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Prioritizing disease and trait causal variants at the TNFAIP3 locus using functional and genomic features.

ABSTRACT: Genome-wide association studies have associated thousands of genetic variants with complex traits and diseases, but pinpointing the causal variant(s) among those in tight linkage disequilibrium with each associated variant remains a major challenge. Here, we use seven experimental assays to characterize all common variants at the multiple disease-associated TNFAIP3 locus in five disease-relevant immune cell lines, based on a set of features related to regulatory potential. Trait/disease-associated variants are enriched among SNPs prioritized based on either: (1) residing within CRISPRi-sensitive regulatory regions, or (2) localizing in a chromatin accessible region while displaying allele-specific reporter activity. Of the 15 trait/disease-associated haplotypes at TNFAIP3, 9 have at least one variant meeting one or both of these criteria, 5 of which are further supported by genetic fine-mapping. Our work provides a comprehensive strategy to characterize genetic variation at important disease-associated loci, and aids in the effort to identify trait causal genetic variants.

SUBMITTER: Ray JP

PROVIDER: S-EPMC7060350 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Prioritizing disease and trait causal variants at the TNFAIP3 locus using functional and genomic features.

Ray John P JP de Boer Carl G CG Fulco Charles P CP Lareau Caleb A CA Kanai Masahiro M Ulirsch Jacob C JC Tewhey Ryan R Ludwig Leif S LS Reilly Steven K SK Bergman Drew T DT Engreitz Jesse M JM Issner Robbyn R Finucane Hilary K HK Lander Eric S ES Regev Aviv A Hacohen Nir N

Nature communications 20200306 1

Genome-wide association studies have associated thousands of genetic variants with complex traits and diseases, but pinpointing the causal variant(s) among those in tight linkage disequilibrium with each associated variant remains a major challenge. Here, we use seven experimental assays to characterize all common variants at the multiple disease-associated TNFAIP3 locus in five disease-relevant immune cell lines, based on a set of features related to regulatory potential. Trait/disease-associat ...[more]

PMID: 32144282

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Project description:BackgroundGenome-wide association studies have identified thousands of SNP variants associated with hundreds of phenotypes. For most associations the causal variants and the molecular mechanisms underlying pathogenesis remain unknown. Exploration of the underlying functional annotations of trait-associated loci has thrown some light on their potential roles in pathogenesis. However, there are some shortcomings of the methods used to date, which may undermine efforts to prioritize variants for further analyses. Here, we introduce and apply novel methods to rigorously identify annotation classes showing enrichment or depletion of trait-associated variants taking into account the underlying associations due to co-location of different functional annotations and linkage disequilibrium.ResultsWe assessed enrichment and depletion of variants in publicly available annotation classes such as genic regions, regulatory features, measures of conservation, and patterns of histone modifications. We used logistic regression to build a multivariate model that identified the most influential functional annotations for trait-association status of genome-wide significant variants. SNPs associated with all of the enriched annotations were 8 times more likely to be trait-associated variants than SNPs annotated with none of them. Annotations associated with chromatin state together with prior knowledge of the existence of a local expression QTL (eQTL) were the most important factors in the final logistic regression model. Surprisingly, despite the widespread use of evolutionary conservation to prioritize variants for study we find only modest enrichment of trait-associated SNPs in conserved regions.ConclusionWe established odds ratios of functional annotations that are more likely to contain significantly trait-associated SNPs, for the purpose of prioritizing GWAS hits for further studies. Additionally, we estimated the relative and combined influence of the different genomic annotations, which may facilitate future prioritization methods by adding substantial information.

Project description:We previously identified a locus at 21q22.3, tagged by the single nucleotide polymorphism (SNP) rs35418111, being associated with breast cancer risk at a genome-wide significance level; however, the underlying causal functional variants and gene(s) responsible for this association are unknown. We performed functional genomic analyses to identify potential functional variants and target genes that may mediate this association. Functional annotation for SNPs in high linkage disequilibrium (LD, r2 > 0.8) with rs35418111 in Asians showed evidence of promoter and/or enhancer activities, including rs35418111, rs2078203, rs8134832, rs57385578, and rs8126917. These five variants were assessed for interactions with nuclear proteins by electrophoretic mobility shift assays. Our results showed that the risk alleles for rs2078203 and rs35418111 altered DNA-protein interaction patterns. Cis-expression quantitative loci (cis-eQTL) analysis, using data from the Genotype-Tissue Expression database (GTEx) European-ancestry female normal breast tissue, indicated that the risk allele of rs35418111 was associated with a decreased expression of the YBEY gene, a relatively uncharacterized endoribonuclease in humans. We investigated the biological effects of YBEY on breast cancer cell lines by transient knock-down of YBEY expression in MCF-7, T47D, and MDA-MB-231 cell lines. Knockdown of YBEY mRNA in breast cancer cell lines consistently decreased cell proliferation, colony formation, and migration/invasion, regardless of estrogen receptor status. We performed RNA sequencing in MDA-MB-231 cells transfected with siRNA targeting YBEY and subsequent gene set enrichment analysis to identify gene networks associated with YBEY knockdown. These data indicated YBEY was involved in networks associated with inflammation and metabolism. Finally, we showed trends in YBEY expression patterns in breast tissues from The Cancer Genome Atlas (TCGA); early-stage breast cancers had elevated YBEY expression compared with normal tissue, but significantly decreased expression in late-stage disease. Our study provides evidence of a significant role for the human YBEY gene in breast cancer pathogenesis and the association between the rs35418111/21q22.3 locus and breast cancer risk, which may be mediated through functional SNPs, rs35418111 and rs2078203, that regulate expression of YBEY.

Dataset Information

Prioritizing disease and trait causal variants at the TNFAIP3 locus using functional and genomic features.

Publications

Prioritizing disease and trait causal variants at the TNFAIP3 locus using functional and genomic features.

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