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Multiple variant enhancers modulate its cardiac gene expression and the QT interval.

TitleMultiple variant enhancers modulate its cardiac gene expression and the QT interval.
Publication TypeJournal Article
Year of Publication2019
AuthorsKapoor A, Lee D, Zhu L, Soliman EZ, Grove ML, Boerwinkle E, Arking DE
Secondary AuthorsChakravarti A
JournalProc Natl Acad Sci U S A
Volume116
Issue22
Pagination10636-10645
Date Published2019 05 28
ISSN1091-6490
KeywordsAlleles, Animals, Cell Line, Electrocardiography, Gene Expression Regulation, Genetic Variation, Genome-Wide Association Study, Heart, Humans, Mice, Myocardium, NAV1.5 Voltage-Gated Sodium Channel, Quantitative Trait Loci, Regulatory Sequences, Nucleic Acid
Abstract

The rationale for genome-wide association study (GWAS) results is sequence variation in -regulatory elements (CREs) modulating a target gene's expression as the major cause of trait variation. To understand the complete molecular landscape of one of these GWAS loci, we performed in vitro reporter screens in cardiomyocyte cell lines for CREs overlapping nearly all common variants associated with any of five independent QT interval (QTi)-associated GWAS hits at the - locus. We identified 13 causal CRE variants using allelic reporter activity, cardiomyocyte nuclear extract-based binding assays, overlap with human cardiac tissue DNaseI hypersensitive regions, and predicted impact of sequence variants on DNaseI sensitivity. Our analyses identified at least one high-confidence causal CRE variant for each of the five sentinel hits that could collectively predict cardiac gene expression and QTi association. Although all 13 variants could explain gene expression, the highest statistical significance was obtained with seven variants (inclusive of the five above). Thus, multiple, causal, mutually associated CRE variants can underlie GWAS signals.

DOI10.1073/pnas.1808734116
Alternate JournalProc Natl Acad Sci U S A
PubMed ID31068470
PubMed Central IDPMC6561183
Grant ListR01 GM104469 / GM / NIGMS NIH HHS / United States
HHSN268201700001I / HL / NHLBI NIH HHS / United States
HHSN268201700002I / HL / NHLBI NIH HHS / United States
HHSN268201700003I / HL / NHLBI NIH HHS / United States
HHSN268201700005I / HL / NHLBI NIH HHS / United States
HHSN268201700004I / HL / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States