The landscape of expression and alternative splicing variation across human traits

García Pérez, Raquel, 1989-; Ramirez, Jose Miguel; Ripoll Cladellas, Aida; Chazarra-Gil, Ruben; Oliveros, Winona; Soldatkina, Oleksandra; Bosio, Mattia; Rognon, Paul Joris; Capella Gutiérrez, Salvador Jesús, 1985-; Calvo, Miquel (Calvo Llorca); Reverter Comes, Ferran; Guigó Serra, Roderic; Aguet, François; Ferreira, Pedro G.; Ardlie, Kristin G.; Melé Messeguer, Marta, 1982-

doi:http://dx.doi.org/10.1016/j.xgen.2022.100244

The landscape of expression and alternative splicing variation across human traits

Citation

García-Pérez R, Ramirez JM, Ripoll-Cladellas A, Chazarra-Gil R, Oliveros W, Soldatkina O, Bosio M, Rognon PJ, Capella-Gutierrez S, Calvo M, Reverter F, Guigó R, Aguet F, Ferreira PG, Ardlie KG, Melé M. The landscape of expression and alternative splicing variation across human traits. Cell Genom. 2022 Dec 30;3(1):100244. DOI: 10.1016/j.xgen.2022.100244

Abstract

Understanding the consequences of individual transcriptome variation is fundamental to deciphering human biology and disease. We implement a statistical framework to quantify the contributions of 21 individual traits as drivers of gene expression and alternative splicing variation across 46 human tissues and 781 individuals from the Genotype-Tissue Expression project. We demonstrate that ancestry, sex, age, and BMI make additive and tissue-specific contributions to expression variability, whereas interactions are rare. Variation in splicing is dominated by ancestry and is under genetic control in most tissues, with ribosomal proteins showing a strong enrichment of tissue-shared splicing events. Our analyses reveal a systemic contribution of types 1 and 2 diabetes to tissue transcriptome variation with the strongest signal in the nerve, where histopathology image analysis identifies novel genes related to diabetic neuropathy. Our multi-tissue and multi-trait approach provides an extensive characterization of the main drivers of human transcriptome variation in health and disease.