A Multilayered Post-Genome-Wide Association Study Analysis Pipeline Defines Functional Variants and Target Genes for
Mehdi Fazel-Najafabadi1, Loren L Looger2, Harikrishna Reddy Rallabandi1
1Oklahoma Medical Research Foundation, Oklahoma City.
Arthritis & Rheumatology (Hoboken, N.J.)
|February 19, 2024
Summary
This study identifies key genetic variants and target genes involved in systemic lupus erythematosus (SLE) pathogenesis. These findings advance our understanding of SLE genetics and provide a foundation for future research into this autoimmune disease.
Area of Science:
- Genetics
- Immunology
- Autoimmune Diseases
Background:
- Systemic lupus erythematosus (SLE) is an autoimmune disease with a significant genetic basis.
- Genome-wide association studies (GWASs) have identified numerous SLE susceptibility loci, but causal variants and mechanisms remain unclear.
Purpose of the Study:
- To perform comprehensive post-GWAS analysis to fine-map and identify causal variants and target genes in SLE.
- To integrate diverse functional genomic and epigenomic data for precise variant and gene identification.
Main Methods:
- Utilized bioinformatics, molecular modeling, and functional genomic analyses.
- Cross-referenced immune cell-specific expression quantitative trait loci (eQTLs) with PCHi-C, chromatin accessibility, and reporter assay data.
- Employed CRISPR/Cas9 genome editing for experimental validation.
Main Results:
- Identified 182 independent non-HLA SLE loci and 564 unique target genes regulated by 3,746 SNPs.
- 329 SNPs demonstrated significant allele-specific chromatin accessibility or enhancer activity.
- Validated rs57668933 as a functional variant regulating SLE-risk gene ELF1 in B cells.
Conclusions:
- Demonstrated the utility of multidimensional data for prioritizing causal SLE variants and their target genes.
- Provided a catalog of SLE-associated SNPs, loci, target genes, and potential mechanisms for further investigation.
