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2015 ; 43
(22
): 10804-20
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The anatomical distribution of genetic associations
#MMPMID26586807
Wells A
; Kopp N
; Xu X
; O'Brien DR
; Yang W
; Nehorai A
; Adair-Kirk TL
; Kopan R
; Dougherty JD
Nucleic Acids Res
2015[Dec]; 43
(22
): 10804-20
PMID26586807
show ga
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.
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