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The impact of sex on gene expression across human tissues.

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.

SUBMITTER: Oliva M

PROVIDER: S-EPMC8136152 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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The impact of sex on gene expression across human tissues.

Oliva Meritxell M Muñoz-Aguirre Manuel M Kim-Hellmuth Sarah S Wucher Valentin V Gewirtz Ariel D H ADH Cotter Daniel J DJ Parsana Princy P Kasela Silva S Balliu Brunilda B Viñuela Ana A Castel Stephane E SE Mohammadi Pejman P Aguet François F Zou Yuxin Y Khramtsova Ekaterina A EA Skol Andrew D AD Garrido-Martín Diego D Reverter Ferran F Brown Andrew A Evans Patrick P Gamazon Eric R ER Payne Anthony A Bonazzola Rodrigo R Barbeira Alvaro N AN Hamel Andrew R AR Martinez-Perez Angel A Soria José Manuel JM Pierce Brandon L BL Stephens Matthew M Eskin Eleazar E Dermitzakis Emmanouil T ET Segrè Ayellet V AV Im Hae Kyung HK Engelhardt Barbara E BE Ardlie Kristin G KG Montgomery Stephen B SB Battle Alexis J AJ Lappalainen Tuuli T Guigó Roderic R Stranger Barbara E BE

Science (New York, N.Y.) 20200901 6509

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 t ...[more]

PMID: 32913072

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Project description:Statins are 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors that alter the synthesis of cholesterol. Some studies have shown a significant association of statins with improved respiratory health outcomes of patients with asthma, chronic obstructive pulmonary disease and lung cancer. Here we hypothesize that statins impact gene expression in human lungs and may reveal the pleiotropic effects of statins that are taking place directly in lung tissues. Human lung tissues were obtained from patients who underwent lung resection or transplantation. Gene expression was measured on a custom Affymetrix array in a discovery cohort (n = 408) and two replication sets (n = 341 and 282). Gene expression was evaluated by linear regression between statin users and non-users, adjusting for age, gender, smoking status, and other covariables. The results of each cohort were combined in a meta-analysis and biological pathways were studied using Gene Set Enrichment Analysis. The discovery set included 141 statin users. The lung mRNA expression levels of eighteen and three genes were up-regulated and down-regulated in statin users (FDR < 0.05), respectively. Twelve of the up-regulated genes were replicated in the first replication set, but none in the second (p-value < 0.05). Combining the discovery and replication sets into a meta-analysis improved the significance of the 12 up-regulated genes, which includes genes encoding enzymes and membrane proteins involved in cholesterol biosynthesis. Canonical biological pathways altered by statins in the lung include cholesterol, steroid, and terpenoid backbone biosynthesis. No genes encoding inflammatory, proteases, pro-fibrotic or growth factors were altered by statins, suggesting that the direct effect of statin in the lung do not go beyond its antilipidemic action. Although more studies are needed with specific lung cell types and different classes and doses of statins, the improved health outcomes and survival observed in statin users with chronic lung diseases do not seem to be mediated through direct regulation of gene expression in the lung.

Dataset Information

The impact of sex on gene expression across human tissues.

Publications

The impact of sex on gene expression across human tissues.

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