Integrated genome-wide analysis of expression quantitative trait loci aids interpretation of genomic association studies

Joehanes, Roby; Zhang, Xiaoling; Huan, Tianxiao; Yao, Chen; Ying, Saixia; Nguyen, Quang Tri; Demirkale, Cumhur Yusuf; Feolo, Michael; Sharopova, Nataliya; Sturcke, Anne; Schäffer, Alejandro A.; Heard‐Costa, Nancy L.; Chen, Han; Liu, Poching; Wang, Thomas J.; Woodhouse, Kimberly A.; Tanrıverdi, Kahraman; Freedman, Jane E.; Raghavachari, Nalini; Dupuis, Josée; Johnson, Andrew D.; O’Donnell, Christopher J.; Levy, Daniel; Munson, Peter J.

doi:10.1186/s13059-016-1142-6

“…In total, we related genotypes for 39,165 genome-wide significant GWAS SNPs reported to be associated with 1,960 traits in GWAS databases with expression levels of 17,873 genes to identify cis-and trans-eQTLs and their associated eGenes. 17 Our results reveal that a large number of eQTLs regulate gene expression in both a cis and trans manner. Additionally, we identified 13 trans-eQTL hotspots and found that about one third of trans regulation is significantly mediated by the expression of cis-eGenes.…”

Section: Introductionmentioning

confidence: 73%

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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“…17 Our results reveal that a large number of eQTLs regulate gene expression in both a cis and trans manner. Additionally, we identified 13 trans-eQTL hotspots and found that about one third of trans regulation is significantly mediated by the expression of cis-eGenes.…”

Section: Introductionmentioning

confidence: 93%

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

Self Cite

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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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“…We interrogated publicly available expression quantitative trait loci (eQTL) datasets through GTEx, ENCODE, RoadMap projects, PhenoScanner 27 , STARNET 25 and Framingham Heart Study 26 to further highlight potential causal genes and mechanisms at each of the newly identified BP loci (Supplemental Table 3). The PP-associated SNV, rs13303, at STAB1 is correlated (r 2 > 0.8 1000G EUR) with the top eQTLs for NT5DC2 in atherosclerotic-lesion free internal mammary artery, atherosclerotic aortic root, subcutaneous adipose, visceral abdominal fat and liver tissues (all P < 1×10 −11 ) 25 .…”

Section: Resultsmentioning

confidence: 99%

“…24 and STARNET 25 . In addition we used the FHS eQTL results from microarray-based gene and exon expression levels in whole blood from 5,257 individuals 26 . We queried whether any of the five BP-associated SNVs were eQTLs for genes in the five BP-associated regions, or whether they were in LD (r 2 > 0.8) with any of the eQTLs for genes in these regions.…”

Section: Methodsmentioning

confidence: 99%

New Blood Pressure–Associated Loci Identified in Meta-Analyses of 475 000 Individuals

Kraja¹,

Cook²,

Warren³

et al. 2017

Circ Cardiovasc Genet

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Background Genome-wide association studies have recently identified over 400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier work identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of Exome Chip genotype data. An additional 100 variants yielded suggestive evidence of association. Methods and Results Here, we augment the sample with 140,886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic or diastolic blood pressure (SBP, DBP) or pulse pressure (PP). We performed two meta-analyses, one in individuals of European, South Asian, African and Hispanic descent (pan-ancestry, ~475,000), and the other in the subset of individuals of European descent (~423,000). Twenty-one SNVs were genome-wide significant (P < 5×10−8) for BP, of which four are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1) and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV (rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at three loci are associated with other traits. One SNV with a minor allele frequency < 0.01, (rs3025380 at DBH) was genome-wide significant. Conclusions We report four novel loci associated with BP regulation, and one independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.

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Integrated genome-wide analysis of expression quantitative trait loci aids interpretation of genomic association studies

Cited by 166 publications

References 60 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

New Blood Pressure–Associated Loci Identified in Meta-Analyses of 475 000 Individuals

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