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

Joyce B Kang; Amber Z Shen; Saori Sakaue; Yang Luo; Saisriram Gurajala; Aparna Nathan; Laurie Rumker; Vitor R C Aguiar; Cristian Valencia; Kaitlyn Lagattuta; Fan Zhang; Anna Helena Jonsson; Seyhan Yazar; Jose Alquicira-Hernandez; Hamed Khalili; Ashwin N Ananthakrishnan; Karthik Jagadeesh; Kushal Dey; Accelerating Medicines Partnership Program: Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Network; Mark J Daly; Ramnik J Xavier; Laura T Donlin; Jennifer H Anolik; Joseph E Powell; Deepak A Rao; Michael B Brenner; Maria Gutierrez-Arcelus; Soumya Raychaudhuri

doi:10.1101/2023.03.14.23287257

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

medRxiv [Preprint]. 2023 Mar 20:2023.03.14.23287257. doi: 10.1101/2023.03.14.23287257.

Authors

Joyce B Kang^{1

2

3

4

5}, Amber Z Shen^{1

2

3

4

5}, Saori Sakaue^{1

2

3

4

5}, Yang Luo^{1

2

3

4

5

6}, Saisriram Gurajala^{1

2

3

4

5}, Aparna Nathan^{1

2

3

4

5}, Laurie Rumker^{1

2

3

4

5}, Vitor R C Aguiar^{4

7}, Cristian Valencia^{1

2

3

4

5}, Kaitlyn Lagattuta^{1

2

3

4

5}, Fan Zhang^{1

2

3

4

5

8}, Anna Helena Jonsson⁵, Seyhan Yazar⁹, Jose Alquicira-Hernandez⁹, Hamed Khalili¹⁰, Ashwin N Ananthakrishnan¹⁰, Karthik Jagadeesh¹¹, Kushal Dey¹¹; Accelerating Medicines Partnership Program: Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Network; Mark J Daly^{12

13

14

15}, Ramnik J Xavier^{16

17

18}, Laura T Donlin^{19

20}, Jennifer H Anolik²¹, Joseph E Powell⁹, Deepak A Rao⁵, Michael B Brenner⁵, Maria Gutierrez-Arcelus^{4

7}, Soumya Raychaudhuri^{1

2

3

4

5}

Affiliations

¹ Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA.
² Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
³ Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
⁴ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵ Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁶ Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
⁷ Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
⁸ Division of Rheumatology and the Center for Health Artificial Intelligence, University of Colorado School of Medicine, Aurora, CO, USA.
⁹ Garvan Institute of Medical Research, Sydney, NSW, Australia.
¹⁰ Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
¹¹ Harvard T. H. Chan School of Public Health, Boston, MA, USA.
¹² Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
¹³ The Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁴ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
¹⁵ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹⁶ Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
¹⁷ Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹⁸ Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹⁹ Hospital for Special Surgery, New York, NY, USA.
²⁰ Weill Cornell Medicine, New York, NY, USA.
²¹ Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA.

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.

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