Trans-Ethnic Mapping of BANK1 Identifies Two Independent SLE-Risk Linkage Groups Enriched for Co-Transcriptional Splicing Marks
| Autor: | Joan T. Merrill, Mikhail G. Dozmorov, Robert P. Kimberly, Gary S. Gilkeson, Manuel Martínez-Bueno, Courtney G. Montgomery, Mary E. Comeau, Nina Oparina, Diane L. Kamen, Jane E. Salmon, Marta E. Alarcón-Riquelme, Michael H. Weisman, Miranda C. Marion, John B. Harley, Judith A. James, Joseph W. McCune, Carl D. Langefeld |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Genetic Linkage Genome-wide association study autoimmune disorders Epigenesis Genetic lcsh:Chemistry Exon 0302 clinical medicine systemic lupus erythematosus Risk Factors BANK1 genetics lcsh:QH301-705.5 Spectroscopy Epigenomics Genetics General Medicine 3. Good health Computer Science Applications RNA splicing transethnic genetic studies Quantitative Trait Loci Single-nucleotide polymorphism Biology Polymorphism Single Nucleotide Article Catalysis White People Autoimmune Diseases Inorganic Chemistry 03 medical and health sciences Humans Enhancer of Zeste Homolog 2 Protein Genetic Predisposition to Disease Epigenetics Physical and Theoretical Chemistry Molecular Biology Adaptor Proteins Signal Transducing Binding Sites Organic Chemistry Intron Membrane Proteins Introns 030104 developmental biology Core Binding Factor Alpha 3 Subunit lcsh:Biology (General) lcsh:QD1-999 Gene Expression Regulation Haplotypes Expression quantitative trait loci 030217 neurology & neurosurgery Genome-Wide Association Study |
| Zdroj: | Digibug. Repositorio Institucional de la Universidad de Granada instname International Journal of Molecular Sciences Volume 19 Issue 8 International Journal of Molecular Sciences, Vol 19, Iss 8, p 2331 (2018) |
| Popis: | BANK1 is a susceptibility gene for several systemic autoimmune diseases in several populations. Using the genome-wide association study (GWAS) data from Europeans (EUR) and African Americans (AA), we performed an extensive fine mapping of ankyrin repeats 1 (BANK1). To increase the SNP density, we used imputation followed by univariate and conditional analysis, combinedwith a haplotypic and expression quantitative trait locus (eQTL) analysis. The data from Europeans showed that the associated region was restricted to a minimal and dependent set of SNPs covering introns two and three, and exon two. In AA, the signal found in the Europeans was split into two independent effects. All of the major risk associated SNPs were eQTLs, and the risks were associated with an increased BANK1 gene expression. Functional annotation analysis revealed the enrichment of repressive B cell epigenomicmarks (EZH2 and H3K27me3) and a strong enrichment of splice junctions. Furthermore, one eQTL located in intron two, rs13106926, was found within the binding site for RUNX3, a transcriptional activator. These results connect the local genome topography, chromatin structure, and the regulatory landscape of BANK1 with co-transcriptional splicing of exon two. Our data defines a minimal set of risk associated eQTLs predicted to be involved in the expression of BANK1 modulated through epigenetic regulation and splicing. These findings allow us to suggest that the increased expression of BANK1 will have an impact on B-cell mediated disease pathways. The work presented in this paper has been supported by the Ministerio de Economía y Competitividad, Spain (SAF2016-78631-P), partly co-financed by FEDER funds of the European Union, the Gustaf den V:e-80-års Fond and the Swedish Association against Rheumatism to M.E.A-R. In addition, this work was financed by the NIH P01 grant P01-AI-083194 to C.D.L., J.B.H., R.K., and M.E.A-R. JBH: NIH grants: R01 AI024717, U01 HG00866, P30 AR070549 and U01 AI130830 and the US Department of Veterans Affairs: I01 BX001834.C.D.L.: Center for Public Health Genomics. R.K.: NIH grant R01-AR33062. J.A.J.: NIH grants U54GM104938, P30AR053483. |
| Databáze: | OpenAIRE |
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