The anatomical distribution of genetic associations. Nucleic Acids Res 2015 Dec 15;43(22):10804-20
Date
11/21/2015Pubmed ID
26586807Pubmed Central ID
PMC4678833DOI
10.1093/nar/gkv1262Scopus ID
2-s2.0-84966269190 (requires institutional sign-in at Scopus site) 30 CitationsAbstract
Deeper understanding of the anatomical intermediaries for disease and other complex genetic traits is essential to understanding mechanisms and developing new interventions. Existing ontology tools provide functional, curated annotations for many genes and can be used to develop mechanistic hypotheses; yet information about the spatial expression of genes may be equally useful in interpreting results and forming novel hypotheses for a trait. Therefore, we developed an approach for statistically testing the relationship between gene expression across the body and sets of candidate genes from across the genome. We validated this tool and tested its utility on three applications. First, we show that the expression of genes in associated loci from GWA studies implicates specific tissues for 57 out of 98 traits. Second, we tested the ability of the tool to identify novel relationships between gene expression and phenotypes. Specifically, we experimentally confirmed an underappreciated prediction highlighted by our tool: that white blood cell count--a quantitative trait of the immune system--is genetically modulated by genes expressed in the skin. Finally, using gene lists derived from exome sequencing data, we show that human genes under selective constraint are disproportionately expressed in nervous system tissues.
Author List
Wells A, Kopp N, Xu X, O'Brien DR, Yang W, Nehorai A, Adair-Kirk TL, Kopan R, Dougherty JDAuthor
Nathan Kopp PhD Assistant Professor in the Pathology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AlgorithmsAnimals
Data Interpretation, Statistical
Disease
Gene Expression
Genome-Wide Association Study
Genomics
Humans
Leukocytes
Mice
Mice, Transgenic
Nervous System
Organ Specificity
Phenotype
Tissue Distribution
