Abstract:
:Genetic and epigenetic mechanisms may interact and together affect biological processes and disease development. However, most previous studies have investigated genetic and epigenetic mechanisms independently, and studies examining their interactions throughout the human genome are lacking. To identify genetic loci that interact with the epigenome, we performed the first genome-wide DNA methylation quantitative trait locus (mQTL) analysis in human pancreatic islets. We related 574,553 single nucleotide polymorphisms (SNPs) with genome-wide DNA methylation data of 468,787 CpG sites targeting 99% of RefSeq genes in islets from 89 donors. We identified 67,438 SNP-CpG pairs in cis, corresponding to 36,783 SNPs (6.4% of tested SNPs) and 11,735 CpG sites (2.5% of tested CpGs), and 2,562 significant SNP-CpG pairs in trans, corresponding to 1,465 SNPs (0.3% of tested SNPs) and 383 CpG sites (0.08% of tested CpGs), showing significant associations after correction for multiple testing. These include reported diabetes loci, e.g. ADCY5, KCNJ11, HLA-DQA1, INS, PDX1 and GRB10. CpGs of significant cis-mQTLs were overrepresented in the gene body and outside of CpG islands. Follow-up analyses further identified mQTLs associated with gene expression and insulin secretion in human islets. Causal inference test (CIT) identified SNP-CpG pairs where DNA methylation in human islets is the potential mediator of the genetic association with gene expression or insulin secretion. Functional analyses further demonstrated that identified candidate genes (GPX7, GSTT1 and SNX19) directly affect key biological processes such as proliferation and apoptosis in pancreatic β-cells. Finally, we found direct correlations between DNA methylation of 22,773 (4.9%) CpGs with mRNA expression of 4,876 genes, where 90% of the correlations were negative when CpGs were located in the region surrounding transcription start site. Our study demonstrates for the first time how genome-wide genetic and epigenetic variation interacts to influence gene expression, islet function and potential diabetes risk in humans.
journal_name
PLoS Genetjournal_title
PLoS geneticsauthors
Olsson AH,Volkov P,Bacos K,Dayeh T,Hall E,Nilsson EA,Ladenvall C,Rönn T,Ling Cdoi
10.1371/journal.pgen.1004735subject
Has Abstractpub_date
2014-11-06 00:00:00pages
e1004735issue
11eissn
1553-7390issn
1553-7404pii
PGENETICS-D-14-00340journal_volume
10pub_type
杂志文章相关文献
PLoS Genetics文献大全abstract::X-chromosome inactivation (XCI) in female lymphocytes is uniquely regulated, as the inactive X (Xi) chromosome lacks localized Xist RNA and heterochromatin modifications. Epigenetic profiling reveals that Xist RNA is lost from the Xi at the pro-B cell stage and that additional heterochromatic modifications are gradual...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1007050
更新日期:2017-10-09 00:00:00
abstract::The extent that both positive and negative selection vary across different portions of plant genomes remains poorly understood. Here, we sequence whole genomes of 13 Capsella grandiflora individuals and quantify the amount of selection across the genome. Using an estimate of the distribution of fitness effects, we sho...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1004622
更新日期:2014-09-25 00:00:00
abstract::rs143383 is a C to T transition SNP located in the 5'untranslated region (5'UTR) of the growth differentiation factor 5 gene GDF5. The T allele of the SNP is associated with increased risk of osteoarthritis (OA) in Europeans and in Asians. This susceptibility is mediated by the T allele producing less GDF5 transcript ...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1003557
更新日期:2013-06-01 00:00:00
abstract::Understanding how axon guidance receptors are activated by their extracellular ligands to regulate growth cone motility is critical to learning how proper wiring is established during development. Roundabout (Robo) is one such guidance receptor that mediates repulsion from its ligand Slit in both invertebrates and ver...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1005402
更新日期:2015-09-03 00:00:00
abstract::Recently, Wu and colleagues [1] proposed two novel statistics for genome-wide interaction analysis using case/control or case-only data. In computer simulations, their proposed case/control statistic outperformed competing approaches, including the fast-epistasis option in PLINK and logistic regression analysis under ...
journal_title:PLoS genetics
pub_type: 评论,杂志文章
doi:10.1371/journal.pgen.1002625
更新日期:2012-01-01 00:00:00
abstract::Immunoregulatory cytokine interleukin-10 (IL-10) is elevated in sera from patients with systemic lupus erythematosus (SLE) correlating with disease activity. The established association of IL10 with SLE and other autoimmune diseases led us to fine map causal variant(s) and to explore underlying mechanisms. We assessed...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1003870
更新日期:2013-01-01 00:00:00
abstract::DNA- and RNA-processing pathways are integrated and interconnected in the eukaryotic nucleus to allow efficient gene expression and to maintain genomic stability. The recruitment of DNA Topoisomerase I (Topo I), an enzyme controlling DNA supercoiling and acting as a specific kinase for the SR-protein family of splicin...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1001124
更新日期:2010-09-16 00:00:00
abstract::Guanine (G)-rich DNA readily forms four-stranded quadruplexes in vitro, but evidence for their participation in genome regulation is limited. We have identified a quadruplex-binding protein, Lia3, that controls the boundaries of germline-limited, internal eliminated sequences (IESs) of Tetrahymena thermophila. Differe...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1005842
更新日期:2016-03-07 00:00:00
abstract::Rheumatoid arthritis is a chronic inflammatory disease with a high prevalence and substantial socioeconomic burden. Despite intense research efforts, its aetiology and pathogenesis remain poorly understood. To identify novel genes and/or cellular pathways involved in the pathogenesis of the disease, we utilized a well...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.0010048
更新日期:2005-10-01 00:00:00
abstract::Previous genetic studies have suggested a history of sub-Saharan African gene flow into some West Eurasian populations after the initial dispersal out of Africa that occurred at least 45,000 years ago. However, there has been no accurate characterization of the proportion of mixture, or of its date. We analyze genome-...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1001373
更新日期:2011-04-01 00:00:00
abstract::The cooperative developmental system of the social amoeba Dictyostelium discoideum is susceptible to exploitation by cheaters-strains that make more than their fair share of spores in chimerae. Laboratory screens in Dictyostelium have shown that the genetic potential for facultative cheating is high, and field surveys...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1000854
更新日期:2010-02-26 00:00:00
abstract::Aging in Caenorhabditis elegans is characterized by widespread physiological and molecular changes, but the mechanisms that determine the rate at which these changes occur are not well understood. In this study, we identify a novel link between reproductive aging and somatic aging in C. elegans. By measuring global ag...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1005725
更新日期:2015-12-11 00:00:00
abstract::Retinoblastoma (Rb), the most common pediatric intraocular neoplasm, results from inactivation of both alleles of the RB1 tumor suppressor gene. The second allele is most commonly lost, as demonstrated by loss of heterozygosity studies. RB1 germline carriers usually develop bilateral tumors, but some Rb families displ...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1005888
更新日期:2016-02-29 00:00:00
abstract::A variety of human diseases arise from mutations that alter muscle contraction. Evolutionary conservation allows genetic studies in Drosophila melanogaster to be used to better understand these myopathies and suggest novel therapeutic strategies. Integrin-mediated adhesion is required to support muscle structure and f...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1003406
更新日期:2013-03-01 00:00:00
abstract::Systemic lupus erythematosus (SLE) is an autoimmune disease with known genetic, epigenetic, and environmental risk factors. To assess the role of DNA methylation in SLE, we collected CD4+ T-cells, CD19+ B-cells, and CD14+ monocytes from 49 SLE patients and 58 controls, and performed genome-wide DNA methylation analysi...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1003678
更新日期:2013-01-01 00:00:00
abstract::Reproductive proteins are among the fastest evolving in the proteome, often due to the consequences of positive selection, and their rapid evolution is frequently attributed to a coevolutionary process between interacting female and male proteins. Such a process could leave characteristic signatures at coevolving gene...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1000570
更新日期:2009-07-01 00:00:00
abstract::The exclusive localization of the histone H3 variant CENP-A to centromeres is essential for accurate chromosome segregation. Ubiquitin-mediated proteolysis helps to ensure that CENP-A does not mislocalize to euchromatin, which can lead to genomic instability. Consistent with this, overexpression of the budding yeast C...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1005930
更新日期:2016-03-16 00:00:00
abstract::Understanding the molecular basis for phenotypic differences between humans and other primates remains an outstanding challenge. Mutations in non-coding regulatory DNA that alter gene expression have been hypothesized as a key driver of these phenotypic differences. This has been supported by differential gene express...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1002789
更新日期:2012-06-01 00:00:00
abstract::Through as yet undefined proteins and pathways, the SUMO-targeted ubiquitin ligase (STUbL) suppresses genomic instability by ubiquitinating SUMO conjugated proteins and driving their proteasomal destruction. Here, we identify a critical function for fission yeast STUbL in suppressing spontaneous and chemically induced...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1001320
更新日期:2011-03-01 00:00:00
abstract::Across phylogeny, glutamate (Glu) signaling plays a critical role in regulating neural excitability, thus supporting many complex behaviors. Perturbed synaptic and extrasynaptic Glu homeostasis in the human brain has been implicated in multiple neuropsychiatric and neurodegenerative disorders including Parkinson's dis...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1007269
更新日期:2018-03-28 00:00:00
abstract::Sideroblastic anemias are acquired or inherited anemias that result in a decreased ability to synthesize hemoglobin in red blood cells and result in the presence of iron deposits in the mitochondria of red blood cell precursors. A common subtype of congenital sideroblastic anemia is due to autosomal recessive mutation...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1005783
更新日期:2016-01-28 00:00:00
abstract::Mitotic and cytokinetic processes harness cell machinery to drive chromosomal segregation and the physical separation of dividing cells. Here, we investigate the functional requirements for exocyst complex function during cell division in vivo, and demonstrate a common mechanism that directs anaphase cell elongation a...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1005632
更新日期:2015-11-03 00:00:00
abstract::Intestinal stem cell (ISC) self-renewal and proliferation are directed by Wnt/β-catenin signaling in mammals, whereas aberrant Wnt pathway activation in ISCs triggers the development of human colorectal carcinoma. Herein, we have utilized the Drosophila midgut, a powerful model for ISC regulation, to elucidate the mec...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1005822
更新日期:2016-02-04 00:00:00
abstract::Dietary factors, including meat, fruits, vegetables and fiber, are associated with colorectal cancer; however, there is limited information as to whether these dietary factors interact with genetic variants to modify risk of colorectal cancer. We tested interactions between these dietary factors and approximately 2.7 ...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1004228
更新日期:2014-04-17 00:00:00
abstract::Plants utilize an innate immune system to protect themselves from disease. While many molecular components of plant innate immunity resemble the innate immunity of animals, plants also have evolved a number of truly unique defense mechanisms, particularly at the physiological level. Plant's flexible developmental prog...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1007132
更新日期:2017-12-18 00:00:00
abstract::A large fraction of human genes are regulated by genetic variation near the transcribed sequence (cis-eQTL, expression quantitative trait locus), and many cis-eQTLs have implications for human disease. Less is known regarding the effects of genetic variation on expression of distant genes (trans-eQTLs) and their biolo...
journal_title:PLoS genetics
pub_type: 杂志文章,随机对照试验
doi:10.1371/journal.pgen.1004818
更新日期:2014-12-04 00:00:00
abstract::RNA silencing is a defense system against "genomic parasites" such as transposable elements (TE), which are potentially harmful to host genomes. In plants, transcripts from TEs induce production of double-stranded RNAs (dsRNAs) and are processed into small RNAs (small interfering RNAs, siRNAs) that suppress TEs by RNA...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1002953
更新日期:2012-09-01 00:00:00
abstract::Comparison of whole genomes has revealed large and frequent changes in the size of gene families. These changes occur because of high rates of both gene gain (via duplication) and loss (via deletion or pseudogenization), as well as the evolution of entirely new genes. Here we use the genomes of 12 fully sequenced Dros...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.0030197
更新日期:2007-11-01 00:00:00
abstract::Bromodomain proteins are key regulators of gene expression. How the levels of these factors are regulated in specific environmental conditions is unknown. Previous work has established that expression of yeast Bromodomain factor 2 (BDF2) is limited by spliceosome-mediated decay (SMD). Here we show that BDF2 is subject...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1004661
更新日期:2014-09-18 00:00:00
abstract::Beckwith-Wiedemann syndrome (BWS) is a fetal overgrowth and human imprinting disorder resulting from the deregulation of a number of genes, including IGF2 and CDKN1C, in the imprinted gene cluster on chromosome 11p15.5. Most cases are sporadic and result from epimutations at either of the two 11p15.5 imprinting centre...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1000423
更新日期:2009-03-01 00:00:00