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

Joyce B. Kang; Amber Z. Shen; Saisriram Gurajala; Aparna Nathan; Laurie Rumker; Vitor R. C. Aguiar; Cristian Valencia; Kaitlyn A. Lagattuta; Fan Zhang; Anna Helena Jonsson; Seyhan Yazar; Jose Alquicira-Hernandez; Hamed Khalili; Ashwin N. Ananthakrishnan; Karthik Jagadeesh; Kushal Dey; Jennifer Albrecht; William Apruzzese; Nirmal Banda; Jennifer L. Barnas; Joan M. Bathon; Ami Ben-Artzi; Brendan F. Boyce; David L. Boyle; S. louis Bridges; Vivian P. Bykerk; Debbie Campbell; Hayley l. Carr; Arnold Ceponis; Adam Chicoine; Andrew Cordle; Michelle Curtis; Kevin D. Deane; Edward DiCarlo; Patrick Dunn; Andrew Filer; Gary S. Firestein; Lindsy Forbess; Laura Geraldino-Pardilla; Susan M. Goodman; Ellen M. Gravallese; Peter K. Gregersen; Joel M. Guthridge; V. Michael Holers; Diane Horowitz; Laura B. Hughes; Kazuyoshi Ishigaki; Lionel B. Ivashkiv; Judith A. James; Gregory Keras; Ilya Korsunsky; Amit Lakhanpal; James A. Lederer; Myles Lewis; Zhihan J. Li; Yuhong Li; Katherine P. Liao; Arthur M. Mandelin; Ian Mantel; Kathryne E. Marks; Mark Maybury; Andrew Mcdavid; Mandy J. Mcgeachy; Joseph Mears; Nida Meednu; Nghia Millard; Larry W. Moreland; Saba Nayar; Alessandra Nerviani; Dana E. Orange; Harris Perlman; Constantino Pitzalis; Javier Rangel-Moreno; Karim Raza; Yakir Reshef; Christopher Ritchlin; Felice Rivellese; William H. Robinson; Ilfita Sahbudin; Anvita Singaraju; Jennifer A. Seifert; Kamil Slowikowski; Melanie H. Smith; Darren Tabechian; Dagmar Scheel-Toellner; Paul J. Utz; Gerald F. M. Watts; Kevin Wei; Kathryn Weinand; Dana Weisenfeld; Michael H. Weisman; Aaron Wyse; Qian Xiao; Zhu Zhu; Mark J. Daly; Ramnik J. Xavier; Laura T. Donlin; Jennifer H. Anolik; Joseph E. Powell; Deepak A. Rao; Michael B. Brenner; Maria Gutierrez-Arcelus; Yang Luo; Saori Sakaue; Soumya Raychaudhuri

doi:10.1038/s41588-023-01586-6

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

Joyce B. Kang, Amber Z. Shen, Saisriram Gurajala, Aparna Nathan, Laurie Rumker, Vitor R. C. Aguiar, Cristian Valencia, Kaitlyn A. Lagattuta, Fan Zhang, Anna Helena Jonsson, Seyhan Yazar, Jose Alquicira-Hernandez, Hamed Khalili, Ashwin N. Ananthakrishnan, Karthik Jagadeesh, Kushal Dey, Jennifer Albrecht, William Apruzzese, Nirmal Banda, Jennifer L. BarnasJoan M. Bathon, Ami Ben-Artzi, Brendan F. Boyce, David L. Boyle, S. louis Bridges, Vivian P. Bykerk, Debbie Campbell, Hayley l. Carr, Arnold Ceponis, Adam Chicoine, Andrew Cordle, Michelle Curtis, Kevin D. Deane, Edward DiCarlo, Patrick Dunn, Andrew Filer, Gary S. Firestein, Lindsy Forbess, Laura Geraldino-Pardilla, Susan M. Goodman, Ellen M. Gravallese, Peter K. Gregersen, Joel M. Guthridge, V. Michael Holers, Diane Horowitz, Laura B. Hughes, Kazuyoshi Ishigaki, Lionel B. Ivashkiv, Judith A. James, Gregory Keras, Ilya Korsunsky, Amit Lakhanpal, James A. Lederer, Myles Lewis, Zhihan J. Li, Yuhong Li, Katherine P. Liao, Arthur M. Mandelin, Ian Mantel, Kathryne E. Marks, Mark Maybury, Andrew Mcdavid, Mandy J. Mcgeachy, Joseph Mears, Nida Meednu, Nghia Millard, Larry W. Moreland, Saba Nayar, Alessandra Nerviani, Dana E. Orange, Harris Perlman, Constantino Pitzalis, Javier Rangel-Moreno, Karim Raza, Yakir Reshef, Christopher Ritchlin, Felice Rivellese, William H. Robinson, Ilfita Sahbudin, Anvita Singaraju, Jennifer A. Seifert, Kamil Slowikowski, Melanie H. Smith, Darren Tabechian, Dagmar Scheel-Toellner, Paul J. Utz, Gerald F. M. Watts, Kevin Wei, Kathryn Weinand, Dana Weisenfeld, Michael H. Weisman, Aaron Wyse, Qian Xiao, Zhu Zhu, Mark J. Daly, Ramnik J. Xavier, Laura T. Donlin, Jennifer H. Anolik, Joseph E. Powell, Deepak A. Rao, Michael B. Brenner, Maria Gutierrez-Arcelus, Yang Luo, Saori Sakaue, Soumya Raychaudhuri^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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. To mitigate technical confounding, we developed scHLApers, a pipeline to accurately quantify single-cell HLA expression using personalized reference genomes. 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. For example, a T cell HLA-DQA1 eQTL ( rs3104371 ) is strongest in cytotoxic cells. Dynamic HLA regulation may underlie important interindividual variability in immune responses.

Original language	English
Pages (from-to)	2255-2268
Number of pages	14
Journal	Nature Genetics
Volume	55
Issue number	12
Early online date	30 Nov 2023
DOIs	https://doi.org/10.1038/s41588-023-01586-6
Publication status	Published - Dec 2023

Bibliographical note

Acknowledgements:
We thank A. Dobin, H. Randolph, H. Lau, C. Stevens and members of the Raychaudhuri Lab, in particular A. Gupta and Y. Baglaenko, for their helpful input and discussions. This work was funded by the National Institutes of Health grants T32GM007753 and T32GM144273 (J.B.K., L.R. and K.A.L.), F30AI172238 (J.B.K.), T32HG002295 (A.Z.S. and L.R.), T32AR007530 (A.N.), F30AI157385 (L.R.), R01AR063759 (S.R.), U01HG012009 (S.R.) and UC2AR081023 (S.R.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This project also received funding from the MGH Center for the Study of Inflammatory Bowel Disease grant DK-43351 (R.J.X.), a fellowship from the Fok Foundation (J.E.P.), the Arthritis National Research Foundation (M.G.-A.), Gilead Sciences Research Scholar grant (M.G.-A.), Lupus Research Alliance (M.G.-A.) and a Kennedy Trust KTRR Senior Research Fellowship (KENN202109) (Y.L).

© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.

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10.1038/s41588-023-01586-6

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Kang, J. B., Shen, A. Z., Gurajala, S., Nathan, A., Rumker, L., Aguiar, V. R. C., Valencia, C., Lagattuta, K. A., Zhang, F., Jonsson, A. H., Yazar, S., Alquicira-Hernandez, J., Khalili, H., Ananthakrishnan, A. N., Jagadeesh, K., Dey, K., Albrecht, J., Apruzzese, W., Banda, N., ... Raychaudhuri, S. (2023). Mapping the dynamic genetic regulatory architecture of HLA genes at single-cell resolution. Nature Genetics, 55(12), 2255-2268. https://doi.org/10.1038/s41588-023-01586-6

@article{935c2665a54542cbb2191091b2554aa8,

title = "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. To mitigate technical confounding, we developed scHLApers, a pipeline to accurately quantify single-cell HLA expression using personalized reference genomes. 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. For example, a T cell HLA-DQA1 eQTL ( rs3104371 ) is strongest in cytotoxic cells. Dynamic HLA regulation may underlie important interindividual variability in immune responses.",

author = "Kang, {Joyce B.} and Shen, {Amber Z.} and Saisriram Gurajala and Aparna Nathan and Laurie Rumker and Aguiar, {Vitor R. C.} and Cristian Valencia and Lagattuta, {Kaitlyn A.} and Fan Zhang and Jonsson, {Anna Helena} and Seyhan Yazar and Jose Alquicira-Hernandez and Hamed Khalili and Ananthakrishnan, {Ashwin N.} and Karthik Jagadeesh and Kushal Dey and Jennifer Albrecht and William Apruzzese and Nirmal Banda and Barnas, {Jennifer L.} and Bathon, {Joan M.} and Ami Ben-Artzi and Boyce, {Brendan F.} and Boyle, {David L.} and Bridges, {S. louis} and Bykerk, {Vivian P.} and Debbie Campbell and Carr, {Hayley l.} and Arnold Ceponis and Adam Chicoine and Andrew Cordle and Michelle Curtis and Deane, {Kevin D.} and Edward DiCarlo and Patrick Dunn and Andrew Filer and Firestein, {Gary S.} and Lindsy Forbess and Laura Geraldino-Pardilla and Goodman, {Susan M.} and Gravallese, {Ellen M.} and Gregersen, {Peter K.} and Guthridge, {Joel M.} and Holers, {V. Michael} and Diane Horowitz and Hughes, {Laura B.} and Kazuyoshi Ishigaki and Ivashkiv, {Lionel B.} and James, {Judith A.} and Gregory Keras and Ilya Korsunsky and Amit Lakhanpal and Lederer, {James A.} and Myles Lewis and Li, {Zhihan J.} and Yuhong Li and Liao, {Katherine P.} and Mandelin, {Arthur M.} and Ian Mantel and Marks, {Kathryne E.} and Mark Maybury and Andrew Mcdavid and Mcgeachy, {Mandy J.} and Joseph Mears and Nida Meednu and Nghia Millard and Moreland, {Larry W.} and Saba Nayar and Alessandra Nerviani and Orange, {Dana E.} and Harris Perlman and Constantino Pitzalis and Javier Rangel-Moreno and Karim Raza and Yakir Reshef and Christopher Ritchlin and Felice Rivellese and Robinson, {William H.} and Ilfita Sahbudin and Anvita Singaraju and Seifert, {Jennifer A.} and Kamil Slowikowski and Smith, {Melanie H.} and Darren Tabechian and Dagmar Scheel-Toellner and Utz, {Paul J.} and Watts, {Gerald F. M.} and Kevin Wei and Kathryn Weinand and Dana Weisenfeld and Weisman, {Michael H.} and Aaron Wyse and Qian Xiao and Zhu Zhu and Daly, {Mark J.} and Xavier, {Ramnik J.} and Donlin, {Laura T.} and Anolik, {Jennifer H.} and Powell, {Joseph E.} and Rao, {Deepak A.} and Brenner, {Michael B.} and Maria Gutierrez-Arcelus and Yang Luo and Saori Sakaue and Soumya Raychaudhuri",

note = "Acknowledgements: We thank A. Dobin, H. Randolph, H. Lau, C. Stevens and members of the Raychaudhuri Lab, in particular A. Gupta and Y. Baglaenko, for their helpful input and discussions. This work was funded by the National Institutes of Health grants T32GM007753 and T32GM144273 (J.B.K., L.R. and K.A.L.), F30AI172238 (J.B.K.), T32HG002295 (A.Z.S. and L.R.), T32AR007530 (A.N.), F30AI157385 (L.R.), R01AR063759 (S.R.), U01HG012009 (S.R.) and UC2AR081023 (S.R.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This project also received funding from the MGH Center for the Study of Inflammatory Bowel Disease grant DK-43351 (R.J.X.), a fellowship from the Fok Foundation (J.E.P.), the Arthritis National Research Foundation (M.G.-A.), Gilead Sciences Research Scholar grant (M.G.-A.), Lupus Research Alliance (M.G.-A.) and a Kennedy Trust KTRR Senior Research Fellowship (KENN202109) (Y.L). {\textcopyright} 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2023",

month = dec,

doi = "10.1038/s41588-023-01586-6",

language = "English",

volume = "55",

pages = "2255--2268",

journal = "Nature Genetics",

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number = "12",

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Kang, JB, Shen, AZ, Gurajala, S, Nathan, A, Rumker, L, Aguiar, VRC, Valencia, C, Lagattuta, KA, Zhang, F, Jonsson, AH, Yazar, S, Alquicira-Hernandez, J, Khalili, H, Ananthakrishnan, AN, Jagadeesh, K, Dey, K, Albrecht, J, Apruzzese, W, Banda, N, Barnas, JL, Bathon, JM, Ben-Artzi, A, Boyce, BF, Boyle, DL, Bridges, SL, Bykerk, VP, Campbell, D, Carr, HL, Ceponis, A, Chicoine, A, Cordle, A, Curtis, M, Deane, KD, DiCarlo, E, Dunn, P, Filer, A, Firestein, GS, Forbess, L, Geraldino-Pardilla, L, Goodman, SM, Gravallese, EM, Gregersen, PK, Guthridge, JM, Holers, VM, Horowitz, D, Hughes, LB, Ishigaki, K, Ivashkiv, LB, James, JA, Keras, G, Korsunsky, I, Lakhanpal, A, Lederer, JA, Lewis, M, Li, ZJ, Li, Y, Liao, KP, Mandelin, AM, Mantel, I, Marks, KE, Maybury, M, Mcdavid, A, Mcgeachy, MJ, Mears, J, Meednu, N, Millard, N, Moreland, LW, Nayar, S, Nerviani, A, Orange, DE, Perlman, H, Pitzalis, C, Rangel-Moreno, J, Raza, K, Reshef, Y, Ritchlin, C, Rivellese, F, Robinson, WH, Sahbudin, I, Singaraju, A, Seifert, JA, Slowikowski, K, Smith, MH, Tabechian, D, Scheel-Toellner, D, Utz, PJ, Watts, GFM, Wei, K, Weinand, K, Weisenfeld, D, Weisman, MH, Wyse, A, Xiao, Q, Zhu, Z, Daly, MJ, Xavier, RJ, Donlin, LT, Anolik, JH, Powell, JE, Rao, DA, Brenner, MB, Gutierrez-Arcelus, M, Luo, Y, Sakaue, S & Raychaudhuri, S 2023, 'Mapping the dynamic genetic regulatory architecture of HLA genes at single-cell resolution', Nature Genetics, vol. 55, no. 12, pp. 2255-2268. https://doi.org/10.1038/s41588-023-01586-6

TY - JOUR

T1 - Mapping the dynamic genetic regulatory architecture of HLA genes at single-cell resolution

AU - Kang, Joyce B.

AU - Shen, Amber Z.

AU - Gurajala, Saisriram

AU - Nathan, Aparna

AU - Rumker, Laurie

AU - Aguiar, Vitor R. C.

AU - Valencia, Cristian

AU - Lagattuta, Kaitlyn A.

AU - Zhang, Fan

AU - Jonsson, Anna Helena

AU - Yazar, Seyhan

AU - Alquicira-Hernandez, Jose

AU - Khalili, Hamed

AU - Ananthakrishnan, Ashwin N.

AU - Jagadeesh, Karthik

AU - Dey, Kushal

AU - Albrecht, Jennifer

AU - Apruzzese, William

AU - Banda, Nirmal

AU - Barnas, Jennifer L.

AU - Bathon, Joan M.

AU - Ben-Artzi, Ami

AU - Boyce, Brendan F.

AU - Boyle, David L.

AU - Bridges, S. louis

AU - Bykerk, Vivian P.

AU - Campbell, Debbie

AU - Carr, Hayley l.

AU - Ceponis, Arnold

AU - Chicoine, Adam

AU - Cordle, Andrew

AU - Curtis, Michelle

AU - Deane, Kevin D.

AU - DiCarlo, Edward

AU - Dunn, Patrick

AU - Filer, Andrew

AU - Firestein, Gary S.

AU - Forbess, Lindsy

AU - Geraldino-Pardilla, Laura

AU - Goodman, Susan M.

AU - Gravallese, Ellen M.

AU - Gregersen, Peter K.

AU - Guthridge, Joel M.

AU - Holers, V. Michael

AU - Horowitz, Diane

AU - Hughes, Laura B.

AU - Ishigaki, Kazuyoshi

AU - Ivashkiv, Lionel B.

AU - James, Judith A.

AU - Keras, Gregory

AU - Korsunsky, Ilya

AU - Lakhanpal, Amit

AU - Lederer, James A.

AU - Lewis, Myles

AU - Li, Zhihan J.

AU - Li, Yuhong

AU - Liao, Katherine P.

AU - Mandelin, Arthur M.

AU - Mantel, Ian

AU - Marks, Kathryne E.

AU - Maybury, Mark

AU - Mcdavid, Andrew

AU - Mcgeachy, Mandy J.

AU - Mears, Joseph

AU - Meednu, Nida

AU - Millard, Nghia

AU - Moreland, Larry W.

AU - Nayar, Saba

AU - Nerviani, Alessandra

AU - Orange, Dana E.

AU - Perlman, Harris

AU - Pitzalis, Constantino

AU - Rangel-Moreno, Javier

AU - Raza, Karim

AU - Reshef, Yakir

AU - Ritchlin, Christopher

AU - Rivellese, Felice

AU - Robinson, William H.

AU - Sahbudin, Ilfita

AU - Singaraju, Anvita

AU - Seifert, Jennifer A.

AU - Slowikowski, Kamil

AU - Smith, Melanie H.

AU - Tabechian, Darren

AU - Scheel-Toellner, Dagmar

AU - Utz, Paul J.

AU - Watts, Gerald F. M.

AU - Wei, Kevin

AU - Weinand, Kathryn

AU - Weisenfeld, Dana

AU - Weisman, Michael H.

AU - Wyse, Aaron

AU - Xiao, Qian

AU - Zhu, Zhu

AU - Daly, Mark J.

AU - Xavier, Ramnik J.

AU - Donlin, Laura T.

AU - Anolik, Jennifer H.

AU - Powell, Joseph E.

AU - Rao, Deepak A.

AU - Brenner, Michael B.

AU - Gutierrez-Arcelus, Maria

AU - Luo, Yang

AU - Sakaue, Saori

AU - Raychaudhuri, Soumya

N1 - Acknowledgements: We thank A. Dobin, H. Randolph, H. Lau, C. Stevens and members of the Raychaudhuri Lab, in particular A. Gupta and Y. Baglaenko, for their helpful input and discussions. This work was funded by the National Institutes of Health grants T32GM007753 and T32GM144273 (J.B.K., L.R. and K.A.L.), F30AI172238 (J.B.K.), T32HG002295 (A.Z.S. and L.R.), T32AR007530 (A.N.), F30AI157385 (L.R.), R01AR063759 (S.R.), U01HG012009 (S.R.) and UC2AR081023 (S.R.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This project also received funding from the MGH Center for the Study of Inflammatory Bowel Disease grant DK-43351 (R.J.X.), a fellowship from the Fok Foundation (J.E.P.), the Arthritis National Research Foundation (M.G.-A.), Gilead Sciences Research Scholar grant (M.G.-A.), Lupus Research Alliance (M.G.-A.) and a Kennedy Trust KTRR Senior Research Fellowship (KENN202109) (Y.L). © 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2023/12

Y1 - 2023/12

N2 - 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. To mitigate technical confounding, we developed scHLApers, a pipeline to accurately quantify single-cell HLA expression using personalized reference genomes. 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. For example, a T cell HLA-DQA1 eQTL ( rs3104371 ) is strongest in cytotoxic cells. Dynamic HLA regulation may underlie important interindividual variability in immune responses.

AB - 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. To mitigate technical confounding, we developed scHLApers, a pipeline to accurately quantify single-cell HLA expression using personalized reference genomes. 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. For example, a T cell HLA-DQA1 eQTL ( rs3104371 ) is strongest in cytotoxic cells. Dynamic HLA regulation may underlie important interindividual variability in immune responses.

U2 - 10.1038/s41588-023-01586-6

DO - 10.1038/s41588-023-01586-6

M3 - Article

C2 - 38036787

SN - 1061-4036

VL - 55

SP - 2255

EP - 2268

JO - Nature Genetics

JF - Nature Genetics

IS - 12

ER -

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

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Bibliographical note

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