Smith, AJ;
Howard, P;
Shah, S;
Eriksson, P;
Stender, S;
Giambartolomei, C;
Folkersen, L;
... Humphries, SE; + view all
(2012)
Use of allele-specific FAIRE to determine functional regulatory polymorphism using large-scale genotyping arrays.
PLoS Genetics
, 8
(8)
, Article e1002908. 10.1371/journal.pgen.1002908.
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Abstract
Following the widespread use of genome-wide association studies (GWAS), focus is turning towards identification of causal variants rather than simply genetic markers of diseases and traits. As a step towards a high-throughput method to identify genome-wide, non-coding, functional regulatory variants, we describe the technique of allele-specific FAIRE, utilising large-scale genotyping technology (FAIRE-gen) to determine allelic effects on chromatin accessibility and regulatory potential. FAIRE-gen was explored using lymphoblastoid cells and the 50,000 SNP Illumina CVD BeadChip. The technique identified an allele-specific regulatory polymorphism within NR1H3 (coding for LXR-α), rs7120118, coinciding with a previously GWAS-identified SNP for HDL-C levels. This finding was confirmed using FAIRE-gen with the 200,000 SNP Illumina Metabochip and verified with the established method of TaqMan allelic discrimination. Examination of this SNP in two prospective Caucasian cohorts comprising 15,000 individuals confirmed the association with HDL-C levels (combined beta = 0.016; p = 0.0006), and analysis of gene expression identified an allelic association with LXR-α expression in heart tissue. Using increasingly comprehensive genotyping chips and distinct tissues for examination, FAIRE-gen has the potential to aid the identification of many causal SNPs associated with disease from GWAS.
| Type: | Article |
|---|---|
| Title: | Use of allele-specific FAIRE to determine functional regulatory polymorphism using large-scale genotyping arrays. |
| Location: | US |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1371/journal.pgen.1002908 |
| Publisher version: | http://dx.doi.org/10.1371/journal.pgen.1002908 |
| Language: | English |
| Additional information: | © Smith et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. PMCID: PMC3420950 |
| Keywords: | Alleles, Cardiovascular Diseases, Cell Line, Cholesterol, HDL, Chromatin, Chromosome Mapping, Cohort Studies, European Continental Ancestry Group, Genome, Human, Genome-Wide Association Study, Genotype, Genotyping Techniques, Humans, Lymphocytes, Oligonucleotide Array Sequence Analysis, Orphan Nuclear Receptors, Phenotype, Polymorphism, Single Nucleotide |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Epidemiology and Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Epidemiology and Health > Epidemiology and Public Health |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1375805 |
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