PQG Working Group

Huwenbo Shi and Martin Zhang

Postdoctoral Research Fellows, Department of Epidemiology
Harvard T.H. Chan School of Public Health

Transcriptome-wide association study and fine-mapping at cell-type resolution

Transcriptome-wide association studies (TWAS) using cis predicted gene expression have identified thousands of genes associated with diseases and complex traits (Gamazon et al. 2015 Nature Genetics, Gusev et al. 2016 Nature Genetics, Zhu et al. 2016 Nature Genetics). However, existing TWAS are based on gene expression models for bulk tissue gene expression, and therefore cannot pinpoint the specific cell types through which a gene is associated with diseases and complex traits.

Here, we introduce an approach to perform TWAS at tissue-cell-type resolution. We apply computational methods to infer cell type proportions and cell-type specific gene expression for each GTEx sample, using the mouse reference single-cell gene expression from the Tabula Muris Consortium in matched tissues, and obtain gene expression models for every tissue-cell-types based on the inferred gene expression.

We performed tissue-cell-type TWAS and fine-mapping for 52 diseases and complex traits. Compared to TWAS at tissue resolution, our tissue-cell-type TWAS discovered on average 84% more unique gene-trait associations at FDR