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

Nature Communications
John P RayNir Hacohen

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.

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Citations

Aug 23, 2020·Current Opinion in Rheumatology·Cindy OrvainYannick Allanore
Jun 5, 2020·Genome Biology·Carl G de BoerAviv Regev
Jul 2, 2020·International Journal of Molecular Sciences·Marek FolMagdalena Druszczyńska
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Mar 14, 2021·Nature Communications·Xiaoming LuLeah C Kottyan
Jul 1, 2021·Nature Reviews. Rheumatology·Yuriy BaglaenkoSoumya Raychaudhuri
Jul 3, 2021·International Journal of Molecular Sciences·Arina O DegtyarevaTatiana I Merkulova
Jul 29, 2021·Trends in Genetics : TIG·Melina Claussnitzer, Katalin Susztak

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Datasets Mentioned

BETA
GM12878
GSE101498

Methods Mentioned

BETA
ChIP-seq
HiChIP
transfection
RNA-seq
PMA
PCR
ChIP
pulldown
Illumina sequencing

Software Mentioned

TapeStation
Plink
C Pro
quantifyRNATags
Bowtie2
MPRA
FINEMAP
Qubit
pyatac
susieR

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