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2017 ; 26
(5
): 1003-1017
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Mapping eQTLs with RNA-seq reveals novel susceptibility genes, non-coding RNAs
and alternative-splicing events in systemic lupus erythematosus
#MMPMID28062664
Odhams CA
; Cortini A
; Chen L
; Roberts AL
; Viñuela A
; Buil A
; Small KS
; Dermitzakis ET
; Morris DL
; Vyse TJ
; Cunninghame Graham DS
Hum Mol Genet
2017[Mar]; 26
(5
): 1003-1017
PMID28062664
show ga
Studies attempting to functionally interpret complex-disease susceptibility loci
by GWAS and eQTL integration have predominantly employed microarrays to quantify
gene-expression. RNA-Seq has the potential to discover a more comprehensive set
of eQTLs and illuminate the underlying molecular consequence. We examine the
functional outcome of 39 variants associated with Systemic Lupus Erythematosus
(SLE) through the integration of GWAS and eQTL data from the TwinsUK microarray
and RNA-Seq cohort in lymphoblastoid cell lines. We use conditional analysis and
a Bayesian colocalisation method to provide evidence of a shared causal-variant,
then compare the ability of each quantification type to detect disease relevant
eQTLs and eGenes. We discovered the greatest frequency of candidate-causal eQTLs
using exon-level RNA-Seq, and identified novel SLE susceptibility genes (e.g.
NADSYN1 and TCF7) that were concealed using microarrays, including four
non-coding RNAs. Many of these eQTLs were found to influence the expression of
several genes, supporting the notion that risk haplotypes may harbour multiple
functional effects. Novel SLE associated splicing events were identified in the
T-reg restricted transcription factor, IKZF2, and other candidate genes (e.g.
WDFY4) through asQTL mapping using the Geuvadis cohort. We have significantly
increased our understanding of the genetic control of gene-expression in SLE by
maximising the leverage of RNA-Seq and performing integrative GWAS-eQTL analysis
against gene, exon, and splice-junction quantifications. We conclude that to
better understand the true functional consequence of regulatory variants,
quantification by RNA-Seq should be performed at the exon-level as a minimum, and
run in parallel with gene and splice-junction level quantification.
|*Genetic Predisposition to Disease
[MESH]
|Alternative Splicing/genetics
[MESH]
|Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor/biosynthesis/genetics
[MESH]