Dynamic Role of trans Regulation of Gene Expression in Relation to Complex Traits

Yao, Chen; Joehanes, Roby; Johnson, Andrew D.; Huan, Tianxiao; Liu, Chunyu; Freedman, Jane E.; Munson, Peter J.; Hill, David E.; Vidal, Marc; Levy, Daniel

doi:10.1016/j.ajhg.2017.02.003

Cited by 106 publications

(99 citation statements)

References 50 publications

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“…Based on the PhenoScanner database, we found that rs10830963 appeared to affect the expression levels of distant genes. Emerging evidence suggests that some SNPs affect the expression of distant genes and genes residing on other chromosomes (trans‐eQTLs) . Thus, it is biologically plausible that rs10830963 may affect the expression of genes and be involved in the pathogenesis of GDM.…”

Section: Discussionmentioning

confidence: 99%

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Genetic predisposition to gestational glucose metabolism and gestational diabetes mellitus risk in a Chinese population

Xie

Zhang

Wen

et al. 2019

Journal of Diabetes

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Background Genome‐wide association studies (GWAS) have identified several genetic variants affecting gestational glucose metabolism. However, information regarding their known associations with gestational diabetes mellitus (GDM) risk remains scarce. Methods This study examined the associations of 12 gestational glucose metabolism‐related variants with GDM risk in a Chinese population (964 GDM cases, 1021 controls). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression analysis. Results Rs10830963 in melatonin receptor 1B (MTNR1B) was found to be associated with an increased risk of GDM, after adjusting for age, prepregnancy body mass index, parity, abnormal pregnancy history, and family history of diabetes (OR 1.20; 95% CI 1.05‐1.36; P = 0.007). Compared with women with a family history of diabetes, there was a significant association of rs7936247 with GDM risk among pregnant women without a family history of diabetes (OR 1.20; 95% CI 1.04‐1.38; P = 0.014; Pheterogeneity = 0.035). Further functional annotations showed that rs10830963 and rs7936247 fell in the functional elements of human pancreatic islets. Genotype‐phenotype associations indicated that the variants may contribute to GDM risk by affecting the expression of nearby or distant genes. Conclusions The findings of this study suggest that rs10830963 and rs7936247 may be markers for susceptibility to GDM in a Chinese population. Additional studies are warranted to validate our findings and clarify the underlying mechanism.

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Section: Discussionmentioning

confidence: 99%

“…Emerging evidence suggests that some SNPs affect the expression of distant genes and genes residing on other chromosomes (trans-eQTLs). 30,31 Thus, it is biologically plausible that rs10830963 may affect the expression of genes and be involved in the pathogenesis of GDM. However, functional studies are needed to confirm this.…”

Section: Discussionmentioning

confidence: 99%

Genetic predisposition to gestational glucose metabolism and gestational diabetes mellitus risk in a Chinese population

Xie

Zhang

Wen

et al. 2019

Journal of Diabetes

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“…A general rule is that the more distant the eQTLs, the more cell‐ and context‐specific and the lower their effect sizes. These distant eQTLs may be cis‐ eQTLs of a transcription factor (TF) that in turn controls distant targets . Besides, a given trans‐ eQTL may control several genes and thus operate as a master regulator like in the Major Histocompatibility Complex (MHC) …”

Section: Genome‐wide Genetic Studies Of Expression Phenotypesmentioning

confidence: 99%

“…These distant eQTLs may be cis-eQTLs of a transcription factor (TF) that in turn controls distant targets. 91 Besides, a given trans- ⋍ 0…”

Section: Demographic and Evolutionary Forcesmentioning

confidence: 99%

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Genetic association of molecular traits: A help to identify causative variants in complex diseases

Vandiedonck

2018

Clinical Genetics

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In the past 15 years, major progresses have been made in the understanding of the genetic basis of regulation of gene expression. These new insights have revolutionized our approach to resolve the genetic variation underlying complex diseases. Gene transcript levels were the first expression phenotypes that were studied. They are heritable and therefore amenable to genome-wide association studies. The genetic variants that modulate them are called expression quantitative trait loci. Their study has been extended to other molecular quantitative trait loci (molQTLs) that regulate gene expression at the various levels, from chromatin state to cellular responses. Altogether, these studies have generated a wealth of basic information on the genome-wide patterns of gene expression and their inter-individual variation. Most importantly, molQTLs have become an invaluable asset in the genetic study of complex diseases. Although the identification of the disease-causing variants on the basis of their overlap with molQTLs requires caution, molQTLs can help to prioritize the relevant candidate gene(s) in the disease-associated regions and bring a functional interpretation of the associated variants, therefore, bridging the gap between genotypes and clinical phenotypes.

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Genetic variation contributes to gene expression response in ischemic stroke: an eQTL study

Amini

Shroff

Stamova

et al. 2020

Ann Clin Transl Neurol

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Objective Single nucleotide polymorphisms (SNPs) contribute to complex disorders such as ischemic stroke (IS). Since SNPs could affect IS by altering gene expression, we studied the association of common SNPs with changes in mRNA expression (i.e. expression quantitative trait loci; eQTL) in blood after IS. Methods RNA and DNA were isolated from 137 patients with acute IS and 138 vascular risk factor controls (VRFC). Gene expression was measured using Affymetrix HTA 2.0 microarrays and SNP variants were assessed with Axiom Biobank Genotyping microarrays. A linear model with a genotype (SNP) × diagnosis (IS and VRFC) interaction term was fit for each SNP‐gene pair. Results The eQTL interaction analysis revealed significant genotype × diagnosis interaction for four SNP‐gene pairs as cis‐eQTL and 70 SNP‐gene pairs as trans‐eQTL. Cis‐eQTL involved in the inflammatory response to IS included rs56348411 which correlated with neurogranin expression (NRGN), rs78046578 which correlated with CXCL10 expression, rs975903 which correlated with SMAD4 expression, and rs62299879 which correlated with CD38 expression. These four genes are important in regulating inflammatory response and BBB stabilization. SNP rs148791848 was a strong trans‐eQTL for anosmin‐1 (ANOS1) which is involved in neural cell adhesion and axonal migration and may be important after stroke. Interpretation This study highlights the contribution of genetic variation to regulating gene expression following IS. Specific inflammatory response to stroke is at least partially influenced by genetic variation. This has implications for progressing toward personalized treatment strategies. Additional research is required to investigate these genes as therapeutic targets.

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Dynamic Role of trans Regulation of Gene Expression in Relation to Complex Traits

Cited by 106 publications

References 50 publications

Genetic predisposition to gestational glucose metabolism and gestational diabetes mellitus risk in a Chinese population

Genetic predisposition to gestational glucose metabolism and gestational diabetes mellitus risk in a Chinese population

Genetic association of molecular traits: A help to identify causative variants in complex diseases

Genetic variation contributes to gene expression response in ischemic stroke: an eQTL study

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