Epistatic and cross-tissue analysis for human gene expression traits Genome wide association studies (GWAS) have delivered unprecedented rates of discovery associating variations in DNA with common human diseases. However, how these SNPs affect human diseases are not clear in most cases. Gene expression is the intermediate between SNPs and disease phenotypes. Methods to maximally leverage gene expression and genetic variation information collected in human cohorts over multiple tissues show great promise for characterizing not only the genetic architecture of disease but the molecule networks that define disease. The long-term goal of this application is to develop and implement novel statistical methods to identify networks of genes affecting an individual's susceptibility to complex phenotypes like disease. Here, we propose several model developments that not only enhance our power to detect eQTL in single or multiple tissues, but that identify eQTL and interactions among eQTL in the molecular network contexts that define biological processes associated with disease: (1) A Bayesian modeling approach that simultaneously models the total distribution of all genes and all markers will be developed. The strength of our approach will be its ability to detect epistasis with high power when the marginal effects are weak, addressing a key weakness of all other eQTL mapping methods. (2) A likelihood based approach for inferring causal relationships that also incorporates transcription factor binding site information will be developed. (3) An approach for linking subnetworks in different tissues to diseases will be developed. Also a method to dissect causal/ reactive relationships between tissues will be developed. (4) The proposed methods will be extensively validated via simulations and, more importantly, on multi-tissue mouse and human cohort data we have generated. All methods will be implemented in user-friendly software and made available to the scientific community.
Epistatic and cross-tissue analysis for human gene expression traits Gene expression is the intermediate between SNPs and disease phenotypes. Methods to maximimally leverage gene expression and genetic variation information collected in human cohorts over multiple tissues show great promise for characterizing not only the genetic architecture of disease but the molecule networks that define disease. We propose several model developments that not only enhance our power to detect eQTL in single or multiple tissues, but that identify eQTL and interactions among eQTL in the molecular network contexts that define biological processes associated with disease.
| Zhang, Mingfeng; Lykke-Andersen, Soren; Zhu, Bin et al. (2018) Characterising cis-regulatory variation in the transcriptome of histologically normal and tumour-derived pancreatic tissues. Gut 67:521-533 |
| Agrawal, A; Chou, Y-L; Carey, C E et al. (2018) Genome-wide association study identifies a novel locus for cannabis dependence. Mol Psychiatry 23:1293-1302 |
| Collado-Torres, Leonardo; Nellore, Abhinav; Kammers, Kai et al. (2017) Reproducible RNA-seq analysis using recount2. Nat Biotechnol 35:319-321 |
| Benítez-Buelga, Carlos; Baquero, Juan Miguel; Vaclova, Tereza et al. (2017) Genetic variation in the NEIL2 DNA glycosylase gene is associated with oxidative DNA damage in BRCA2 mutation carriers. Oncotarget 8:114626-114636 |
| Tukiainen, Taru; Villani, Alexandra-Chloé; Yen, Angela et al. (2017) Landscape of X chromosome inactivation across human tissues. Nature 550:244-248 |
| 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 |
| 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 |
| 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 |
| Varma, V R; Varma, S; An, Y et al. (2017) Alpha-2 macroglobulin in Alzheimer's disease: a marker of neuronal injury through the RCAN1 pathway. Mol Psychiatry 22:13-23 |
| 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 |
Showing the most recent 10 out of 61 publications
