Inferring Relevant Cell Types for Complex Traits by Using Single-Cell Gene Expression

Diego Calderon, Anand Bhaskar, David A. Knowles, David Golan, Towfique Raj, Audrey Q. Fu, Jonathan K. Pritchard

Research output: Contribution to journalArticlepeer-review

82 Scopus citations

Abstract

Previous studies have prioritized trait-relevant cell types by looking for an enrichment of genome-wide association study (GWAS) signal within functional regions. However, these studies are limited in cell resolution by the lack of functional annotations from difficult-to-characterize or rare cell populations. Measurement of single-cell gene expression has become a popular method for characterizing novel cell types, and yet limited work has linked single-cell RNA sequencing (RNA-seq) to phenotypes of interest. To address this deficiency, we present RolyPoly, a regression-based polygenic model that can prioritize trait-relevant cell types and genes from GWAS summary statistics and gene expression data. RolyPoly is designed to use expression data from either bulk tissue or single-cell RNA-seq. In this study, we demonstrated RolyPoly's accuracy through simulation and validated previously known tissue-trait associations. We discovered a significant association between microglia and late-onset Alzheimer disease and an association between schizophrenia and oligodendrocytes and replicating fetal cortical cells. Additionally, RolyPoly computes a trait-relevance score for each gene to reflect the importance of expression specific to a cell type. We found that differentially expressed genes in the prefrontal cortex of individuals with Alzheimer disease were significantly enriched with genes ranked highly by RolyPoly gene scores. Overall, our method represents a powerful framework for understanding the effect of common variants on cell types contributing to complex traits.

Original languageEnglish
Pages (from-to)686-699
Number of pages14
JournalAmerican Journal of Human Genetics
Volume101
Issue number5
DOIs
StatePublished - 2 Nov 2017

Keywords

  • GWAS
  • complex traits
  • neuropsychiatric disease
  • single-cell gene expression

Fingerprint

Dive into the research topics of 'Inferring Relevant Cell Types for Complex Traits by Using Single-Cell Gene Expression'. Together they form a unique fingerprint.

Cite this