Journal Article

Using an atlas of gene regulation across 44 human tissues to inform complex disease- and trait-associated variation

Dermitzakis, Emmanouil T., Eskin, Eleazar, Aguet, François, McCarthy, Mark I., van de Bunt, Martijn, Ongen, Halit, Nicolae, Dan L., Kellis, Manolis, Segrè, Ayellet V., Gamazon, Eric R., Xi, Hualin S., Konkashbaev, Anuar, Wen, Xiaoquan, Cox, Nancy J., Hormozdiari, Farhad, Quan, Jie, Ardlie, Kristin G., Derks, Eske M., Getz, Gad

2018

Overview

We apply integrative approaches to expression quantitative loci (eQTLs) from 44 tissues from the Genotype-Tissue Expression project and genome-wide association study data. About 60% of known trait-associated loci are in linkage disequilibrium with a cis -eQTL, over half of which were not found in previous large-scale whole blood studies. Applying polygenic analyses to metabolic, cardiovascular, anthropometric, autoimmune, and neurodegenerative traits, we find that eQTLs are significantly enriched for trait associations in relevant pathogenic tissues and explain a substantial proportion of the heritability (40–80%). For most traits, tissue-shared eQTLs underlie a greater proportion of trait associations, although tissue-specific eQTLs have a greater contribution to some traits, such as blood pressure. By integrating information from biological pathways with eQTL target genes and applying a gene-based approach, we validate previously implicated causal genes and pathways, and propose new variant and gene associations for several complex traits, which we replicate in the UK BioBank and BioVU. Integration of expression quantitative trait locus (eQTL) data from the Genotype-Tissue Expression project with genome-wide association study data shows that eQTLs are enriched for trait associations in disease-relevant tissues.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 38/43 / 45/91 / 631/114/2785 / 631/208/191 / 631/208/200 / 631/208/205/2138 / 692/308/2056 / Agriculture / Alzheimer's disease / Animal Genetics and Genomics / Anthropometry / Biomedical and Life Sciences / Biomedicine / Blood pressure / Cancer Research / Cardiovascular disease / Coronary vessels / Diabetes / Disease - genetics / Gene Expression / Gene Expression Profiling - methods / Gene Expression Regulation / Gene Function / Gene regulation / Genes / Genetic regulation / Genetic variation / Genome-wide association studies / Genome-Wide Association Study - methods / Genomes / Genomics / Genotype / Genotypes / Health aspects / Heritability / Human Genetics / Human tissues / Humans / Hypertension / Linkage disequilibrium / Loci / Metabolism / Phenotype / Polygenic inheritance / Polymorphism, Single Nucleotide / Quantitative Trait Loci / Quantitative Trait, Heritable / Studies / Tissues / Tissues (Anatomy) / Type 2 diabetes