310
• DOI: doi:10.1038/s41588-021-00913-z
• Link: https://www.nature.com/articles/s41588-021-00913-z