Leveraging molecular quantitative trait loci to understand the genetic architecture of diseases and complex traits.

Nat Genet 2018 07 25;50(7):1041-1047. Epub 2018 Jun 25.

Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA.

There is increasing evidence that many risk loci found using genome-wide association studies are molecular quantitative trait loci (QTLs). Here we introduce a new set of functional annotations based on causal posterior probabilities of fine-mapped molecular cis-QTLs, using data from the Genotype-Tissue Expression (GTEx) and BLUEPRINT consortia. We show that these annotations are more strongly enriched for heritability (5.84× for eQTLs; P = 1.19 × 10) across 41 diseases and complex traits than annotations containing all significant molecular QTLs (1.80× for expression (e)QTLs). eQTL annotations obtained by meta-analyzing all GTEx tissues generally performed best, whereas tissue-specific eQTL annotations produced stronger enrichments for blood- and brain-related diseases and traits. eQTL annotations restricted to loss-of-function intolerant genes were even more enriched for heritability (17.06×; P = 1.20 × 10). All molecular QTLs except splicing QTLs remained significantly enriched in joint analysis, indicating that each of these annotations is uniquely informative for disease and complex trait architectures.

Download full-text PDF

Source
http://www.nature.com/articles/s41588-018-0148-2
Publisher Site
http://dx.doi.org/10.1038/s41588-018-0148-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6030458PMC
July 2018
10 Reads
4 Citations
29.352 Impact Factor

Publication Analysis

Top Keywords

eqtl annotations
12
enriched heritability
8
molecular qtls
8
trait loci
8
quantitative trait
8
diseases complex
8
complex traits
8
molecular quantitative
8
annotations
7
expression gtex
4
traits eqtl
4
brain-related diseases
4
annotations enriched
4
blood- brain-related
4
consortia annotations
4
blueprint consortia
4
gtex blueprint
4
diseases traits
4
data genotype-tissue
4
intolerant genes
4

References

(Supplied by CrossRef)
Article in Nature
Schizophrenia Working Group of the Psychiatric Genomics Consortium.. et al.
Nature 2014
Article in Nature
A Okbay et al.
Nature 2016
Article in Am. J. Hum. Genet.
PM Visscher et al.
Am. J. Hum. Genet. 2017
Article in Proc. Natl Acad. Sci. USA
LA Hindorff et al.
Proc. Natl Acad. Sci. USA 2009
Article in PLoS Genet.
DL Nicolae et al.
PLoS Genet. 2010
Article in PLoS Genet.
AC Nica et al.
PLoS Genet. 2010
Article in Science
MT Maurano et al.
Science 2012
Article in Am. J. Hum. Genet.
G Trynka et al.
Am. J. Hum. Genet. 2015
Article in Nature
Roadmap Epigenomics Consortium. et al.
Nature 2015
Article in Nat. Genet.
FA Wright et al.
Nat. Genet. 2014
Article in Nat. Genet.
X Zhang et al.
Nat. Genet. 2015

Similar Publications