Genetic Analysis of Human Traits In Vitro: Drug Response and Gene Expression in Lymphoblastoid Cell Lines

Choy, Edwin; Yelensky, Roman; Bonakdar, S.; Plenge, Robert M.; Saxena, Richa; Jager, Philip L. De; Shaw, Stanley Y.; Wolfish, Cara S.; Slavik, Jacqueline M.; Cotsapas, Chris; Rivas, Manuel A.; Dermitzakis, Emmanouil T.; Cahir-McFarland, Ellen; Kieff, Elliott; Hafler, David A.; Daly, Mark J.; Altshuler, David

doi:10.1371/journal.pgen.1000287

Cited by 209 publications

(262 citation statements)

References 42 publications

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“…Several lines of evidence suggest that our desire to biologically control eQTL analysis was successful. The cis-eQTLs were highly reproducible in the biological replicates based on simple power calculations accounting for effect size detected in one replicate, suggesting that, even if cell culture-induced confounders play a role in gene expression of individual lines (Choy et al 2008), the detected cis-eQTLs are true down to P < 10 À5 level. Consequently, significant improvement in detection of cis-eQTLs was achieved by combining the data from independent replicates.…”

Section: Discussionmentioning

confidence: 95%

“…Although eQTL studies in tissues may better represent disease physiology, the cell specificity of cis-regulation indicates that in heterogeneous tissues the genotype-expression correlations are confounded and large samples may be needed to pinpoint the true causal variants. However, even in cell models, nongenetic confounders can be significant as demonstrated in a recent study using the HapMap LCL samples showing that biological noise and in vitro artifacts can explain much of the population variation in gene expression (Choy et al 2008).…”

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confidence: 99%

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Population genomics in a disease targeted primary cell model

Grundberg

Kwan²,

Ge³

et al. 2009

Genome Res.

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The common genetic variants associated with complex traits typically lie in noncoding DNA and may alter gene regulation in a cell type-specific manner. Consequently, the choice of tissue or cell model in the dissection of disease associations is important. We carried out an expression quantitative trait loci (eQTL) study of primary human osteoblasts (HOb) derived from 95 unrelated donors of Swedish origin, each represented by two independently derived primary lines to provide biological replication. We combined our data with publicly available information from a genome-wide association study (GWAS) of bone mineral density (BMD). The top 2000 BMD-associated SNPs (P < ;10 À3 ) were tested for cisassociation of gene expression in HObs and in lymphoblastoid cell lines (LCLs) using publicly available data and showed that HObs have a significantly greater enrichment (threefold) of converging cis-eQTLs as compared to LCLs. The top 10 BMD loci with SNPs showing strong cis-effects on gene expression in HObs (P = 6 3 10 À10 À 7 3 10 À16 ) were selected for further validation using a staged design in two cohorts of Caucasian male subjects. All 10 variants were tested in the Swedish MrOS Cohort (n = 3014), providing evidence for two novel BMD loci (SRR and MSH3). These variants were then tested in the Rotterdam Study (n = 2090), yielding converging evidence for BMD association at the 17p13.3 SRR locus (P combined = 5.6 3 10 À5 ). The cis-regulatory effect was further fine-mapped to the proximal promoter of the SRR gene (rs3744270, r 2 = 0.5, P = 2.6 3 10 À15 ). Our results suggest that primary cells relevant to disease phenotypes complement traditional approaches for prioritization and validation of GWAS hits for follow-up studies.

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Section: Discussionmentioning

confidence: 95%

mentioning

confidence: 99%

Population genomics in a disease targeted primary cell model

Grundberg

Kwan²,

Ge³

et al. 2009

Genome Res.

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“…The reason for this apparent discrepancy may be that the previous study used replicate arrays and thus may have had more statistical power to find subtle differences; or it may be because we only called heritable any probe set that was similar between parents and offspring (narrow-sense heritability), whereas they considered all differences between two cell lines (broad-sense heritability). Differences between cell lines such as those due, for example, to different Epstein-Barr virus titers or other in vitro artifacts (Choy et al 2008) not inherited from parents would thus be included in their list, but not in ours.…”

Section: Discussionmentioning

confidence: 99%

Common polymorphic transcript variation in human disease

Fraser¹,

Xie²

2009

Genome Res.

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Most human genes are thought to express different transcript isoforms in different cell types; however, the full extent and functional consequences of polymorphic transcript variation (PTV), which differ between individuals within the same cell type, are unknown. Here we show that PTV is widespread in B-cells from two human populations. Tens of thousands of exons were found to be polymorphically expressed in a heritable fashion, and over 1000 of these showed strong correlations with single nucleotide polymorphism (SNP) genotypes in cis. The SNPs associated with PTV display signs of having been subject to recent positive selection in humans, and they are also highly enriched for SNPs implicated by recent genome-wide association studies of four autoimmune diseases. From this disease-association overlap, we infer that PTV is the likely mechanism by which eight common polymorphisms contribute to disease risk. A catalog of PTV will be a valuable resource for interpreting results from future disease-association studies and understanding the spectrum of phenotypic differences among humans.

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“…Associations between gene expression and genotype (eQTLs) have been established for many nuclear genes. 8,9,[43][44][45][46] We hypothesized that the expression variation of mtDNA genes may be associated with genotypes defined by autosomal SNPs, although the regulatory mechanisms through which these SNPs might affect mtDNA gene expression is not clear. Because all SNPs in mtDNA were of low frequency (MAFo10%), no cis-acting mitochondrial eQTLs (ie, the expression-controlling SNPs located in mtDNA) could be detected.…”

Section: Effects Of Subcellular Co-localizationmentioning

confidence: 99%

Population-level expression variability of mitochondrial DNA-encoded genes in humans

et al. 2014

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Human mitochondria contain multiple copies of a circular genome made up of double-stranded DNA (mtDNA) that encodes proteins involved in cellular respiration. Transcript abundance of mtDNA-encoded genes varies between human individuals, yet the level of variation in the general population has not been systematically assessed. In the present study, we revisited large-scale RNA sequencing data generated from lymphoblastoid cell lines of HapMap samples of European and African ancestry to estimate transcript abundance and quantify expression variation for mtDNA-encoded genes. In both populations, we detected up to over 100-fold difference in mtDNA gene expression between individuals. The marked variation was not due to differences in mtDNA copy number between individuals, but was shaped by the transcription of hundreds of nuclear genes. Many of these nuclear genes were co-expressed with one another, resulting in a module-enriched co-expression network. Significant correlations in expression between genes of the mtDNA and nuclear genomes were used to identify factors involved with the regulation of mitochondrial functions. In conclusion, we determined the baseline amount of variability in mtDNA gene expression in general human populations and cataloged a complete set of nuclear genes whose expression levels are correlated with those of mtDNA-encoded genes. Our findings will enable the integration of information from both mtDNA and nuclear genetic systems, and facilitate the discovery of novel regulatory pathways involving mitochondrial functions.

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Genetic Analysis of Human Traits In Vitro: Drug Response and Gene Expression in Lymphoblastoid Cell Lines

Cited by 209 publications

References 42 publications

Population genomics in a disease targeted primary cell model

Population genomics in a disease targeted primary cell model

Common polymorphic transcript variation in human disease

Population-level expression variability of mitochondrial DNA-encoded genes in humans

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