The impact of sex on gene expression across human tissues
Meritxell Oliva, Manuel Muñoz-Aguirre, Sarah Kim-Hellmuth, Valentin Wucher, Ariel DH Gewirtz, Daniel J. Cotter, Princy Parsana, Silva Kasela, Brunilda Balliu, Ana Viñuela, Stephane E. Castel, Pejman Mohammadi, François Aguet, Yuxin Zou, Ekaterina Khramtsova, Andrew D. Skol, Diego Garrido-Martín, Ferrán Reverter, Andrew Brown, Patrick Evans, Eric R. Gamazon, A. J. Payne, Rodrigo Bonazzola, Alvaro Barbeira, Andrew R. Hamel, Ángel Martínez-Pérez, José Manuel Soria, Brandon L. Pierce, Matthew Stephens, Eleazar Eskin, Emmanouil T. Dermitzakis, Ayellet V. Segrè, Hae Kyung Im, Barbara E. Engelhardt, Kristin Ardlie, Stephen B. Montgomery, Alexis Battle, Tuuli Lappalainen, Roderic Guigó, Barbara E. Stranger, François Aguet, Shankara Anand, Kristin Ardlie, Stacey Gabriel, Gad Getz, Aaron Graubert, Kane Hadley, Robert E. Handsaker, Katherine Huang, Seva Kashin, Xiao Li, Daniel G. MacArthur, Samuel R. Meier, Jared L. Nedzel, Duyen T. Nguyen, Ayellet V. Segrè, Ellen Todres, Brunilda Balliu, Alvaro Barbeira, Alexis Battle, Rodrigo Bonazzola, Andrew Brown, Christopher D. Brown, Stephane E. Castel, Donald F. Conrad, Daniel J. Cotter, Nancy J. Cox, Sayantan Das, Olivia M. de Goede, Emmanouil T. Dermitzakis, Jonah Einson, Barbara E. Engelhardt, Eleazar Eskin, Tiffany Eulalio, Nicole M. Ferraro, Elise D. Flynn, Laure Frésard, Eric R. Gamazon, Diego Garrido-Martín, Nicole R. Gay, Michael J. Gloudemans, Roderic Guigó, Andrew R. Hame, Yuan He, Paul Hoffman, Farhad Hormozdiari, Lei Hou, Hae Kyung Im, Brian Jo, Silva Kasela, Manolis Kellis, Sarah Kim-Hellmuth, Alan Kwong, Tuuli Lappalainen, Xin Li, Yanyu Liang, Serghei Mangul, Pejman Mohammadi, Stephen B. Montgomery, Manuel Muñoz-Aguirre
Abstract
Many complex human phenotypes exhibit sex-differentiated characteristics. However, the molecular mechanisms underlying these differences remain largely unknown. We generated a catalog of sex differences in gene expression and in the genetic regulation of gene expression across 44 human tissue sources surveyed by the Genotype-Tissue Expression project (GTEx, v8 release). We demonstrate that sex influences gene expression levels and cellular composition of tissue samples across the human body. A total of 37% of all genes exhibit sex-biased expression in at least one tissue. We identify cis expression quantitative trait loci (eQTLs) with sex-differentiated effects and characterize their cellular origin. By integrating sex-biased eQTLs with genome-wide association study data, we identify 58 gene-trait associations that are driven by genetic regulation of gene expression in a single sex. These findings provide an extensive characterization of sex differences in the human transcriptome and its genetic regulation.