Publication:
Optimized high-throughput screening of non-coding variants identified from genome-wide association studies

Thumbnail Image

School / College / Institute

Organizational Unit
Organizational Unit
SCHOOL OF MEDICINE
Upper Org Unit

Program

KU Authors

Co-Authors

Morova, Tunc
Ding, Yi
Huang, Chia-Chi F.
Sar, Funda
Schwarz, Tommer
Giambartolomei, Claudia
Baca, Sylvan C.
Grishin, Dennis
Hach, Faraz
Gusev, Alexander

Publication Date

Language

Embargo Status

Journal Title

Journal ISSN

Volume Title

Alternative Title

Abstract

The vast majority of disease-associated single nucleotide polymorphisms (SNP) identified from genome-wide association studies (GWAS) are localized in non-coding regions. A significant fraction of these variants impact transcription factors binding to enhancer elements and alter gene expression. To functionally interrogate the activity of such variants we developed snpSTARRseq, a high-throughput experimental method that can interrogate the functional impact of hundreds to thousands of non-coding variants on enhancer activity. snpSTARRseq dramatically improves signal-to-noise by utilizing a novel sequencing and bioinformatic approach that increases both insert size and the number of variants tested per loci. Using this strategy, we interrogated known prostate cancer (PCa) risk-associated loci and demonstrated that 35% of them harbor SNPs that significantly altered enhancer activity. Combining these results with chromosomal looping data we could identify interacting genes and provide a mechanism of action for 20 PCa GWAS risk regions. When benchmarked to orthogonal methods, snpSTARRseq showed a strong correlation with in vivo experimental allelic-imbalance studies whereas there was no correlation with predictive in silico approaches. Overall, snpSTARRseq provides an integrated experimental and computational framework to functionally test non-coding genetic variants.

Source

Publisher

Oxford University Press (OUP)

Subject

Biochemistry, Molecular biology

Citation

Has Part

Source

Nucleic Acids Research

Book Series Title

Edition

DOI

10.1093/nar/gkac1198

item.page.datauri

Link

Rights

Copyrights Note

Endorsement

Review

Supplemented By

Referenced By

5

Views

6

Downloads

View PlumX Details