Analysis of putative cis-regulatory elements regulating blood pressure variation
| Autor: | Carlos Iribarren, Dongwon Lee, Aravinda Chakravarti, Eric Boerwinkle, Dilrini K. Ranatunga, Georg B. Ehret, Man Li, Dan E. Arking, Priyanka Nandakumar, Pui-Yan Kwok, Catherine Schaefer, Megan L. Grove, Neil Risch, Thomas J. Hoffmann |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Aging
Genome-wide association study Blood Pressure 030204 cardiovascular system & hematology Regulatory Sequences Nucleic Acid Cardiovascular Kidney Medical and Health Sciences 0302 clinical medicine Genotype Gene expression 2.1 Biological and endogenous factors Aetiology Association Studies Article Genetics (clinical) Aorta Genetics & Heredity Genetics Regulation of gene expression 0303 health sciences Intracellular Signaling Peptides and Proteins Heart General Medicine Biological Sciences Chromatin Tibial Arteries Regulatory sequence Biotechnology Cell type Quantitative Trait Loci Computational biology Biology 03 medical and health sciences Humans Molecular Biology Gene 030304 developmental biology Genetic association Nucleic Acid Human Genome Membrane Proteins Atherosclerosis Genetic epidemiology Gene Expression Regulation Expression quantitative trait loci Regulatory Sequences Genome-Wide Association Study |
| Zdroj: | Hum Mol Genet Human molecular genetics, vol 29, iss 11 |
| DOI: | 10.1101/820522 |
| Popis: | Hundreds of loci have been associated with blood pressure traits from many genome-wide association studies. We identified an enrichment of these loci in aorta and tibial artery expression quantitative trait loci in our previous work in ∼100,000 Genetic Epidemiology Research on Aging (GERA) study participants. In the present study, we subsequently focused on determining putative regulatory regions for these and other tissues of relevance to blood pressure, to both fine-map these loci by pinpointing genes and variants of functional interest within them, and to identify any novel genes.We constructed maps of putative cis-regulatory elements using publicly available open chromatin data for the heart, aorta and tibial arteries, and multiple kidney cell types. Sequence variants within these regions may be evaluated quantitatively for their tissue- or cell-type-specific regulatory impact using deltaSVM functional scores, as described in our previous work. In order to identify genes of interest, we aggregate these variants in these putative cis-regulatory elements within 50Kb of the start or end of genes considered as “expressed” in these tissues or cell types using publicly available gene expression data, and use the deltaSVM scores as weights in the well-known group-wise sequence kernel association test (SKAT). We test for association with both blood pressure traits as well as expression within these tissues or cell types of interest, and identify several genes, includingMTHFR,C10orf32,CSK,NOV,ULK4,SDCCAG8,SCAMP5,RPP25,HDGFRP3,VPS37B, andPPCDC. Although our study centers on blood pressure traits, we additionally examined two known genes,SCN5AandNOS1APinvolved in the cardiac trait QT interval, in the Atherosclerosis Risk in Communities Study (ARIC), as a positive control, and observed an expected heart-specific effect. Thus, our method may be used to identify variants and genes for further functional testing using tissue- or cell-type-specific putative regulatory information.Author SummarySequence change in genes (“variants”) are linked to the presence and severity of different traits or diseases. However, as genes may be expressed in different tissues and at different times and degrees, using this information is expected to more accurately identify genes of interest. Variants within the genes are essential, but also in the sequences (“regulatory elements”) that control the genes’ expression in different tissues or cell types. In this study, we aim to use this information about expression and variants potentially involved in gene expression regulation to better pinpoint genes and variants in regulatory elements of interest for blood pressure regulation. We do so by taking advantage of such data that are publicly available, and use methods to combine information about variants in aggregate within a gene’s putative regulatory elements in tissues thought to be relevant for blood pressure, and identify several genes, meant to enable experimental follow-up. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|