Mediation Analysis Demonstrates That Trans-eQTLs Are Often Explained by Cis-Mediation: A Genome-Wide Analysis among 1,800 South Asians

Pierce, Brandon L.; Lin, Tong; Chen, Lin S.; Rahaman, Ronald; Argos, Maria; Jasmine, Farzana; Roy, Shantanu; Paul-Brutus, Rachelle; Westra, Harm Jan; Franke, Lude; Esko, Tõnu; Rakibuz, Zaman,; Islam, Tariqul; Rahman, Mahfuzar; Baron, John A.; Kibriya, Muhammad G.; Ahsan, Habibul

doi:10.1371/journal.pgen.1004818

“…The mechanisms by which trans-eQTLs alter transcription of their linked trans-eGenes are largely unknown and likely reflect indirect or cryptic regulation. 14,15 For example, it has been proposed that expression of trans-eGenes could be mediated by transcription factors residing close to the corresponding trans-eQTLs. 14 This phenomenon would allow cis-eQTLs near regulatory genes to serve as master regulators for a large number of trans-eGenes.…”

Section: Introductionmentioning

confidence: 99%

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

Yao

¹

,

Joehanes

²

,

Johnson

³

et al. 2017

The American Journal of Human Genetics

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Identifying causal genetic variants and understanding their mechanisms of effect on traits remains a challenge in genome-wide association studies (GWASs). In particular, how genetic variants (i.e., trans-eQTLs) affect expression of remote genes (i.e., trans-eGenes) remains unknown. We hypothesized that some trans-eQTLs regulate expression of distant genes by altering the expression of nearby genes (cis-eGenes). Using published GWAS datasets with 39,165 single-nucleotide polymorphisms (SNPs) associated with 1,960 traits, we explored whole blood gene expression associations of trait-associated SNPs in 5,257 individuals from the Framingham Heart Study. We identified 2,350 trans-eQTLs (at p < 10 À7 ); more than 80% of them were found to have cis-associated eGenes. Mediation testing suggested that for 35% of trans-eQTL-transeGene pairs in different chromosomes and 90% pairs in the same chromosome, the disease-associated SNP may alter expression of the transeGene via cis-eGene expression. In addition, we identified 13 trans-eQTL hotspots, affecting from ten to hundreds of genes, suggesting the existence of master genetic regulators. Using causal inference testing, we searched causal variants across eight cardiometabolic traits (BMI, systolic and diastolic blood pressure, LDL cholesterol, HDL cholesterol, total cholesterol, triglycerides, and fasting blood glucose) and identified several cis-eGenes (ALDH2 for systolic and diastolic blood pressure, MCM6 and DARS for total cholesterol, and TRIB1 for triglycerides) that were causal mediators for the corresponding traits, as well as examples of trans-mediators (TAGAP for LDL cholesterol). The finding of extensive evidence of genome-wide mediation effects suggests a critical role of cryptic gene regulation underlying many disease traits.

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“…Using different cell types and populations, Pierce et al 15 also reported a similar proportion (~20%) of trans-eQTLs that act through cis-mediation, indicating that the mechanism of cis-eGene mediation of trans-eGene expression may be a common feature genome wide. To extend this concept, we explored how this phenomenon affects disease pathways.…”

Section: Discussionmentioning

confidence: 91%

“…The mechanisms by which trans-eQTLs alter transcription of their linked trans-eGenes are largely unknown and likely reflect indirect or cryptic regulation. 14,15 For example, it has been proposed that expression of trans-eGenes could be mediated by transcription factors residing close to the corresponding trans-eQTLs. 14 This phenomenon would allow cis-eQTLs near regulatory genes to serve as master regulators for a large number of trans-eGenes.…”

Section: Introductionmentioning

confidence: 99%

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

Chen¹,

Joehanes²,

Johnson³

et al. 2017

The American Journal of Human Genetics

View full text Add to dashboard Cite

Identifying causal genetic variants and understanding their mechanisms of effect on traits remains a challenge in genome-wide association studies (GWASs). In particular, how genetic variants (i.e., trans-eQTLs) affect expression of remote genes (i.e., trans-eGenes) remains unknown. We hypothesized that some trans-eQTLs regulate expression of distant genes by altering the expression of nearby genes (cis-eGenes). Using published GWAS datasets with 39,165 single-nucleotide polymorphisms (SNPs) associated with 1,960 traits, we explored whole blood gene expression associations of trait-associated SNPs in 5,257 individuals from the Framingham Heart Study. We identified 2,350 trans-eQTLs (at p < 10 À7 ); more than 80% of them were found to have cis-associated eGenes. Mediation testing suggested that for 35% of trans-eQTL-transeGene pairs in different chromosomes and 90% pairs in the same chromosome, the disease-associated SNP may alter expression of the transeGene via cis-eGene expression. In addition, we identified 13 trans-eQTL hotspots, affecting from ten to hundreds of genes, suggesting the existence of master genetic regulators. Using causal inference testing, we searched causal variants across eight cardiometabolic traits (BMI, systolic and diastolic blood pressure, LDL cholesterol, HDL cholesterol, total cholesterol, triglycerides, and fasting blood glucose) and identified several cis-eGenes (ALDH2 for systolic and diastolic blood pressure, MCM6 and DARS for total cholesterol, and TRIB1 for triglycerides) that were causal mediators for the corresponding traits, as well as examples of trans-mediators (TAGAP for LDL cholesterol). The finding of extensive evidence of genome-wide mediation effects suggests a critical role of cryptic gene regulation underlying many disease traits.

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“…Recent studies have demonstrated that many expression quantitative trait loci (eQTLs) that affect expression of local transcripts (ciseQTLs) also affect the expression of distant genes (trans-eQTLs) (Battle et al 2014;Pierce et al 2014). This observation suggests the effects of trans-eQTLs are "mediated" by the local (cis-) gene transcripts near the eQTLs (Fehrmann et al 2011;Pierce et al 2014).…”

Section: [Supplemental Materials Is Available For This Article]mentioning

confidence: 99%

“…This observation suggests the effects of trans-eQTLs are "mediated" by the local (cis-) gene transcripts near the eQTLs (Fehrmann et al 2011;Pierce et al 2014). In other words, some cis-eQTLs are also trans-eQTLs because the variation in the expression of the cis-gene affects the expression of a trans-gene or genes.…”

Section: [Supplemental Materials Is Available For This Article]mentioning

confidence: 99%

Identifying cis-mediators for trans-eQTLs across many human tissues using genomic mediation analysis

Yang

¹

,

Wang

²

,

Pierce

³

et al. 2017

Self Cite

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The impact of inherited genetic variation on gene expression in humans is well-established. The majority of known expression quantitative trait loci (eQTLs) impact expression of local genes (cis-eQTLs). More research is needed to identify effects of genetic variation on distant genes (trans-eQTLs) and understand their biological mechanisms. One common trans-eQTLs mechanism is “mediation” by a local (cis) transcript. Thus, mediation analysis can be applied to genome-wide SNP and expression data in order to identify transcripts that are “cis-mediators” of trans-eQTLs, including those “cis-hubs” involved in regulation of many trans-genes. Identifying such mediators helps us understand regulatory networks and suggests biological mechanisms underlying trans-eQTLs, both of which are relevant for understanding susceptibility to complex diseases. The multitissue expression data from the Genotype-Tissue Expression (GTEx) program provides a unique opportunity to study cis-mediation across human tissue types. However, the presence of complex hidden confounding effects in biological systems can make mediation analyses challenging and prone to confounding bias, particularly when conducted among diverse samples. To address this problem, we propose a new method: Genomic Mediation analysis with Adaptive Confounding adjustment (GMAC). It enables the search of a very large pool of variables, and adaptively selects potential confounding variables for each mediation test. Analyses of simulated data and GTEx data demonstrate that the adaptive selection of confounders by GMAC improves the power and precision of mediation analysis. Application of GMAC to GTEx data provides new insights into the observed patterns of cis-hubs and trans-eQTL regulation across tissue types.

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Mediation Analysis Demonstrates That Trans-eQTLs Are Often Explained by Cis-Mediation: A Genome-Wide Analysis among 1,800 South Asians

Cited by 95 publications

References 31 publications

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

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

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

Identifying cis-mediators for trans-eQTLs across many human tissues using genomic mediation analysis

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