TY - JOUR
T1 - Disentangling the Effects of Colocalizing Genomic Annotations to Functionally Prioritize Non-coding Variants within Complex-Trait Loci
AU - Trynka, Gosia
AU - Westra, Harm Jan
AU - Slowikowski, Kamil
AU - Hu, Xinli
AU - Xu, Han
AU - Stranger, Barbara E.
AU - Klein, Robert J.
AU - Han, Buhm
AU - Raychaudhuri, Soumya
N1 - Funding Information:
We acknowledge the GIANT consortium for providing us access to the height SNPs. We also acknowledge Joel Hirschhorn, X. Shirley Liu, Mark Daly, Tonu Esko, Dorothee Diogo, and Joshua Randall for helpful scientific discussions. This work was supported by funding from the NIH (NIAMS-1R01AR063759 [S.R.], 1UH2AR067677-01 [S.R.], 1U19AI111224-01 [S.R.], and NHGRI-1U01HG0070033 [R.J.K.]), a Doris Duke Clinical Scientist Development Award (S.R.), the Rubicon grant from the Netherlands Organization for Scientific Research (G.T.), and the Wellcome Trust Sanger Institute (WT098051 [G.T.]).
Publisher Copyright:
© 2015 The Authors.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajhg.2015.05.016
DO - 10.1016/j.ajhg.2015.05.016
M3 - Article
C2 - 26140449
AN - SCOPUS:84937424402
SN - 0002-9297
VL - 97
SP - 139
EP - 152
JO - American journal of human genetics
JF - American journal of human genetics
IS - 1
ER -