Genetic Architecture of Transcript-Level Variation in Humans

Duan, Shiwei; Huang, R. Stephanie; Zhang, Wei; Bleibel, Wasim K.; Roe, Cheryl; Clark, Tyson A.; Chen, Tina X.; Schweitzer, Anthony; Blume, John E.; Cox, Nancy J.; Dolan, M. Eileen

doi:10.1016/j.ajhg.2008.03.006

Cited by 125 publications

(130 citation statements)

References 44 publications

(65 reference statements)

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“…Genome-wide studies of gene expression have demonstrated that gene expression levels are highly heritable (22) and that variation in gene expression can be mapped to the genome as eQTLs (14,17). We therefore evaluated our broad set of cancer chemotherapeutic drug susceptibility-associated SNPs (P < 0.0001) for enrichment in eQTLs.…”

Section: Resultsmentioning

confidence: 99%

“…GSE7761). Using the quantitative trait disequilibrium test, we conducted GWAS of more than 13,000 transcript clusters (gene level) with reliable expression (i.e., the average log 2 -transformed expression values are >5.34) and more than 2 million SNPs in the CEU population (14).…”

Section: Methodsmentioning

confidence: 99%

“…Recent genomewide studies of gene expression have considered transcript abundance as a quantitative trait (14)(15)(16). These studies have shown that gene expression traits-transcript abundance levels considered as quantitative traits-can be mapped to particular genomic loci by integrating genome-wide genotyping and transcriptome studies of variation in gene expression (14,17). These genomic loci, known as expression quantitative trait loci (eQTLs), can be identified by using association mapping approaches similar to the ones used in genetic association studies of human disease and quantitative phenotypes.…”

mentioning

confidence: 99%

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Chemotherapeutic drug susceptibility associated SNPs are enriched in expression quantitative trait loci

Gamazon¹,

Huang

Cox

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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106

109

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Pharmacogenomics has employed candidate gene studies and, more recently, genome-wide association studies (GWAS) in efforts to identify loci associated with drug response and/or toxicity. The advantage of GWAS is the simultaneous, unbiased testing of millions of SNPs; the challenge is that functional information is absent for the vast majority of loci that are implicated. In the present study, we systematically evaluated SNPs associated with chemotherapeutic agent-induced cytotoxicity for six different anticancer agents and evaluated whether these SNPs were disproportionately likely to be within a functional class such as coding (consisting of missense, nonsense, or frameshift polymorphisms), noncoding (such as 3′UTRs or splice sites), or expression quantitative trait loci (eQTLs; indicating that a SNP genotype is associated with the transcript abundance level of a gene). We found that the chemotherapeutic drug susceptibility-associated SNPs are more likely to be eQTLs, and, in fact, more likely to be associated with the transcriptional expression level of multiple genes (n ≥ 10) as potential master regulators, than a random set of SNPs in the genome, conditional on minor allele frequency. Furthermore, we observed that this enrichment compared with random expectation is not present for other traditionally important coding and noncoding SNP functional categories. This research therefore has significant implications as a general approach for the identification of genetic predictors of drug response and provides important insights into the likely function of SNPs identified in GWAS analysis of pharmacologic studies.genome-wide association study | pharmacogenomics

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Chemotherapeutic drug susceptibility associated SNPs are enriched in expression quantitative trait loci

Gamazon¹,

Huang

Cox

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

106

109

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“…A limitation of this design is an inability to partition the observed covariance of the twins into components due to genetic factors and common environmental factors, leading to a possible upward bias of heritability, although this might be mitigated by the use of LCLs, which are maintained in a homogeneous environment (Cheung et al 2003;Cheung and Spielman 2009) (see Methods). Although to date many studies have investigated the role of regulatory variation in gene expression using LCLs (Monks et al 2004;Duan et al 2008;Dimas et al 2009), the application of immortalization and virus transformation steps has led to some criticism of their use, particularly in relation to understanding the role of expression in the etiology of disease (Carter et al 2002;C xalıs xkan et al 2011). Nevertheless, LCLs have been used in many studies investigating regulatory control and have shown high levels of replication across populations and samples (Li et al 2008;Ding et al 2010).…”

Section: Discussionmentioning

confidence: 99%

Genetic control of gene expression in whole blood and lymphoblastoid cell lines is largely independent

Powell

Henders²,

McRae³

et al. 2011

Genome Res.

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The degree to which the level of genetic variation for gene expression is shared across multiple tissues has important implications for research investigating the role of expression on the etiology of complex human traits and diseases. In the last few years, several studies have been published reporting the extent of overlap in expression quantitative trait loci (eQTL) identified in multiple tissues or cell types. Although these studies provide important information on the regulatory control of genes across tissues, their limited power means that they can typically only explain a small proportion of genetic variation for gene expression. Here, using expression data from monozygotic twins (MZ), we investigate the genetic control of gene expression in lymphoblastoid cell lines (LCL) and whole blood (WB). We estimate the genetic correlation that represents the combined effects of all causal loci across the whole genome and is a measure of the level of common genetic control of gene expression between the two RNA sources. Our results show that, when averaged across the genome, mean levels of genetic correlation for gene expression in LCL and WB samples are close to zero. We support our results with evidence from gene expression in an independent sample of LCL, T-cells, and fibroblasts. In addition, we provide evidence that housekeeping genes, which maintain basic cellular functions, are more likely to have high genetic correlations between the RNA sources than non-housekeeping genes, implying a relationship between the transcript function and the degree to which a gene has tissue-specific genetic regulatory control.

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“…The eQTL analysis using Genevar was conducted using expression data from the total RNA of 109 lymphoblastoid cell lines of European ancestry (Stranger et al 2012). The eQTL analysis using SCAN: SNP and CNV annotation database was conducted using expression data from total RNA from lymphoblastoid cell lines of 30 trios of European ancestry and 30 trios of African ancestry (Duan et al 2008), though based on our population, only significant results from the population of European ancestry are included.…”

Section: In Silico Eqtl Analysismentioning

confidence: 99%

A Genome-Wide Association Study of Chronic Otitis Media with Effusion and Recurrent Otitis Media Identifies a Novel Susceptibility Locus on Chromosome 2

Allen

Chen

Weeks

et al. 2013

JARO

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Chronic otitis media with effusion (COME) and recurrent otitis media (ROM) have been shown to be heritable, but candidate gene and linkage studies to date have been equivocal. Our aim was to identify genetic susceptibility factors using a genome-wide association study (GWAS). We genotyped 602 subjects from 143 families with 373 COME/ROM subjects using the Illumina Human CNV370-Duo DNA Bead Chip (324,748 SNPs). We carried out the GWAS scan and imputed SNPs at the regions with the most significant associations. Replication genotyping in an independent family-based sample was conducted for 53 SNPs: the 41 most significant SNPs with PG10 −4 and 12 imputed SNPs with PG10 −4 on chromosome 15 (near the strongest signal). We replicated the association of rs10497394 (GWAS discovery P= 1.30×10 −5 ) on chromosome 2 in the independent otitis media population (P=4.7×10 −5 ; meta-analysis P= 1.52×10 −8 ). Three additional SNPs had replication PvaluesG0.10. Two were on chromosome 15q26.1 including rs1110060, the strongest association with COME/ROM in the primary GWAS (P=3.4×10 −7 ) in KIF7 intron 7 (P=0.072), and rs10775247, a nonsynonymous SNP in TICRR exon 2 (P=0.075). The third SNP rs386057 was on chromosome 5 in TPPP intron 1 (P=0.045). We have performed the first GWAS of COME/ROM and have identified a SNP rs10497394 on chromosome 2 is significantly associated with COME/ROM susceptibility. This SNP is within a 537 kb intergenic region, bordered by CDCA7 and SP3. The genomic and functional significance of this newly identified locus in COME/ROM pathogenesis requires additional investigation.

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Genetic Architecture of Transcript-Level Variation in Humans

Cited by 125 publications

References 44 publications

Chemotherapeutic drug susceptibility associated SNPs are enriched in expression quantitative trait loci

Chemotherapeutic drug susceptibility associated SNPs are enriched in expression quantitative trait loci

Genetic control of gene expression in whole blood and lymphoblastoid cell lines is largely independent

A Genome-Wide Association Study of Chronic Otitis Media with Effusion and Recurrent Otitis Media Identifies a Novel Susceptibility Locus on Chromosome 2

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