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      Systematic identification of trans eQTLs as putative drivers of known disease associations

      Author(s): , , , , , , , , , , , , , , , , , , ,   , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
      Publication date (Electronic):
      Journal: Nature Genetics
      Publisher: Springer Science and Business Media LLC

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          Abstract

          Identifying the downstream effects of disease-associated SNPs is challenging. To help overcome this problem, we performed expression quantitative trait locus (eQTL) meta-analysis in non-transformed peripheral blood samples from 5,311 individuals with replication in 2,775 individuals. We identified and replicated trans eQTLs for 233 SNPs (reflecting 103 independent loci) that were previously associated with complex traits at genome-wide significance. Some of these SNPs affect multiple genes in trans that are known to be altered in individuals with disease: rs4917014, previously associated with systemic lupus erythematosus (SLE), altered gene expression of C1QB and five type I interferon response genes, both hallmarks of SLE. DeepSAGE RNA sequencing showed that rs4917014 strongly alters the 3' UTR levels of IKZF1 in cis, and chromatin immunoprecipitation and sequencing analysis of the trans-regulated genes implicated IKZF1 as the causal gene. Variants associated with cholesterol metabolism and type 1 diabetes showed similar phenomena, indicating that large-scale eQTL mapping provides insight into the downstream effects of many trait-associated variants.

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          An Integrated Encyclopedia of DNA Elements in the Human Genome

          Iakes Ezkurdia (2016)
          Summary The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure, and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall the project provides new insights into the organization and regulation of our genes and genome, and an expansive resource of functional annotations for biomedical research.
          Article 0 comments Cited 3317 times – based on 0 reviews     Review now
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            A map of human genome variation from population-scale sequencing.

            Amit Indap, Carlo Sidore (2011)
            The 1000 Genomes Project aims to provide a deep characterization of human genome sequence variation as a foundation for investigating the relationship between genotype and phenotype. Here we present results of the pilot phase of the project, designed to develop and compare different strategies for genome-wide sequencing with high-throughput platforms. We undertook three projects: low-coverage whole-genome sequencing of 179 individuals from four populations; high-coverage sequencing of two mother-father-child trios; and exon-targeted sequencing of 697 individuals from seven populations. We describe the location, allele frequency and local haplotype structure of approximately 15 million single nucleotide polymorphisms, 1 million short insertions and deletions, and 20,000 structural variants, most of which were previously undescribed. We show that, because we have catalogued the vast majority of common variation, over 95% of the currently accessible variants found in any individual are present in this data set. On average, each person is found to carry approximately 250 to 300 loss-of-function variants in annotated genes and 50 to 100 variants previously implicated in inherited disorders. We demonstrate how these results can be used to inform association and functional studies. From the two trios, we directly estimate the rate of de novo germline base substitution mutations to be approximately 10(-8) per base pair per generation. We explore the data with regard to signatures of natural selection, and identify a marked reduction of genetic variation in the neighbourhood of genes, due to selection at linked sites. These methods and public data will support the next phase of human genetic research.
            Article 0 comments Cited 745 times – based on 0 reviews     Review now
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              Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus.

              E. Baechler, F Batliwalla, G Karypis … (2003)
              Systemic lupus erythematosus (SLE) is a complex, inflammatory autoimmune disease that affects multiple organ systems. We used global gene expression profiling of peripheral blood mononuclear cells to identify distinct patterns of gene expression that distinguish most SLE patients from healthy controls. Strikingly, about half of the patients studied showed dysregulated expression of genes in the IFN pathway. Furthermore, this IFN gene expression "signature" served as a marker for more severe disease involving the kidneys, hematopoetic cells, and/or the central nervous system. These results provide insights into the genetic pathways underlying SLE, and identify a subgroup of patients who may benefit from therapies targeting the IFN pathway.
              Article 0 comments Cited 629 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Harm-Jan Westra: (View ORCID Profile)
                Journal
                Title: Nature Genetics
                Abbreviated Title: Nat Genet
                Publisher: Springer Science and Business Media LLC
                ISSN (Print): 1061-4036
                ISSN (Electronic): 1546-1718
                Publication date Created: October 2013
                Publication date (Electronic): September 8 2013
                Publication date (Print): October 2013
                Volume: 45
                Issue: 10
                Pages: 1238-1243
                Article
                DOI: 10.1038/ng.2756
                PMC ID: 3991562
                PubMed ID: 24013639
                SO-VID: fca43ed9-6cad-4939-bfab-3a60d668fdf5
                Copyright © © 2013
                License:

                http://www.springer.com/tdm

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