Journal Article

Genetic effects on gene expression across human tissues

Montgomery, Stephen B, Battle, Alexis, Brown, Christopher D, Engelhardt, Barbara E

2017

Overview

Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of disease. Samples of different body regions from hundreds of human donors are used to study how genetic variation influences gene expression levels in 44 disease-relevant tissues. Genetic effects on gene expression across human tissues The GTEx (Genotype-Tissue Expression) Consortium has established a reference catalogue and associated tissue biobank for gene-expression levels across individuals for diverse tissues of the human body, with a broad sampling of normal, non-diseased human tissues from postmortem donors. The consortium now presents the deepest survey of gene expression across multiple tissues and individuals to date, encompassing 7,051 samples from 449 donors across 44 human tissues. Barbara Engelhardt and colleagues characterize the relationship between genetic variation and gene expression, and find that most genes are regulated by genetic variation near to the affected gene. In accompanying GTEx studies, Alexis Battle, Stephen Montgomery and colleagues examine the effect of rare genetic variation on gene expression across human tissues, Daniel MacArthur and colleagues systematically survey the landscape of X chromosome inactivation in human tissues, and Jin Billy Li and colleagues provide a comprehensive cross-species analysis of adenosine-to-inosine RNA editing in mammals. In an accompanying News & Views, Michelle Ward and Yoav Gilad put the latest results in context and discuss how these findings are helping to crack the regulatory code of the human genome.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 38/23 / 38/91 / 45 / 631/208/200 / 631/208/212/2019 / Alleles / Chromosomes, Human - genetics / Disease / Disease - genetics / Female / Gene expression / Gene Expression Profiling / Gene Expression Regulation - genetics / Gene regulation / Genes / Genetic diversity / Genetic effects / Genetic Variation / Genome, Human - genetics / Genomes / Genotype / Genotype & phenotype / Human tissues / Humanities and Social Sciences / Humans / Male / multidisciplinary / Organ Specificity - genetics / Proteins / Quantitative Trait Loci - genetics / Science / Studies / Tissues / Transcriptomics