Mapping the dynamic genetic regulatory architecture of HLA genes at single-cell resolution

Abstract

The human leukocyte antigen (HLA) locus plays a critical role in complex traits spanning autoimmune and infectious diseases, transplantation, and cancer. While coding variation in HLA genes has been extensively documented, regulatory genetic variation modulating HLA expression levels has not been comprehensively investigated. Here, we mapped expression quantitative trait loci (eQTLs) for classical HLA genes across 1,073 individuals and 1,131,414 single cells from three tissues, using personalized reference genomes to mitigate technical confounding. We identified cell-type-specific cis-eQTLs for every classical HLA gene. Modeling eQTLs at single-cell resolution revealed that many eQTL effects are dynamic across cell states even within a cell type. HLA-DQ genes exhibit particularly cell-state-dependent effects within myeloid, B, and T cells. Dynamic HLA regulation may underlie important interindividual variability in immune responses.

Competing Interest Statement

S.R. is a scientific advisor to Pfizer, Janssen, and Sonoma Biotherapeutics, a founder of Mestag Therapeutics, and a consultant for AbbVie and Sanofi.

Funding Statement

This study was funded by the National Institutes of Health grants T32GM144273 (J.B.K., L.R., K.L.), F30AI172238 (J.B.K.), T32HG002295 (A.Z.S., L.R.), T32AR007530 (A.N.), F30AI157385 (L.R.), R01AR063759 (S.R.), U01HG012009 (S.R.), and UC2AR081023 (S.R.). This study also received funding from MGH Center for the Study of Inflammatory Bowel Disease grant DK-43351 (R.J.X.), Arthritis National Research Foundation (M.G.-A.), Gilead Sciences Research Scholar grant (M.G.-A.), and Lupus Research Alliance grant (M.G.-A.).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The IRB of Massachusetts General Hospital gave ethical approval for this work.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data Availability

For the Synovium dataset, the genotype and raw scRNA-seq data will become available upon publication of the original manuscript (Zhang et al., bioRxiv, 2022). For Intestine, the raw scRNA-seq data (bam files) was obtained from the Broad Data Use Oversight System (DUOS) (dataset name: Ulcerative_Colitis_in_Colon_Regev_Xavier); the genotype data will become available on dbGaP. For PBMC-cultured, the raw scRNA-seq data (FASTQ files) was obtained from GEO (PRJNA682434), and the imputed low-pass WGS data is publicly available at SRA (PRJNA736483) and Zenodo (https://doi.org/10.5281/zenodo.4273999). For PBMC-blood (OneK1K cohort), both the raw scRNA-seq data (bam files) and genotyping data are publicly available on GEO (GSE196830).

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