SNPs matter: impact on detection of differential expression

Walter, Nicole A.R.; McWeeney, Shannon K.; Peters, Sandra T; Belknap, John K.; Hitzemann, Robert; Buck, Kari J.

doi:10.1038/nmeth0907-679

Cited by 63 publications

(89 citation statements)

References 2 publications

(1 reference statement)

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“…However, it is also possible that, as others have observed, sequence polymorphisms within the probe sequences are causing artifactual cis-eQTLs (Alberts et al 2007;Walter et al 2007). The extensive SNP data sets available for the mouse make it possible to investigate the contribution of SNPs to cis-eQTLs (Frazer et al 2007;Yang et al 2007).…”

Section: Resultsmentioning

confidence: 97%

“…(3) Exclude artifactual explanations for eQTLs. Single-nucleotide polymorphisms (SNPs) can have a significant impact on microarray-based assays of transcript abundance (Alberts et al 2007;Walter et al 2007;Benovoy et al 2008). Analysis of data from Affymetrix arrays on 30 recombinant mouse inbred lines (Bystrykh et al 2005) indicated that almost half of the reported 100 most significant cis-eQTLs could be attributed to sequence diversity in probe regions (Alberts et al 2007).…”

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confidence: 99%

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High resolution mapping of expression QTLs in heterogeneous stock mice in multiple tissues

Huang

Shifman

Valdar³

et al. 2009

Genome Res.

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A proportion of the genetic variants underlying complex phenotypes do so through their effects on gene expression, so an important challenge in complex trait analysis is to discover the genetic basis for the variation in transcript abundance. So far, the potential of mapping both quantitative trait loci (QTLs) and expression quantitative trait loci (eQTLs) in rodents has been limited by the low mapping resolution inherent in crosses between inbred strains. We provide a megabase resolution map of thousands of eQTLs in hippocampus, lung, and liver samples from heterogeneous stock (HS) mice in which 843 QTLs have also been mapped at megabase resolution. We exploit dense mouse SNP data to show that artifacts due to allele-specific hybridization occur in ;30% of the cis-acting eQTLs and, by comparison with exon expression data, we show that alternative splicing of the 39 end of the genes accounts for <1% of cis-acting eQTLs. Approximately one third of cis-acting eQTLs and one half of trans-acting eQTLs are tissue specific. We have created an important systems biology resource for the genetic analysis of complex traits in a key model organism.

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Section: Resultsmentioning

confidence: 97%

mentioning

confidence: 99%

High resolution mapping of expression QTLs in heterogeneous stock mice in multiple tissues

Huang

Shifman

Valdar³

et al. 2009

Genome Res.

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show abstract

“…Conventional microarrays based on the human reference sequence are often confounded by sequence variation not accounted for in probe design (Walter et al 2007), and, to date, the difficulties of mapping reads from highthroughput sequencing technologies to the highly polymorphic MHC have limited the application of RNA sequencing to this genomic region. Thus, we developed a hybrid microarray for the MHC (denoted ''MHC array'') that included alternate allele probes to account for known sequence diversity (Supplemental Methods).…”

Section: The Mhc Array: Design and Validationmentioning

confidence: 99%

Pervasive haplotypic variation in the spliceo-transcriptome of the human major histocompatibility complex

Vandiedonck¹,

Taylor²,

Lockstone³

et al. 2011

Genome Res.

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The human major histocompatibility complex (MHC) on chromosome 6p21 is a paradigm for genomics, showing remarkable polymorphism and striking association with immune and non-immune diseases. The complex genomic landscape of the MHC, notably strong linkage disequilibrium, has made resolving causal variants very challenging. A promising approach is to investigate gene expression levels considered as tractable intermediate phenotypes in mapping complex diseases. However, how transcription varies across the MHC, notably relative to specific haplotypes, remains unknown. Here, using an original hybrid tiling and splice junction microarray that includes alternate allele probes, we draw the first high-resolution strand-specific transcription map for three common MHC haplotypes (HLA-A1-B8-Cw7-DR3, HLA-A3-B7-Cw7-DR15, and HLA-A26-B18-Cw5-DR3-DQ2) strongly associated with autoimmune diseases including type 1 diabetes, systemic lupus erythematosus, and multiple sclerosis. We find that haplotype-specific differences in gene expression are common across the MHC, affecting 96 genes (46.4%), most significantly the zing finger protein gene ZFP57. Differentially expressed probes are correlated with polymorphisms between haplotypes, consistent with cis effects that we directly demonstrate for ZFP57 in a cohort of healthy volunteers (P = 1.2 3 10 -14 ). We establish that alternative splicing is significantly more frequent in the MHC than genome-wide (72.5% vs. 62.1% of genes, P # 1 3 10 -4 ) and shows marked haplotypic differences. We also unmask novel and abundant intergenic transcription involving 31% of transcribed blocks identified. Our study reveals that the renowned MHC polymorphism also manifests as transcript diversity, and our novel haplotype-based approach marks a new step toward identification of regulatory variants involved in the control of MHCassociated phenotypes and diseases.

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“…The number of significant cis-acting eQTL discovered increased dramatically. The enrichment in cis-acting eQTL serves as a good indicator of the statistical power to identify differential expressions due to true genetic effects, even though some of the cis associations might be due to polymorphic SNPs residing in the probe sequences (Walter et al 2007). For the whole brain data set, ICE eQTL mapping identified nearly three times as many genes with cisacting eQTL (120) than the t-test (43) and 52% more than SVA (79) at a significance level of 10 false positives per genome (Table 1, Figure 5).…”

Section: Spurious Regulatory Hotspots In Recombinant Inbred Micementioning

confidence: 99%

Accurate Discovery of Expression Quantitative Trait Loci Under Confounding From Spurious and Genuine Regulatory Hotspots

Kang¹,

2008

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In genomewide mapping of expression quantitative trait loci (eQTL), it is widely believed that thousands of genes are trans-regulated by a small number of genomic regions called ''regulatory hotspots,'' resulting in ''trans-regulatory bands'' in an eQTL map. As several recent studies have demonstrated, technical confounding factors such as batch effects can complicate eQTL analysis by causing many spurious associations including spurious regulatory hotspots. Yet little is understood about how these technical confounding factors affect eQTL analyses and how to correct for these factors. Our analysis of data sets with biological replicates suggests that it is this intersample correlation structure inherent in expression data that leads to spurious associations between genetic loci and a large number of transcripts inducing spurious regulatory hotspots. We propose a statistical method that corrects for the spurious associations caused by complex intersample correlation of expression measurements in eQTL mapping. Applying our intersample correlation emended (ICE) eQTL mapping method to mouse, yeast, and human identifies many more cis associations while eliminating most of the spurious trans associations. The concordances of cis and trans associations have consistently increased between different replicates, tissues, and populations, demonstrating the higher accuracy of our method to identify real genetic effects.

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SNPs matter: impact on detection of differential expression

Cited by 63 publications

References 2 publications

High resolution mapping of expression QTLs in heterogeneous stock mice in multiple tissues

High resolution mapping of expression QTLs in heterogeneous stock mice in multiple tissues

Pervasive haplotypic variation in the spliceo-transcriptome of the human major histocompatibility complex

Accurate Discovery of Expression Quantitative Trait Loci Under Confounding From Spurious and Genuine Regulatory Hotspots

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