Mapping determinants of human gene expression by regional and genome-wide association

Cheung, Vivian G.; Spielman, Richard S.; Ewens, Kathryn G.; Weber, Teresa; Morley, Michael; Burdick, Joshua T.

doi:10.1038/nature04244

Cited by 554 publications

(529 citation statements)

References 21 publications

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“…The majority of expression QTLs were regulated by one locus, which could indicate that mRNA levels display a less complex etiology and thus are easier to map than disease traits. 9,10 Taken together, these results further support that genes, which are encoded in a disease locus and whose mRNA levels correlate with the disease, are strong candidate genes.…”

Section: Introductionsupporting

confidence: 52%

“…As shown by Cheung et al, a significant proportion of variation in levels of specific mRNAs maps to the chromosome regions harboring the regulated genes indicating that the genes regulate their own expression. 9,10 Furthermore, a number of reported genes displaying allelic association with obesity such as PPARG and SREBP1C give additional support that susceptibility genes can be found among those with mRNA levels in adipose tissue associated with obesity. 29,30 Based on the above statement we conclude that also when linkage and expression data are from different subjects genes encoded in obesity QTLs and with obesity-associated variation in mRNA levels are good candidate genes for the QTL.…”

Section: Discussionmentioning

confidence: 96%

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Association analysis of positional obesity candidate genes based on integrated data from transcriptomics and linkage analysis

et al. 2008

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Context: Obesity is a typical complex disorder resulting from behaviors promoted in westernized societies in the presence of a genetic predisposition. We hypothesized that new genes predisposing to obesity can be detected at the mRNA level. Objective: To identify susceptibility genes for obesity. Design: Linkage and expression profile data from different cohorts were combined to select novel candidate genes that were analyzed for association with obesity. Setting and participants: University Hospital in Stockholm. Adipose tissue mRNA levels were quantified in 96 women. Two large cohorts with a wide distribution in body mass index (BMI, n ¼ 1013 and 1423) were genotyped. Main outcome measure: mRNA levels and allelic association with obesity. Results: We confirmed association between candidate gene mRNA levels in adipose tissue and obesity. A total of 118 polymorphisms in 16 genes were analyzed for association with obesity. Single nucleotide polymorphism rs1064891, located in the 3 0 UTR of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) gene, was nominally associated with obesity in combined analysis of cohorts 1 and 2 (P ¼ 0.007) and, in men that were lean or had severe obesity, with BMI (P ¼ o0.005). Conclusion: To combine linkage and expression profile data is valuable in finding new obesity genes. PFKFB3, a potential regulator of glycolysis, displays decreased mRNA levels in adipose tissue of obese women, is associated with obesity and is a new promising candidate gene for obesity warranting further studies.

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Section: Introductionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 96%

Association analysis of positional obesity candidate genes based on integrated data from transcriptomics and linkage analysis

et al. 2008

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“…89,90 They found 10 significant markers spanning 90 kb of chromosome 7 where IRF5 gene is located. Among them, rs2280714 was identified as the strongest cis-acting determinant of IRF5 expression.…”

Section: Irf5 In Murine Lupusmentioning

confidence: 99%

“…91 IRF5 polyadenylation (poly A) site SNP was the second genetic risk factor for SLE in Caucasians Among four SNPs in 3 0 -UTR region of IRF5, we found two SNPs (rs10954213 and rs10954214) that were in strong LD with rs2280714. Since rs2280714 was shown to be associated with high gene expression of IRF5, 89,90 we next examined the correlation between these 3 0 -UTR SNPs and IRF5 expression level. The mRNA expression data of 210 HapMap samples (CEU, CHB, JAP and YRI populations) collected at Sanger Institute (http:// www.sanger.ac.uk/humgen/genevar/) and mRNA expression data set of 233 CEPH samples 89 both revealed that rs10954213 SNP was most strongly associated with gene expression among all the tagSNPs encompassing the entire IRF5 gene.…”

Section: Irf5 In Murine Lupusmentioning

confidence: 99%

A compass that points to lupus: genetic studies on type I interferon pathway

Kyogoku

Tsuchiya

2007

Genes Immun

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It was more than 20 years ago that patients with systemic lupus erythematosus (SLE) were first reported to display elevated serum levels of type I interferon (IFN). Since then, extensive studies revealed a crucial role for type I IFN in SLE pathogenesis. The current model proposes that small increase of type I IFN production by plasmacytoid dendritic cells (pDCs) is sufficient to induce unabated activation of immature peripheral DCs. IFN-matured DCs select and activate autoreactive T cells and B cells, rather than deleting them, resulting in peripheral tolerance breakdown, a characteristic feature of SLE. Furthermore, immune complexes provide an amplification loop to pDCs for further IFN production. In the past 5 years, high-throughput technologies such as expression profiling and single-nucleotide polymorphism (SNP) typing established the role of altered type I IFN system in SLE, and a detailed picture of its molecular mechanisms is beginning to emerge. In this review, we discuss two major lines of genetics studies on type I IFN pathway related to human SLE: (1) expression profiling of IFN-responsive genes and (2) disease-associated SNPs of IFN-related genes, especially IRF5 (IFN-regulatory factor 5). Lastly, we discuss how such genetic alterations in type I IFN pathway fit in the current model of SLE pathogenesis.

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“…Following formaldehyde cross-linking of cells and isolation of chromatin, sonication was optimised for the cell lines to give rise to chromatin ranging in size between 200 and 1000 bp. Each of the cell lines examined was also selected for heterozygosity for an internal control, rs755467, a CHI3L2 SNP previously shown to confer allelic enrichment in asChIP for RNA pol II 15 in the same cell line. This confirmed the previous findings, with a 64.4% proportion of T allele present in the asChIP sample, compared with 50% in the control (P ¼ 0.0002), thus confirming the reliability of the assay.…”

Section: Resultsmentioning

confidence: 99%

Effects of genetic variation on chromatin structure and the transcriptional machinery: analysis of the IL6 gene locus

et al. 2012

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The presence of functional regulatory polymorphism at the interleukin 6 (IL6) locus is uncertain, with many conflicting in vitro findings. To examine the in vivo effect of the three putative functional IL6 promoter variants, À 174G4C, À 572G4C and À 6331T4C, two complementary techniques, allele-specific chromatin immunoprecipitation and allele-specific formaldehydeassisted isolation of regulatory elements, were carried out using unrelated lymphoblast cell lines of known genotype. There were no allele-specific effects for all three single-nucleotide polymorphisms (SNPs) under basal conditions. Upon IL-1b stimulation, however, allele-specific effects were seen for the À 6331 allele, which showed both increased RNA polymerase II loading (56%, P ¼ 0.001) and increased open chromatin (59%, P ¼ 0.004) for the T allele, which is in line with previous reports of this SNP and the effects from acute inflammation. These studies highlight the importance of examining chromatin under different environmental conditions when studying the functionality of regulatory polymorphisms.

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Mapping determinants of human gene expression by regional and genome-wide association

Cited by 554 publications

References 21 publications

Association analysis of positional obesity candidate genes based on integrated data from transcriptomics and linkage analysis

Association analysis of positional obesity candidate genes based on integrated data from transcriptomics and linkage analysis

A compass that points to lupus: genetic studies on type I interferon pathway

Effects of genetic variation on chromatin structure and the transcriptional machinery: analysis of the IL6 gene locus

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