Optimized summary-statistic-based single-cell eQTL meta-analysis

The identification of expression quantitative trait loci (eQTLs) holds great potential to improve the interpretation of disease-associated genetic variation. As many such disease-associated variants act in a context-, tissue- or even cell-type-specific manner, single-cell RNA-sequencing (scRNA-seq) data is uniquely suitable for identifying the specific cell type or context in which these genetic variants act. However, due to the limited sample sizes in single-cell studies, discovery of cell-type-specific eQTLs is now limited. To improve power to detect such eQTLs, large-scale joint analyses are needed. These are however, complicated by privacy constraints due to sharing of genotype data and the measurement and technical variety across different scRNA-seq datasets as a result of differences in mRNA capture efficiency, experimental protocols, and sequencing strategies. A solution to these issues is a federated weighted meta-analysis (WMA) approach in which summary statistics are integrated using dataset-specific weights. Here, we compare different strategies and provide best practice recommendations for eQTL WMA across scRNA-seq datasets.