000004065 001__ 4065
000004065 041__ $$aen_US
000004065 100__ $$aYelensky, Roman
000004065 245__ $$aGenetic Analysis of Human Traits In Vitro: Drug Response and Gene Expression in Lymphoblastoid Cell Lines
000004065 260__ $$bPublic Library of Science$$c2010-10-07T17:36:56Z
000004065 500__ $$aLymphoblastoid cell lines (LCLs), originally collected as renewable sources of DNA, are now being used as a model system to study genotype–phenotype relationships in human cells, including searches for QTLs influencing levels of individual mRNAs and responses to drugs and radiation. In the course of attempting to map genes for drug response using 269 LCLs from the International HapMap Project, we evaluated the extent to which biological noise and non-genetic confounders contribute to trait variability in LCLs. While drug responses could be technically well measured on a given day, we observed significant day-to-day variability and substantial correlation to non-genetic confounders, such as baseline growth rates and metabolic state in culture. After correcting for these confounders, we were unable to detect any QTLs with genome-wide significance for drug response. A much higher proportion of variance in mRNA levels may be attributed to non-genetic factors (intra-individual variance—i.e., biological noise, levels of the EBV virus used to transform the cells, ATP levels) than to detectable eQTLs. Finally, in an attempt to improve power, we focused analysis on those genes that had both detectable eQTLs and correlation to drug response; we were unable to detect evidence that eQTL SNPs are convincingly associated with drug response in the model. While LCLs are a promising model for pharmacogenetic experiments, biological noise and in vitro artifacts may reduce power and have the potential to create spurious association due to confounding.
000004065 520__ $$aMolecular and Cellular Biology
000004065 65017 $$agentics and genomics
000004065 6557_ $$aJournal Article
000004065 700__ $$aBonakdar, Sasha
000004065 700__ $$aWolfish, Cara S.
000004065 700__ $$aCotsapas, Chris
000004065 700__ $$aRivas, Manuel
000004065 700__ $$aDermitzakis, Emmanouil T.
000004065 700__ $$aChoy, Edwin
000004065 700__ $$aPlenge, Robert M.
000004065 700__ $$aSaxena, Richa
000004065 700__ $$aDe Jager, Philip Lawrence
000004065 700__ $$aShaw, Stanley Yang
000004065 700__ $$aSlavik, Jacqueline Marie
000004065 700__ $$aCahir-McFarland, Ellen D.
000004065 700__ $$aKieff, Elliott D.
000004065 700__ $$aHafler, David A.
000004065 700__ $$aDaly, Mark Joseph
000004065 700__ $$aAltshuler, David Matthew
000004065 7860_ $$ndoi:0.1371/journal.pgen.1000287
000004065 8564_ $$uhttp://dash.harvard.edu/handle/1/4461124$$zDASH:1/4461124
000004065 909C0 $$Y2008
000004065 909C4 $$dhttp://dash.harvard.edu/handle/1/4461124$$pDASH:1/4461124
000004065 980__ $$aDASH