Use of allele-specific FAIRE to determine functional regulatory polymorphism using large-scale genotyping arrays.

Smith AJ, Howard P, Shah S, Eriksson P, Stender S, Giambartolomei C, Folkersen L, Tybjærg-Hansen A, Kumari M, Palmen J, Hingorani AD, Talmud PJ, Humphries SE

PLoS Genet. 8 (8) e1002908 [2012-08-16; online 2012-08-16]

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.

NGI Uppsala (SNP&SEQ Technology Platform)

National Genomics Infrastructure

PubMed 22916038

DOI 10.1371/journal.pgen.1002908

Crossref 10.1371/journal.pgen.1002908

pii: PGENETICS-D-12-00477
pmc: PMC3420950