Single-cell RNA Sequencing Identifies Celltype-specific Cis-eQTLs and Co-expression QTLs

Overview

Journal Nat Genet

Specialty Genetics

Date 2018 Apr 4

PMID 29610479

Citations 179

Authors

Monique G P van der Wijst

Harm Brugge

Dylan H de Vries

Patrick Deelen

Morris A Swertz

Lude Franke

Affiliations

Soon will be listed here.

Abstract

Genome-wide association studies have identified thousands of genetic variants that are associated with disease . Most of these variants have small effect sizes, but their downstream expression effects, so-called expression quantitative trait loci (eQTLs), are often large and celltype-specific. To identify these celltype-specific eQTLs using an unbiased approach, we used single-cell RNA sequencing to generate expression profiles of ~25,000 peripheral blood mononuclear cells from 45 donors. We identified previously reported cis-eQTLs, but also identified new celltype-specific cis-eQTLs. Finally, we generated personalized co-expression networks and identified genetic variants that significantly alter co-expression relationships (which we termed 'co-expression QTLs'). Single-cell eQTL analysis thus allows for the identification of genetic variants that impact regulatory networks.

Citing Articles

Single-cell eQTL mapping in yeast reveals a tradeoff between growth and reproduction.

Boocock J, Alexander N, Alamo Tapia L, Walter-McNeill L, Patel S, Munugala C Elife. 2025; 13.

PMID: 40073070 PMC: 11903034. DOI: 10.7554/eLife.95566.

Sex-stratified genome-wide meta-analysis identifies novel loci for cognitive decline in older adults.

Acharya V, Fan K, Snitz B, Ganguli M, DeKosky S, Lopez O Alzheimers Dement. 2025; 21(3):e14461.

PMID: 40042063 PMC: 11880917. DOI: 10.1002/alz.14461.

Leveraging prior knowledge to infer gene regulatory networks from single-cell RNA-sequencing data.

Stock M, Losert C, Zambon M, Popp N, Lubatti G, Hormanseder E Mol Syst Biol. 2025; 21(3):214-230.

PMID: 39939367 PMC: 11876610. DOI: 10.1038/s44320-025-00088-3.

Single-cell transcriptome-wide Mendelian randomization and colocalization reveals immune-mediated regulatory mechanisms and drug targets for COVID-19.

Ying H, Wu X, Jia X, Yang Q, Liu H, Zhao H EBioMedicine. 2025; 113:105596.

PMID: 39933264 PMC: 11867302. DOI: 10.1016/j.ebiom.2025.105596.

Missing Regulation Between Genetic Association and Transcriptional Abundance for Hypercholesterolemia Genes.

Hakim A, Connally N, Schnitzler G, Cho M, Jiang Z, Sunyaev S Genes (Basel). 2025; 16(1).

PMID: 39858631 PMC: 11764661. DOI: 10.3390/genes16010084.

References

Westra H, Peters M, Esko T, Yaghootkar H, Schurmann C, Kettunen J . Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat Genet. 2013; 45(10):1238-1243. PMC: 3991562. DOI: 10.1038/ng.2756. View

Rosser Z, Balaresque P, Jobling M . Gene conversion between the X chromosome and the male-specific region of the Y chromosome at a translocation hotspot. Am J Hum Genet. 2009; 85(1):130-4. PMC: 2706966. DOI: 10.1016/j.ajhg.2009.06.009. View

Das S, Forer L, Schonherr S, Sidore C, Locke A, Kwong A . Next-generation genotype imputation service and methods. Nat Genet. 2016; 48(10):1284-1287. PMC: 5157836. DOI: 10.1038/ng.3656. View

Wills Q, Livak K, Tipping A, Enver T, Goldson A, Sexton D . Single-cell gene expression analysis reveals genetic associations masked in whole-tissue experiments. Nat Biotechnol. 2013; 31(8):748-52. DOI: 10.1038/nbt.2642. View

Zhernakova D, Deelen P, Vermaat M, van Iterson M, van Galen M, Arindrarto W . Identification of context-dependent expression quantitative trait loci in whole blood. Nat Genet. 2016; 49(1):139-145. DOI: 10.1038/ng.3737. View

Ilicic T, Kim J, Kolodziejczyk A, Bagger F, McCarthy D, Marioni J . Classification of low quality cells from single-cell RNA-seq data. Genome Biol. 2016; 17:29. PMC: 4758103. DOI: 10.1186/s13059-016-0888-1. View

Sul J, Han B, Ye C, Choi T, Eskin E . Effectively identifying eQTLs from multiple tissues by combining mixed model and meta-analytic approaches. PLoS Genet. 2013; 9(6):e1003491. PMC: 3681686. DOI: 10.1371/journal.pgen.1003491. View

Venet D, Pecasse F, Maenhaut C, Bersini H . Separation of samples into their constituents using gene expression data. Bioinformatics. 2001; 17 Suppl 1:S279-87. DOI: 10.1093/bioinformatics/17.suppl_1.s279. View

Fairfax B, Makino S, Radhakrishnan J, Plant K, Leslie S, Dilthey A . Genetics of gene expression in primary immune cells identifies cell type-specific master regulators and roles of HLA alleles. Nat Genet. 2012; 44(5):502-10. PMC: 3437404. DOI: 10.1038/ng.2205. View

10.

Chen L, Ge B, Casale F, Vasquez L, Kwan T, Garrido-Martin D . Genetic Drivers of Epigenetic and Transcriptional Variation in Human Immune Cells. Cell. 2016; 167(5):1398-1414.e24. PMC: 5119954. DOI: 10.1016/j.cell.2016.10.026. View

11.

Visscher P, Brown M, McCarthy M, Yang J . Five years of GWAS discovery. Am J Hum Genet. 2012; 90(1):7-24. PMC: 3257326. DOI: 10.1016/j.ajhg.2011.11.029. View

12.

McCarthy S, Das S, Kretzschmar W, Delaneau O, Wood A, Teumer A . A reference panel of 64,976 haplotypes for genotype imputation. Nat Genet. 2016; 48(10):1279-83. PMC: 5388176. DOI: 10.1038/ng.3643. View

13.

Macosko E, Basu A, Satija R, Nemesh J, Shekhar K, Goldman M . Highly Parallel Genome-wide Expression Profiling of Individual Cells Using Nanoliter Droplets. Cell. 2015; 161(5):1202-1214. PMC: 4481139. DOI: 10.1016/j.cell.2015.05.002. View

14.

Naranbhai V, Fairfax B, Makino S, Humburg P, Wong D, Ng E . Genomic modulators of gene expression in human neutrophils. Nat Commun. 2015; 6:7545. PMC: 4507005. DOI: 10.1038/ncomms8545. View

15.

Shalek A, Satija R, Shuga J, Trombetta J, Gennert D, Lu D . Single-cell RNA-seq reveals dynamic paracrine control of cellular variation. Nature. 2014; 510(7505):363-9. PMC: 4193940. DOI: 10.1038/nature13437. View

16.

Kasela S, Kisand K, Tserel L, Kaleviste E, Remm A, Fischer K . Pathogenic implications for autoimmune mechanisms derived by comparative eQTL analysis of CD4+ versus CD8+ T cells. PLoS Genet. 2017; 13(3):e1006643. PMC: 5352142. DOI: 10.1371/journal.pgen.1006643. View

17.

Ishigaki K, Kochi Y, Suzuki A, Tsuchida Y, Tsuchiya H, Sumitomo S . Polygenic burdens on cell-specific pathways underlie the risk of rheumatoid arthritis. Nat Genet. 2017; 49(7):1120-1125. DOI: 10.1038/ng.3885. View

18.

Villani A, Satija R, Reynolds G, Sarkizova S, Shekhar K, Fletcher J . Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors. Science. 2017; 356(6335). PMC: 5775029. DOI: 10.1126/science.aah4573. View

19.

Li W, Li J . An accurate and robust imputation method scImpute for single-cell RNA-seq data. Nat Commun. 2018; 9(1):997. PMC: 5843666. DOI: 10.1038/s41467-018-03405-7. View

20.

. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007; 447(7145):661-78. PMC: 2719288. DOI: 10.1038/nature05911. View