This application addresses RFA RM-09-006: Novel statistical methods for human gene expression quantitative trait loci (eQTL) analysis. Genome-wide association studies (GWAS) are rapidly becoming the preferred approach for discovery of phenotype- genotype associations;however, statistical power, replication and validation of candidates remain to be challenging. In addition to genotypes, gene expression data are now being collected along with disease and exposure data in large human cohorts, across multiple tissues, and in animal experiments. We will test the hypothesis that expression quantitative trait locus (eQTL) analysis is an effective and mechanistically- relevant approach to the discovery and validation of candidate genomic loci/genes that control biological pathways and networks, using expression data from various tissues, from disease vs. normal conditions, or under experimental perturbation. The ultimate goal is to elucidate the underpinnings of human disease. In this project we will develop new statistical tools and graphical user interface-enabled software to handle these diverse data streams. The primary goal of the analysis is to identify the interactions among genetic polymorphisms, expression, and tissue type or phenotype, which would not be found using traditional GWAS. We have assembled an experienced team of biomedical scientists, statistical geneticists, and statisticians, and we already laid out the methodological and computational groundwork for the statistical approaches. In addition, we have a track record of successful software development, and we have already begun building user-friendly eQTL software aimed at the broad scientific community. We describe how a number of key remaining challenges in applying eQTL mapping to large-scale GWAS studies will be addressed in a two-year period by: (i) enabling fast and statistically rigorous eQTL analyses in large homo- and hetero-zygous populations;(ii) developing fast ANOVA-based modeling of expression as a function of genotype and tissue type;(iii) modeling phenotypic traits as a function of expression and genotype;and (iv) indentifying patterns of significant individual-transcript associations using biclustering.

Public Health Relevance

PROJECT NARRATIVE We present a two-year plan to develop new statistical tools and graphical user-friendly software to facilitate the analysis of eQTL studies. The proposal is highly responsive to the RFA, with specific plans to address multiple tissue sources (as with GTEx data) and studies combining disease phenotype, genotype and expression. The project will create effective tools for elucidating the complex biology underlying disease.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-GGG-A (52))
Program Officer
Bender, Patrick
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Carolina Chapel Hill
Public Health & Prev Medicine
Schools of Public Health
Chapel Hill
United States
Zip Code
Chiang, Colby; Scott, Alexandra J; Davis, Joe R et al. (2017) The impact of structural variation on human gene expression. Nat Genet 49:692-699
Mohammadi, Pejman; Castel, Stephane E; Brown, Andrew A et al. (2017) Quantifying the regulatory effect size of cis-acting genetic variation using allelic fold change. Genome Res 27:1872-1884
Tan, Meng How; Li, Qin; Shanmugam, Raghuvaran et al. (2017) Dynamic landscape and regulation of RNA editing in mammals. Nature 550:249-254
Dolan, M Eileen; El Charif, Omar; Wheeler, Heather E et al. (2017) Clinical and Genome-Wide Analysis of Cisplatin-Induced Peripheral Neuropathy in Survivors of Adult-Onset Cancer. Clin Cancer Res 23:5757-5768
Yang, Fan; Wang, Jiebiao; GTEx Consortium et al. (2017) Identifying cis-mediators for trans-eQTLs across many human tissues using genomic mediation analysis. Genome Res 27:1859-1871
Agrawal, A; Chou, Y-L; Carey, C E et al. (2017) Genome-wide association study identifies a novel locus for cannabis dependence. Mol Psychiatry :
Gudmundsson, Julius; Thorleifsson, Gudmar; Sigurdsson, Jon K et al. (2017) A genome-wide association study yields five novel thyroid cancer risk loci. Nat Commun 8:14517
Bai, Xue; Mangum, Kevin D; Dee, Rachel A et al. (2017) Blood pressure-associated polymorphism controls ARHGAP42 expression via serum response factor DNA binding. J Clin Invest 127:670-680
Mercader, Josep M; Liao, Rachel G; Bell, Avery D et al. (2017) A Loss-of-Function Splice Acceptor Variant in IGF2 Is Protective for Type 2 Diabetes. Diabetes 66:2903-2914
Peckham-Gregory, Erin C; Chakraborty, Rikhia; Scheurer, Michael E et al. (2017) A genome-wide association study of LCH identifies a variant in SMAD6 associated with susceptibility. Blood 130:2229-2232

Showing the most recent 10 out of 59 publications