Aggregative trans-eQTL analysis detects trait-specific target gene sets in whole blood

• Published in: Nature communications Vol. 13; no. 1; p. 4323
• Main Authors: Dutta, Diptavo, He, Yuan, Saha, Ashis, Arvanitis, Marios, Battle, Alexis, Chatterjee, Nilanjan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.07.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 38; 38/43; 631/114/2114; 631/208/199; 631/208/205; Correlation analysis; Gene expression; Gene regulation; Genes; Genetic Association Studies; Genetic diversity; Genetic variance; Genome-Wide Association Study - methods; Humanities and Social Sciences; Identification methods; multidisciplinary; Multifactorial Inheritance; Phenotype; Polymorphism, Single Nucleotide; Quantitative Trait Loci - genetics; Science; Science (multidisciplinary); Statistical analysis; Target detection
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-31845-9

Large scale genetic association studies have identified many trait-associated variants and understanding the role of these variants in the downstream regulation of gene-expressions can uncover important mediating biological mechanisms. Here we propose ARCHIE, a summary statistic based sparse canonical correlation analysis method to identify sets of gene-expressions trans-regulated by sets of known trait-related genetic variants. Simulation studies show that compared to standard methods, ARCHIE is better suited to identify “core”-like genes through which effects of many other genes may be mediated and can capture disease-specific patterns of genetic associations. By applying ARCHIE to publicly available summary statistics from the eQTLGen consortium, we identify gene sets which have significant evidence of trans- association with groups of known genetic variants across 29 complex traits. Around half (50.7%) of the selected genes do not have any strong trans -associations and are not detected by standard methods. We provide further evidence for causal basis of the target genes through a series of follow-up analyses. These results show ARCHIE is a powerful tool for identifying sets of genes whose trans -regulation may be related to specific complex traits. Large-scale genetic association studies have identified many trait-associated variants that influence gene expression. Here, the authors present ARCHIE, a tool for identifying sets of genes whose regulation may be related to specific complex traits.