Allelic expression mapping across cellular lineages to establish impact of non-coding SNPs.

Veronique Adoue,Nicholas Light,Bing Ge,Chuan Wang,Shu‐Huang Chen,Ann‐Christine Syvänen,Per Lundmark,Panos Deloukas,Willem H Ouwehand,Jonas Carlsson Almlöf,Lars Rönnblom,Alicia Schiavi,Francois Cambien,Maxime Caron,Alison H Goodall,Tony Kwan,Tomi Pastinen

doi:10.15252/msb.20145114

Abstract

Most complex disease-associated genetic variants are located in non-coding regions and are therefore thought to be regulatory in nature. Association mapping of differential allelic expression (AE) is a powerful method to identify SNPs with direct cis-regulatory impact (cis-rSNPs). We used AE mapping to identify cis-rSNPs regulating gene expression in 55 and 63 HapMap lymphoblastoid cell lines from a Caucasian and an African population, respectively, 70 fibroblast cell lines, and 188 purified monocyte samples and found 40–60% of these cis-rSNPs to be shared across cell types. We uncover a new class of cis-rSNPs, which disrupt footprint-derived de novo motifs that are predominantly bound by repressive factors and are implicated in disease susceptibility through overlaps with GWAS SNPs. Finally, we provide the proof-of-principle for a new approach for genome-wide functional validation of transcription factor–SNP interactions. By perturbing NFκB action in lymphoblasts, we identified 489 cis-regulated transcripts with altered AE after NFκB perturbation. Altogether, we perform a comprehensive analysis of cis-variation in four cell populations and provide new tools for the identification of functional variants associated to complex diseases.

Highlights

Most complex disease-associated genetic variants are located in non-coding regions and are thought to be regulatory in nature
In addition to 55 HapMap lymphoblastoid cell lines (LCLs) from a Caucasian population (CEU), we included 63 LCLs from an African population (YRI), 70 fibroblast cell lines from a Caucasian population (FBs) (Wagner et al, 2014), and 188 purified monocyte samples (MNCs) from unrelated healthy donors residing in the UK (Almlof et al, 2012)
We applied a filter for the statistical significance of genetic effects on allelic expression in order to limit the discovery of false-positive associations, requiring that loci be mapped below the threshold of 1% FDR

Summary

Introduction

Most complex disease-associated genetic variants are located in non-coding regions and are thought to be regulatory in nature. Association mapping of differential allelic expression (AE) is a powerful method to identify SNPs with direct cis-regulatory impact (cis-rSNPs). We used AE mapping to identify cis-rSNPs regulating gene expression in 55 and 63 HapMap lymphoblastoid cell lines from a Caucasian and an African population, respectively, 70 fibroblast cell lines, and 188 purified monocyte samples and found 40–60% of these cis-rSNPs to be shared across cell types. We uncover a new class of cis-rSNPs, which disrupt footprint-derived de novo motifs that are predominantly bound by repressive factors and are implicated in disease susceptibility through overlaps with GWAS SNPs. we provide the proof-of-principle for a new approach for genome-wide functional validation of transcription factor–SNP interactions. We perform a comprehensive analysis of cis-variation in four cell populations and provide new tools for the identification of functional variants associated to complex diseases

Methods

Results

Conclusion