Trait-Associated SNPs Are More Likely to Be eQTLs: Annotation to Enhance Discovery from GWAS

Nicolae, Dan L.; Gamazon, Eric R.; Zhang, Wei; Duan, Shiwei; Dolan, M. Eileen; Cox, Nancy J.

doi:10.1371/journal.pgen.1000888

Cited by 1,222 publications

(1,158 citation statements)

References 30 publications

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“…In total, we determined that 23,951 out of 39,165 (61%) statistically significant GWAS SNPs are eQTLs, which is consistent with previous findings that GWAS SNPs are enriched for eQTLs (p < 0.0001 for 10,000 random sets of 39,165 SNPs at MAF > 0.01 and r 2 > 0.3; average eQTL number ¼ 9,022). 13,31 Reproducibility and Mediation Effects of trans-eQTLs In accordance with previous results, 32 12 as a reference database, we found that 331 out of 1,686 (20%) transeQTL-trans-eGene pairs from the database were statistically significant (at p < 1 3 10 À7 ) in our results. Among them, 323 pairs (98%) have concordant directions of effects (Table S4).…”

Section: Results Eqtls Associated With Complex Disease Traitssupporting

confidence: 92%

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

Yao

Joehanes

Johnson

et al. 2017

The American Journal of Human Genetics

106

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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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Section: Results Eqtls Associated With Complex Disease Traitssupporting

confidence: 92%

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

Yao

Joehanes

Johnson

et al. 2017

The American Journal of Human Genetics

106

View full text Add to dashboard Cite

show abstract

“…As GWAS hits are often expression quantitative trait loci (eQTLs) [Nicolae DL et al, 2010], we asked whether this is also true for the above variants. The correlation between genotype and the expression levels of the respective gene transcripts was examined in the temporal lobe (N = 162), the prefrontal cortex (N = 88), as well as in the combined sample (N = 250), adjusting for brain region.…”

Section: Resultsmentioning

confidence: 99%

Common genetic variation and schizophrenia polygenic risk influence neurocognitive performance in young adulthood

Hatzimanolis

Bhatnagar

Moes

et al. 2015

American J of Med Genetics Pt B

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Neurocognitive abilities constitute complex traits with considerable heritability. Impaired neurocognition is typically observed in schizophrenia (SZ), whereas convergent evidence has shown shared genetic determinants between neurocognition and SZ. Here, we report a genome‐wide association study (GWAS) on neuropsychological and oculomotor traits, linked to SZ, in a general population sample of healthy young males (n = 1079). Follow‐up genotyping was performed in an identically phenotyped internal sample (n = 738) and an independent cohort of young males with comparable neuropsychological measures (n = 825). Heritability estimates were determined based on genome‐wide single‐nucleotide polymorphisms (SNPs) and potential regulatory effects on gene expression were assessed in human brain. Correlations with general cognitive ability and SZ risk polygenic scores were tested utilizing meta‐analysis GWAS results by the Cognitive Genomics Consortium (COGENT) and the Psychiatric Genomics Consortium (PGC‐SZ). The GWAS results implicated biologically relevant genetic loci encoding protein targets involved in synaptic neurotransmission, although no robust individual replication was detected and thus additional validation is required. Secondary permutation‐based analysis revealed an excess of strongly associated loci among GWAS top‐ranked signals for verbal working memory (WM) and antisaccade intra‐subject reaction time variability (empirical P < 0.001), suggesting multiple true‐positive single‐SNP associations. Substantial heritability was observed for WM performance. Further, sustained attention/vigilance and WM were suggestively correlated with both COGENT and PGC‐SZ derived polygenic scores. Overall, these results imply that common genetic variation explains some of the variability in neurocognitive functioning among young adults, particularly WM, and provide supportive evidence that increased SZ genetic risk predicts neurocognitive fluctuations in the general population. © 2015 The Authors American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

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“…Indeed, GWASascertained phenotype-associated single-nucleotide polymorphisms (SNPs) are enriched in cis-eQTLs. 15 It is recognized that cis-eQTLs are highly tissue-specific. 16,17 However, the acquisition of the appropriate tissue type is logistically challenging and the majority of eQTL studies were based on lymphoblastoid cell lines (LCLs).…”

Section: Introductionmentioning

confidence: 99%

Variants at IRX4 as prostate cancer expression quantitative trait loci

Hussain

Vijai

et al. 2013

Eur J Hum Genet

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Genome-wide association studies (GWAS) have identified numerous prostate cancer-associated risk loci. Some variants at these loci may be regulatory and influence expression of nearby genes. Such loci are known as cis-expression quantitative trait loci (cis-eQTL). As cis-eQTLs are highly tissue-specific, we asked if GWAS-identified prostate cancer risk loci are cis-eQTLs in human prostate tumor tissues. We investigated 50 prostate cancer samples for their genotype at 59 prostate cancer riskassociated single-nucleotide polymorphisms (SNPs) and performed cis-eQTL analysis of transcripts from paired primary tumors within two megabase windows. We tested 586 transcript-genotype associations, of which 27 were significant (false discovery rate r10%). An equivalent eQTL analysis of the same prostate cancer risk loci in lymphoblastoid cell lines did not result in any significant associations. The top-ranked cis-eQTL involved the IRX4 (Iroquois homeobox protein 4) transcript and rs12653946, tagged by rs10866528 in our study (P ¼ 4.91 Â 10 À5 ). Replication studies, linkage disequilibrium, and imputation analyses highlight population specificity at this locus. We independently validated IRX4 as a potential prostate cancer risk gene through cis-eQTL analysis of prostate cancer risk variants. Cis-eQTL analysis in relevant tissues, even with a small sample size, can be a powerful method to expedite functional follow-up of GWAS.

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Trait-Associated SNPs Are More Likely to Be eQTLs: Annotation to Enhance Discovery from GWAS

Cited by 1,222 publications

References 30 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

Common genetic variation and schizophrenia polygenic risk influence neurocognitive performance in young adulthood

Variants at IRX4 as prostate cancer expression quantitative trait loci

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