title: Population differences in transcript-regulator expression quantitative trait loci.
abstract: Gene expression quantitative trait loci (eQTL) are useful for identifying single nucleotide polymorphisms (SNPs) associated with diseases. At times, a genetic variant may be associated with a master regulator involved in the manifestation of a disease. The downstream target genes of the master regulator are typically co-expressed and share biological function. Therefore, it is practical to screen for eQTLs by identifying SNPs associated with the targets of a transcript-regulator (TR). We used a multivariate regression with the gene expression of known targets of TRs and SNPs to identify TReQTLs in European (CEU) and African (YRI) HapMap populations. A nominal p-value of <1×10(-6) revealed 234 SNPs in CEU and 154 in YRI as TReQTLs. These represent 36 independent (tag) SNPs in CEU and 39 in YRI affecting the downstream targets of 25 and 36 TRs respectively. At a false discovery rate (FDR) = 45%, one cis-acting tag SNP (within 1 kb of a gene) in each population was identified as a TReQTL. In CEU, the SNP (rs16858621) in Pcnxl2 was found to be associated with the genes regulated by CREM whereas in YRI, the SNP (rs16909324) was linked to the targets of miRNA hsa-miR-125a. To infer the pathways that regulate expression, we ranked TReQTLs by connectivity within the structure of biological process subtrees. One TReQTL SNP (rs3790904) in CEU maps to Lphn2 and is associated (nominal p-value = 8.1×10(-7)) with the targets of the X-linked breast cancer suppressor Foxp3. The structure of the biological process subtree and a gene interaction network of the TReQTL revealed that tumor necrosis factor, NF-kappaB and variants in G-protein coupled receptors signaling may play a central role as communicators in Foxp3 functional regulation. The potential pleiotropic effect of the Foxp3 TReQTLs was gleaned from integrating mRNA-Seq data and SNP-set enrichment into the analysis.
authors.affiliation: Biostatistics Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States of America. bushel@niehs.nih.gov
authors.forename: Pierre R
authors.initials: PR
authors.lastname: Bushel
authors.forename: Ray
authors.initials: R
authors.lastname: McGovern
authors.forename: Liwen
authors.initials: L
authors.lastname: Liu
authors.forename: Oliver
authors.initials: O
authors.lastname: Hofmann
authors.forename: Ahsan
authors.initials: A
authors.lastname: Huda
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.forename: Winston
authors.initials: W
authors.lastname: Hide
authors.forename: Xihong
authors.initials: X
authors.lastname: Lin
mesh_terms: D044383:Black People / Q000235:genetics; D002874:Chromosome Mapping / Q000379:methods; D005189:False Positive Reactions; D014644:Genetic Variation; D016678:Genome; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008954:Models, Biological; D008957:Models, Genetic; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012044:Regression Analysis; D015398:Signal Transduction; D044465:White People / Q000235:genetics
chemical_list: D016328:NF-kappa B