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Comparative and Functional Genomic Resource for Mechanistic Studies of Human Blood Pressure-Associated Single Nucleotide Polymorphisms. Hypertension 2020 Mar;75(3):859-868

Date

01/07/2020

Pubmed ID

31902252

Pubmed Central ID

PMC7035167

DOI

10.1161/HYPERTENSIONAHA.119.14109

Scopus ID

2-s2.0-85081142576 (requires institutional sign-in at Scopus site)   14 Citations

Abstract

The objective of the current study is to use comparative and functional genomic analysis to help to understand the biological mechanism mediating the effect of single nucleotide polymorphisms (SNPs) on blood pressure. We mapped 26 585 SNPs that are in linkage disequilibrium with 1071 human blood pressure-associated sentinel SNPs to 9447 syntenic regions in the mouse genome. Approximately 21.8% of the 1071 linkage disequilibrium regions are located at least 10 kb from any protein-coding gene. Approximately 300 blood pressure-associated SNPs are expression quantitative trait loci for a few dozen known blood pressure physiology genes in tissues including specific kidney regions. Blood pressure-associated sentinel SNPs are significantly enriched for expression quantitative trait loci for blood pressure physiology genes compared with randomly selected SNPs (P<0.00023, Fisher exact test). Using a newly developed deep learning method and other methods, we identified SNPs that were predicted to influence the conservation of CTCF (CCCTC-binding factor) binding across cell types, transcription factor binding, mRNA splicing, or secondary structures of RNA including long noncoding RNA. The SNPs were more likely to be located in CTCF-binding regions than what would be expected from the whole genome (P=4.90×10-7, Pearson χ2 test). One example synonymous SNP rs9337951 was predicted to influence the secondary structure of its host mRNA JCAD (junctional cadherin 5 associated) and was experimentally validated to influence JCAD protein expression. These findings provide an extensive comparative and functional genomic resource for developing experiments to test the functional significance of human blood pressure-associated SNPs in human cells and animal models.

Author List

Mishra MK, Liang EY, Geurts AM, Auer PWL, Liu P, Rao S, Greene AS, Liang M, Liu Y

Authors

Paul L. Auer PhD Professor in the Data Science Institute department at Medical College of Wisconsin
Aron Geurts PhD Professor in the Physiology department at Medical College of Wisconsin
Sridhar Rao MD, PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Blood Pressure
CCCTC-Binding Factor
Cell Adhesion Molecules
Enhancer Elements, Genetic
Genetic Predisposition to Disease
Haplotypes
Humans
Linkage Disequilibrium
Mice
MicroRNAs
Models, Genetic
Mutagenesis, Site-Directed
Nucleic Acid Conformation
Nucleotide Motifs
Polymorphism, Single Nucleotide
Proof of Concept Study
Protein Binding
Quantitative Trait Loci
RNA Splicing
RNA, Long Noncoding
RNA, Messenger
Synteny
Transcription Factors