03861nas a2200661   4500000000100000008004100001260001300042653002800055653003900083653001600122653002300138653002300161653004000184653001100224653003000235653002000265653001800285653003400303653001300337653001700350653002300367653001100390653001000401653002900411653000900440653003600449653003300485653003000518653002800548653003100576653001600607653001700623100001600640700001300656700001500669700001500684700001300699700001300712700001400725700001000739700001000749700001400759700001400773700001600787700001400803700001700817700001400834700001400848700001300862700001400875700001000889700001300899245013000912300001301042490000601055520212401061022001403185       2011                            d  c2011 May10a3' Untranslated Regions10aAfrican Continental Ancestry Group10aAge Factors10aChromosome Mapping10aCloning, Molecular10aEuropean Continental Ancestry Group10aFemale10aGene Expression Profiling10aGenetic Vectors10aGenome, Human10aGenome-Wide Association Study10agenotype10aHep G2 Cells10aHispanic Americans10aHumans10aLiver10aLuminescent Measurements10aMale10aPolymorphism, Single Nucleotide10aPrincipal Component Analysis10aPromoter Regions, Genetic10aQuantitative Trait Loci10aReproducibility of Results10aSex Factors10aTransfection1 aInnocenti F1 aCooper G1 aStanaway I1 aGamazon ER1 aSmith JD1 aMirkov S1 aRamirez J1 aLiu W1 aLin Y1 aMoloney C1 aAldred SF1 aTrinklein N1 aSchuetz E1 aNickerson DA1 aThummel K1 aRieder MJ1 aRettie A1 aRatain MJ1 aCox N1 aBrown CD00aIdentification, replication, and functional fine-mapping of expression quantitative trait loci in primary human liver tissue.  ae10020780 v73 a<p>The discovery of expression quantitative trait loci ("eQTLs") can help to unravel genetic contributions to complex traits. We identified genetic determinants of human liver gene expression variation using two independent collections of primary tissue profiled with Agilent (n = 206) and Illumina (n = 60) expression arrays and Illumina SNP genotyping (550K), and we also incorporated data from a published study (n = 266). We found that ∼30% of SNP-expression correlations in one study failed to replicate in either of the others, even at thresholds yielding high reproducibility in simulations, and we quantified numerous factors affecting reproducibility. Our data suggest that drug exposure, clinical descriptors, and unknown factors associated with tissue ascertainment and analysis have substantial effects on gene expression and that controlling for hidden confounding variables significantly increases replication rate. Furthermore, we found that reproducible eQTL SNPs were heavily enriched near gene starts and ends, and subsequently resequenced the promoters and 3'UTRs for 14 genes and tested the identified haplotypes using luciferase assays. For three genes, significant haplotype-specific in vitro functional differences correlated directly with expression levels, suggesting that many bona fide eQTLs result from functional variants that can be mechanistically isolated in a high-throughput fashion. Finally, given our study design, we were able to discover and validate hundreds of liver eQTLs. Many of these relate directly to complex traits for which liver-specific analyses are likely to be relevant, and we identified dozens of potential connections with disease-associated loci. These included previously characterized eQTL contributors to diabetes, drug response, and lipid levels, and they suggest novel candidates such as a role for NOD2 expression in leprosy risk and C2orf43 in prostate cancer. In general, the work presented here will be valuable for future efforts to precisely identify and functionally characterize genetic contributions to a variety of complex traits.</p>  a1553-7404