Oral Presentation 43rd Lorne Genome Conference 2022

Single-cell eQTL mapping identifies cell type specific genetic control of autoimmune disease (#37)

Seyhan Yazar 1 , Jose Alquicira 1 2 , Kristof Wing 3 4 , Anne Senabouth 1 , Gracie Gordon 5 6 7 , Stacey Anderson 2 , Qinyi Lu 3 , Antonia Rawson 3 8 , Thomas RP Taylor 3 , Linda Clarke 9 , Katia Maccora 3 8 , Christine Chen 8 , Anthony L Cook 10 , Chun Jimmie Ye 5 6 7 11 12 13 , Kirsten Fairfax 3 , Alex Hewitt 3 4 9 , Joseph Powell 1 14
  1. Garvan Institute of Medical Research, Sydney, NSW, Australia
  2. Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
  3. Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia
  4. Department of Ophthalmology, Royal Hobart Hospital, Hobart, TAS, Australia
  5. Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
  6. Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
  7. Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA
  8. Department of Surgery, School of Clinical Science at Monash Health, Monash University, Melbourne, VIC, Australia
  9. Centre for Eye Research Australia, University of Melbourne, Melbourne, VIC, Australia
  10. Wicking Dementia Research and Education Centre, University of Tasmania, Hobart, VIC, Australia
  11. Institute of Computational Health Sciences, University of California, San Francisco, CA, USA
  12. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA
  13. Chan Zuckerberg Biohub, San Francisco, CA, Australia
  14. UNSW Cellular Genomics Futures Institute, University of New South Wales, Sydney, NSW, Australia

Genome-wide association studies in large populations have enriched our understanding of genetic variants implicated in health and disease while expression quantitative trait loci (eQTL) studies with microarray and bulk-RNA sequencing data showed us how these genetic variants affect the expression of one or more genes in a tissue-specific manner. However, it is much less known how genetic variants influence gene expression in various cell types within a tissue. This study, therefore, set to identify the cell specific eQTLs in the human immune cells using single-cell sequencing technology. We have performed conditional cis-eQTL analysis on 14 cell types in 1,267,758 peripheral blood mononuclear cells from 982 healthy human subjects and identified 25,606 independent cis-eQTLs. Our results suggest majority of these eQTLs have an allelic effect on gene expression that is cell type-specific and demonstrate how commonly segregating alleles lead to inter-individual variation in immune function. Using the top associated SNP at each locus outside the MHC region, we also identified 990 trans-acting effects, the majority of which were cell type specific. Then we investigated how eQTLs have dynamic allelic effects in B cells transitioning from naïve to memory states. Overall, we identified a set of 1,988 trajectory eSNP-eGene pairs expressed across the B cell maturation landscape, of which 333 were found to have a statistically significant change in their allelic effect as B cells differentiate. Finally, utilising a Mendelian randomisation approach, we identified the causal route by which 305 risk loci contribute to autoimmune disease at the cellular level. This work brings together genetic epidemiology with scRNA-seq to uncover drivers of inter-individual variation in the immune system.