Disentangling the Effects of Colocalizing Genomic Annotations to Functionally Prioritize Non-coding Variants within Complex-Trait Loci.

Am J Hum Genet
Authors
Keywords
Abstract

Identifying genomic annotations that differentiate causal from trait-associated variants is essential to fine mapping disease loci. Although many studies have identified non-coding functional annotations that overlap disease-associated variants, these annotations often colocalize, complicating the ability to use these annotations for fine mapping causal variation. We developed a statistical approach (Genomic Annotation Shifter [GoShifter]) to assess whether enriched annotations are able to prioritize causal variation. GoShifter defines the null distribution of an annotation overlapping an allele by locally shifting annotations; this approach is less sensitive to biases arising from local genomic structure than commonly used enrichment methods that depend on SNP matching. Local shifting also allows GoShifter to identify independent causal effects from colocalizing annotations. Using GoShifter, we confirmed that variants in expression quantitative trail loci drive gene-expression changes though DNase-I hypersensitive sites (DHSs) near transcription start sites and independently through 3' UTR regulation. We also showed that (1) 15%-36% of trait-associated loci map to DHSs independently of other annotations; (2) loci associated with breast cancer and rheumatoid arthritis harbor potentially causal variants near the summits of histone marks rather than full peak bodies; (3) variants associated with height are highly enriched in embryonic stem cell DHSs; and (4) we can effectively prioritize causal variation at specific loci.

Year of Publication
2015
Journal
Am J Hum Genet
Volume
97
Issue
1
Pages
139-52
Date Published
2015 Jul 02
ISSN
1537-6605
URL
DOI
10.1016/j.ajhg.2015.05.016
PubMed ID
26140449
PubMed Central ID
PMC4572568
Links
Grant list
U01 HG007033 / HG / NHGRI NIH HHS / United States
U19 AI111224 / AI / NIAID NIH HHS / United States
1U01HG0070033 / HG / NHGRI NIH HHS / United States
WT098051 / Wellcome Trust / United Kingdom
U01 GM092691 / GM / NIGMS NIH HHS / United States
R01 AR063759 / AR / NIAMS NIH HHS / United States
UH2 AR067677 / AR / NIAMS NIH HHS / United States
1UH2AR067677-01 / AR / NIAMS NIH HHS / United States
1U19AI111224-01 / AI / NIAID NIH HHS / United States
1R01AR063759 / AR / NIAMS NIH HHS / United States