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

Frank Andrew Smith; Philip Howard; Sonia Shah; Per Eriksson; Stefan Stender; Claudia Giambartolomei; Lasse Westergaard Folkersen; Anne Tybjærg-Hansen; Meena Kumari; Jutta Palmen; Aroon D Hingorani; Philippa J Talmud; Steve E Humphries

doi:10.1371/journal.pgen.1002908

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

Frank Andrew Smith, Philip Howard, Sonia Shah, Per Eriksson, Stefan Stender, Claudia Giambartolomei, Lasse Westergaard Folkersen, Anne Tybjærg-Hansen, Meena Kumari, Jutta Palmen, Aroon D Hingorani, Philippa J Talmud, Steve E Humphries

18 Citations (Scopus)

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.

Original language	English
Journal	P L o S Genetics
Volume	8
Issue number	8
Pages (from-to)	e1002908
ISSN	1553-7390
DOIs	https://doi.org/10.1371/journal.pgen.1002908
Publication status	Published - Aug 2012

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Smith, F. A., Howard, P., Shah, S., Eriksson, P., Stender, S., Giambartolomei, C., Folkersen, L. W., Tybjærg-Hansen, A., Kumari, M., Palmen, J., Hingorani, A. D., Talmud, P. J., & Humphries, S. E. (2012). Use of allele-specific FAIRE to determine functional regulatory polymorphism using large-scale genotyping arrays. P L o S Genetics, 8(8), e1002908. https://doi.org/10.1371/journal.pgen.1002908

Smith, FA, Howard, P, Shah, S, Eriksson, P, Stender, S, Giambartolomei, C, Folkersen, LW, Tybjærg-Hansen, A, Kumari, M, Palmen, J, Hingorani, AD, Talmud, PJ & Humphries, SE 2012, 'Use of allele-specific FAIRE to determine functional regulatory polymorphism using large-scale genotyping arrays', P L o S Genetics, vol. 8, no. 8, pp. e1002908. https://doi.org/10.1371/journal.pgen.1002908

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title = "Use of allele-specific FAIRE to determine functional regulatory polymorphism using large-scale genotyping arrays",

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.",

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AU - Tybjærg-Hansen, Anne

AU - Kumari, Meena

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AU - Hingorani, Aroon D

AU - Talmud, Philippa J

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N2 - 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.

AB - 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.

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

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