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

Authors: Võsa, 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; 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; Kronberg, Jaanika; Kettunen, Johannes; Lee, Bernett; Zhang, Futao; Qi, Ting; Hernandez, Jose Alquicira; Arindrarto, Wibowo; Beutner, Frank; BIOS Consortium; i2QTL Consortium; 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; Frayling, Timothy; van Meurs, Joyce; Prokisch, Holger; Ahsan, Habibul; Pierce, Brandon L; Lehtimäki, 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, Tõnu; Franke, Lude

Published In Nat Genet, (2021 Sep)

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.

PubMed ID: 34475573

MeSH Terms: Blood Proteins/genetics*; Gene Expression Regulation/genetics*; Genome-Wide Association Study; Humans; Multifactorial Inheritance/genetics; Polymorphism, Single Nucleotide/genetics; Quantitative Trait Loci/genetics*; Transcriptome/genetics