Allelic Variation in Human Gene Expression

Yan, Hai; Yuan, Weishi; Velculescu, Victor E.; Vogelstein, Bert; Kinzler, Kenneth W.

doi:10.1126/science.1072545

Cited by 616 publications

(586 citation statements)

References 2 publications

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“…This would imply that the À512C4T polymorphism is not the causal one. Although differences in gene expression due to allelic variation are relatively common in humans, 21 it must be stressed that it is presently not known whether the FOXC2 5 0 UTR polymorphism is of direct We were unable to confirm an association between the Callele of À512C4T and insulin resistance or hypertriglyceridemia in the present investigation, but we observed a significant association between FOXC2 À512C and a concomitant diagnosis of the dysmetabolic syndrome in male type 2 diabetic subjects. The gender-specific effects are more evident in females in previous reports, whereas the effect is stronger in males in this study.…”

Section: Discussioncontrasting

confidence: 87%

Role of the FOXC2 –512C>T polymorphism in type 2 diabetes: possible association with the dysmetabolic syndrome

2004

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OBJECTIVE: Overexpression of the human transcription factor FOXC2 gene (FOXC2) protects against insulin resistance in mice and a common FOXC2 polymorphism (À512C4T) has been suggested to be associated with insulin resistance in humans. Here, we addressed the potential role for FOXC2 as a candidate gene for type 2 diabetes and associated phenotypes. MATERIALS AND METHODS: A case-control study was performed in 390 type 2 diabetic patients and 307 control subjects. The number of patients was increased to a total of 768 subjects for further study of phenotypic differences relating to the dysmetabolic syndrome relative to genetic variation. The FOXC2 -512C4T polymorphism was genotyped by a restriction fragment length polymorphism PCR assay. RESULTS: FOXC2 À512C4T allele and genotype distribution did not differ between patients with type 2 diabetes and control subjects, but the C/C genotype was associated with increased body mass index (BMI, kg/m 2 ) (P a ¼ 0.03) among type 2 diabetic patients. The FOXC2 -512C4T polymorphism was a significant independent predictor of BMI (P ¼ 0.001) in a multiple regression model including age, gender and affection status. We found no significant association with type 2 diabetes-related metabolic parameters but that the C-allele (P ¼ 0.01) and C/C and C/T genotypes (P ¼ 0.03) were significantly over-represented in type 2 diabetic males with a concomitant diagnosis of dysmetabolic syndrome. CONCLUSION: We conclude that FOXC2 is associated with obesity and metabolic deterioration but does not contribute to an increased risk for type 2 diabetes.

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Section: Discussioncontrasting

confidence: 87%

Role of the FOXC2 –512C>T polymorphism in type 2 diabetes: possible association with the dysmetabolic syndrome

2004

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“…Using a highly sensitive method for assessing variable cis ‐effects on gene expression [Yan et al, 2002; Bray et al, 2003a,2003b], we have found that several of the principal candidate genes at this locus exhibit altered cis ‐regulation in the developing and adult human brain in association with the most strongly supported schizophrenia risk variants. Largest and most consistent effects were observed on BORCS7 , AS3MT , and NT5C2 , providing functional support for these as genuine susceptibility genes for schizophrenia.…”

Section: Discussionmentioning

confidence: 99%

“…Measures of allele‐specific expression provide a powerful means of assessing such cis ‐regulatory influences, because they allow the level of gene expression from chromosomes carrying the risk and non‐risk alleles of a given variant to be compared simultaneously within individual samples [Bray et al, 2003a]. This approach typically makes use of exonic (i.e., expressed) single nucleotide polymorphisms (SNPs) in genes of interest as allele‐specific tags, allowing the RNA transcribed from each parental chromosome to be distinguished and relatively quantified in individual heterozygotes [Yan et al, 2002]. A major advantage of this method over traditional expression quantitative trait loci (eQTL) approaches based on total gene expression is that it effectively controls for tissue variables such as RNA quality as well as confounding effects of other genetic and environmental variables, since these influences will usually act on both alleles to the same extent [Bray et al, 2003b].…”

Section: Introductionmentioning

confidence: 99%

Genome‐wide significant schizophrenia risk variation on chromosome 10q24 is associated with altered cis‐regulation of BORCS7, AS3MT, and NT5C2 in the human brain

Duarte

Troakes

Nolan

et al. 2016

American J of Med Genetics Pt B

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Chromosome 10q24.32‐q24.33 is one of the most robustly supported risk loci to emerge from genome‐wide association studies (GWAS) of schizophrenia. However, extensive linkage disequilibrium makes it difficult to distinguish the actual susceptibility gene(s) at the locus, limiting its value for improving biological understanding of the condition. In the absence of coding changes that can account for the association, risk is likely conferred by altered regulation of one or more genes in the region. We, therefore, used highly sensitive measures of allele‐specific expression to assess cis‐regulatory effects associated with the two best‐supported schizophrenia risk variants (SNP rs11191419 and indel ch10_104957618_I/rs202213518) on the primary positional candidates BORCS7, AS3MT, CNNM2, and NT5C2 in the human brain. Heterozygosity at rs11191419 was associated with increased allelic expression of BORCS7 and AS3MT in the fetal and adult brain, and with reduced allelic expression of NT5C2 in the adult brain. Heterozygosity at ch10_104957618_I was associated with reduced allelic expression of NT5C2 in both the fetal and adult brain. Comparisons between cDNA ratios in heterozygotes and homozygotes for the risk alleles indicated that cis‐effects on NT5C2 expression in the adult dorsolateral prefrontal cortex could be largely accounted for by genotype at these two risk variants. While not excluding effects on other genes in the region, this study implicates altered neural expression of BORCS7, AS3MT, and NT5C2 in susceptibility to schizophrenia arising from genetic variation at the chromosome 10q24 locus. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

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“…43 Genetic variants that differentially affect mRNA expression from a given allele cause allelic expression imbalance (AEI), which can be quantitatively measured in individuals who are heterozygous for a marker SNP within the mRNA. 44 The existence of AEI indicates the presence of cis-acting factors that influence intracellular levels of mRNA by modifying transcription, mRNA processing, or epigenetic effects. [44][45][46][47][48] Genetic analyses suggest that cis-acting genetic variants are one of the main sources of variability in human phenotype, including susceptibility to disease.…”

Section: Introductionmentioning

confidence: 99%

Allelic expression of serotonin transporter (SERT) mRNA in human pons: lack of correlation with the polymorphism SERTLPR

Papp

Pinsonneault

et al. 2006

Mol Psychiatry

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An insertion/deletion polymorphism in the SERT linked promoter region (SERTLPR), previously reported to regulate mRNA expression in vitro, has been associated with mental disorders and response to psychotropic drugs. Contradictory evidence, however, has raised questions about the role of SERTLPR in regulating mRNA expression in vivo. We have used analysis of allelic expression imbalance (AEI) of SERT mRNA to assess quantitatively the contribution of SERTLPR to mRNA expression in human post-mortem pons tissue sections containing serotonergic neurons of the dorsal and median raphe nuclei. Any difference in the expression of one allele over the other indicates the presence of cis-acting elements that differentially affect transcription and/or mRNA processing and turnover. Using a marker SNP in the 3 0 untranslated region of SERT mRNA, statistically significant differences in allelic mRNA levels were detected in nine out of 29 samples heterozygous for the marker SNP. While the allelic expression differences were relatively small (15-25%), they could nevertheless be physiologically relevant. Although previous results had suggested that the long form of SERTLPR yields higher mRNA levels than the short form, we did not observe a correlation between SERTLPR and allelic expression ratios. Also in contrast to previous results, we found no correlation between SERTLPR and allelic expression ratios or SERT mRNA levels in Blymphocytes. This study demonstrates that regulation of SERT mRNA is independent of SERTLPR, but could be associated with polymorphisms in partial linkage disequilibrium with SERTLPR.

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Allelic Variation in Human Gene Expression

Cited by 616 publications

References 2 publications

Role of the FOXC2 –512C>T polymorphism in type 2 diabetes: possible association with the dysmetabolic syndrome

Role of the FOXC2 –512C>T polymorphism in type 2 diabetes: possible association with the dysmetabolic syndrome

Genome‐wide significant schizophrenia risk variation on chromosome 10q24 is associated with altered cis‐regulation of BORCS7, AS3MT, and NT5C2 in the human brain

Allelic expression of serotonin transporter (SERT) mRNA in human pons: lack of correlation with the polymorphism SERTLPR

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