Direct Identification of Hundreds of Expression-Modulating Variants using a Multiplexed Reporter Assay.

Cell
Authors
Keywords
Abstract

Although studies have identified hundreds of loci associated with human traits and diseases, pinpointing causal alleles remains difficult, particularly for non-coding variants. To address this challenge, we adapted the massively parallel reporter assay (MPRA) to identify variants that directly modulate gene expression. We applied it to 32,373 variants from 3,642 cis-expression quantitative trait loci and control regions. Detection by MPRA was strongly correlated with measures of regulatory function. We demonstrate MPRA's capabilities for pinpointing causal alleles, using it to identify 842 variants showing differential expression between alleles, including 53 well-annotated variants associated with diseases and traits. We investigated one in detail, a risk allele for ankylosing spondylitis, and provide direct evidence of a non-coding variant that alters expression of the prostaglandin EP4 receptor. These results create a resource of concrete leads and illustrate the promise of this approach for comprehensively interrogating how non-coding polymorphism shapes human biology.

Year of Publication
2016
Journal
Cell
Volume
165
Issue
6
Pages
1519-29
Date Published
2016 Jun 02
ISSN
1097-4172
DOI
10.1016/j.cell.2016.04.027
PubMed ID
27259153
PubMed Central ID
PMC4957403
Links
Grant list
R01 AI114855 / AI / NIAID NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
K99 HG008179 / HG / NHGRI NIH HHS / United States
Howard Hughes Medical Institute / United States
R01 HG006785 / HG / NHGRI NIH HHS / United States
HHMI / HHMI / United States
DP2 OD006514 / OD / NIH HHS / United States
U19 AI110818 / AI / NIAID NIH HHS / United States
Additional Materials