title: Integrative analysis of mRNA expression and half-life data reveals trans-acting genetic variants associated with increased expression of stable transcripts.
abstract: Genetic variation in gene expression makes an important contribution to phenotypic variation and susceptibility to disease. Recently, a subset of cis-acting expression quantitative loci (eQTLs) has been found to result from polymorphisms that affect RNA stability. Here we carried out a search for trans-acting variants that influence RNA stability. We first demonstrate that differences in the activity of trans-acting factors that stabilize RNA can be detected by comparing the expression levels of long-lived (stable) and short-lived (unstable) transcripts in high-throughput gene expression experiments. Using gene expression microarray data generated from eight HapMap3 populations, we calculated the relative expression ranks of long-lived transcripts versus short-lived transcripts in each sample. Treating this as a quantitative trait, we applied genome-wide association and identified a single nucleotide polymorphism (SNP), rs6137010, on chromosome 20p13 with which it is strongly associated in two Asian populations (p = 4×10(-10) in CHB - Han Chinese from Beijing; p = 1×10(-4) in JPT - Japanese from Tokyo). This SNP is a cis-eQTL for SNRPB in CHB and JPT but not in the other six HapMap3 populations. SNRPB is a core component of the spliceosome, and has previously been shown to affect the expression of many RNA processing factors. We propose that a cis-eQTL of SNRPB may be directly responsible for inter-individual variation in relative expression of long-lived versus short-lived transcript in Asian populations. In support of this hypothesis, knockdown of SNRPB results in a significant reduction in the relative expression of long-lived versus short-lived transcripts. Samples with higher relative expression of long-lived transcripts also had higher relative expression of coding compared to non-coding RNA and of RNA from housekeeping compared to non-housekeeping genes, due to the lower decay rates of coding RNAs, particularly those that perform housekeeping functions, compared to non-coding RNAs.
authors.affiliation: School of Mathematics, Statistics & Applied Mathematics, National University of Ireland, Galway, Ireland.
authors.forename: Thong T
authors.initials: TT
authors.lastname: Nguyen
authors.forename: Cathal
authors.initials: C
authors.lastname: Seoighe
mesh_terms: D014644:Genetic Variation / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics; D020871:RNA Stability / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics*; D055517:snRNP Core Proteins / Q000235:genetics
chemical_list: D012333:RNA, Messenger; C526407:SNRPB protein, human; D055517:snRNP Core Proteins