Fine-Mapping Causal Tissues and Genes at Disease-Associated Loci
Abstract: Complex diseases often have distinct mechanisms spanning multiple tissues. We propose Tissue-Gene Fine-Mapping (TGFM), which infers the posterior probability (PIP) for each gene-tissue pair to mediate a disease locus by analyzing summary statistics and eQTL data; TGFM also assigns PIPs to non-mediated variants. TGFM accounts for co-regulation across genes and tissues and models uncertainty in cis-predicted expression models, enabling correct calibration. We applied TGFM to 45 UK Biobank diseases/traits using eQTL data from 38 GTEx tissues. TGFM identified an average of 147 PIP>0.5 causal genetic elements per disease/trait, of which 11% were gene-tissue pairs. Causal gene-tissue pairs identified by TGFM reflected both known biology (e.g., TPO-thyroid for Hypothyroidism) and biologically plausible findings (e.g., SLC20A2-artery aorta for Diastolic blood pressure). Application of TGFM to single-cell eQTL data from 9 cell types in peripheral blood mononuclear cells (PBMC), analyzed jointly with GTEx tissues, identified 30 additional causal gene-PBMC cell type pairs.
Bio:
Alkes Price – Dr. Price is a professor in the Program in Genetic Epidemiology and Statistical Genetics in the Department of Epidemiology at Harvard Chan, with a secondary appointment in the Department of Biostatistics. He is an associate member of the Program in Medical and Population Genetics at the Broad Institute, and a member of the Program in Quantitative Genomics at Harvard Chan. Dr. Price received a Ph.D. in mathematics and M.S.E. in computer science from the University of Pennsylvania. His post-doctoral training was mentored by Dr. Pavel Pevzner in the department of computer science at UCSD and Dr. David Reich in the department of genetics at Harvard Medical School. He has been a faculty member at Harvard Chan since 2008. Dr. Price’s research focuses on the development of statistical methods for uncovering the genetic basis of human disease, and on the population genetics underlying these methods. Areas of interest include functional components of disease heritability, common vs. rare variant architectures of disease, and disease mapping in structured populations.
Ben Strober – Dr. Strober is a post-doctoral researcher in the Department of Epidemiology at Harvard School of Public Health supervised by Dr. Alkes Price. He completed his Ph.D. in 2021 in the Department of Biomedical Engineering at Johns Hopkins University with Dr. Alexis Battle. Dr. Strober’s research focuses on context-specific genetic regulation of gene expression, and understanding its contribution to the genetic architecture of complex traits and disease.