@article{abdo_xia_brown_kosyk_huang_sakamuru_zhou_jack_gallins_xia_et al._2015, title={Population-Based in Vitro Hazard and Concentration-Response Assessment of Chemicals: The 1000 Genomes High-Throughput Screening Study}, volume={123}, ISSN={["1552-9924"]}, DOI={10.1289/ehp.1408775}, abstractNote={Background: Understanding of human variation in toxicity to environmental chemicals remains limited, so human health risk assessments still largely rely on a generic 10-fold factor (10½ each for toxicokinetics and toxicodynamics) to account for sensitive individuals or subpopulations. Objectives: We tested a hypothesis that population-wide in vitro cytotoxicity screening can rapidly inform both the magnitude of and molecular causes for interindividual toxicodynamic variability. Methods: We used 1,086 lymphoblastoid cell lines from the 1000 Genomes Project, representing nine populations from five continents, to assess variation in cytotoxic response to 179 chemicals. Analysis included assessments of population variation and heritability, and genome-wide association mapping, with attention to phenotypic relevance to human exposures. Results: For about half the tested compounds, cytotoxic response in the 1% most “sensitive” individual occurred at concentrations within a factor of 10½ (i.e., approximately 3) of that in the median individual; however, for some compounds, this factor was > 10. Genetic mapping suggested important roles for variation in membrane and transmembrane genes, with a number of chemicals showing association with SNP rs13120371 in the solute carrier SLC7A11, previously implicated in chemoresistance. Conclusions: This experimental approach fills critical gaps unaddressed by recent large-scale toxicity testing programs, providing quantitative, experimentally based estimates of human toxicodynamic variability, and also testable hypotheses about mechanisms contributing to interindividual variation. Citation: Abdo N, Xia M, Brown CC, Kosyk O, Huang R, Sakamuru S, Zhou YH, Jack JR, Gallins P, Xia K, Li Y, Chiu WA, Motsinger-Reif AA, Austin CP, Tice RR, Rusyn I, Wright FA. 2015. Population-based in vitro hazard and concentration–response assessment of chemicals: the 1000 Genomes high-throughput screening study. Environ Health Perspect 123:458–466; http://dx.doi.org/10.1289/ehp.1408775}, number={5}, journal={ENVIRONMENTAL HEALTH PERSPECTIVES}, author={Abdo, Nour and Xia, Menghang and Brown, Chad C. and Kosyk, Oksana and Huang, Ruili and Sakamuru, Srilatha and Zhou, Yi-Hui and Jack, John R. and Gallins, Paul and Xia, Kai and et al.}, year={2015}, month={May}, pages={458–466} }
 @article{che_jack_motsinger-reif_brown_2014, title={An adaptive permutation approach for genome-wide association study: Evaluation and recommendations for use}, volume={7}, journal={Biodata Mining}, author={Che, R. L. and Jack, J. R. and Motsinger-Reif, A. A. and Brown, C. C.}, year={2014} }
 @article{brown_havener_medina_jack_krauss_mcleod_motsinger-reif_2014, title={Genome-wide association and pharmacological profiling of 29 anticancer agents using lymphoblastoid cell lines}, volume={15}, ISSN={["1744-8042"]}, DOI={10.2217/pgs.13.213}, abstractNote={ Aim: Association mapping with lymphoblastoid cell lines (LCLs) is a promising approach in pharmacogenomics research, and in the current study we utilized LCLs to perform association mapping for 29 chemotherapy drugs. Materials & methods: Currently, we use LCLs to perform genome-wide association mapping of the cytotoxic response of 520 European–Americans to 29 different anticancer drugs; the largest LCL study to date. A novel association approach using a multivariate analysis of covariance design was employed with the software program MAGWAS, testing for differences in the dose–response profiles between genotypes without making assumptions about the response curve or the biologic mode of association. Additionally, by classifying 25 of the 29 drugs into eight families according to structural and mechanistic relationships, MAGWAS was used to test for associations that were shared across each drug family. Finally, a unique algorithm using multivariate responses and multiple linear regressions across pairs of response curves was used for unsupervised clustering of drugs. Results: Among the single-drug studies, suggestive associations were obtained for 18 loci, 12 within/near genes. Three of these, MED12L, CHN2 and MGMT, have been previously implicated in cancer pharmacogenomics. The drug family associations resulted in four additional suggestive loci (three contained within/near genes). One of these genes, HDAC4, associated with the DNA alkylating agents, shows possible clinical interactions with temozolomide. For the drug clustering analysis, 18 of 25 drugs clustered into the appropriate family. Conclusion: This study demonstrates the utility of LCLs in identifying genes that have clinical importance in drug response and for assigning unclassified agents to specific drug families, and proposes new candidate genes for follow-up in a large number of chemotherapy drugs. }, number={2}, journal={PHARMACOGENOMICS}, author={Brown, Chad C. and Havener, Tammy M. and Medina, Marisa W. and Jack, John R. and Krauss, Ronald M. and McLeod, Howard L. and Motsinger-Reif, Alison A.}, year={2014}, month={Feb}, pages={137–146} }
 @article{brown_havener_medina_auman_mangravite_krauss_mcleod_motsinger-reif_2012, title={A genome-wide association analysis of temozolomide response using lymphoblastoid cell lines shows a clinically relevant association with MGMT}, volume={22}, ISSN={["1744-6872"]}, DOI={10.1097/fpc.0b013e3283589c50}, abstractNote={Objective Recently, lymphoblastoid cell lines (LCLs) have emerged as an innovative model system for mapping gene variants that predict the dose response to chemotherapy drugs. Methods In the current study, this strategy was expanded to the in-vitro genome-wide association approach, using 516 LCLs derived from a White cohort to assess the cytotoxic response to temozolomide. Results Genome-wide association analysis using ∼2.1 million quality-controlled single-nucleotide polymorphisms (SNPs) identified a statistically significant association (P<10−8) with SNPs in the O6-methylguanine-DNA methyltransferase (MGMT) gene. We also show that the primary SNP in this region is significantly associated with the differential gene expression of MGMT (P<10–26) in LCLs and differential methylation in glioblastoma samples from The Cancer Genome Atlas. Conclusion The previously documented clinical and functional relationships between MGMT and temozolomide response highlight the potential of well-powered genome-wide association studies of the LCL model system to identify meaningful genetic associations.}, number={11}, journal={PHARMACOGENETICS AND GENOMICS}, author={Brown, Chad C. and Havener, Tammy M. and Medina, Marisa W. and Auman, J. Todd and Mangravite, Lara M. and Krauss, Ronald M. and McLeod, Howard L. and Motsinger-Reif, Alison A.}, year={2012}, month={Nov}, pages={796–802} }
 @article{brown_oki_hariani_motsinger-reif_2012, title={A predictive model for Efavirenz dosing}, volume={13}, number={2}, journal={Pharmacogenomics}, author={Brown, C. and Oki, N. O. and Hariani, G. and Motsinger-Reif, A. A.}, year={2012}, pages={137–138} }
 @misc{che_motsinger-reif_brown_2012, title={Loss of power in two-stage residual-outcome regression analysis in genetic association studies}, volume={36}, number={8}, journal={Genetic Epidemiology}, author={Che, R. L. and Motsinger-Reif, A. A. and Brown, C. C.}, year={2012}, pages={890–894} }
 @article{brown_havener_medina_krauss_mcleod_motsinger-reif_2012, title={Multivariate methods and software for association mapping in dose-response genome-wide association studies}, volume={5}, journal={Biodata Mining}, author={Brown, C. C. and Havener, T. M. and Medina, M. W. and Krauss, R. M. and McLeod, H. L. and Motsinger-Reif, A. A.}, year={2012} }