An Accurate Genetic Colocalisation Method for the HLA Locus.
HLA 2026 May; 107(5):e70759.

Abstract

Genetic colocalisation analyses are frequently conducted to determine if causal signals at a genetic locus are shared between two phenotypes. However, colocalisation is rarely undertaken at the HLA locus, due to its complex linkage disequilibrium (LD) and high polymorphism density. This lack of genetic causal inference method limits our ability to translate HLA associations into therapeutic targets. Here we present a method that uses HLA alleles, instead of nucleotide variants, to perform genetic colocalisation of two traits at HLA genes. The method, which we call HLA-colocalisation, works by controlling for LD using a Bayesian variable selection algorithm (here implemented with SuSiE), then performing Bayesian regression on the resulting posterior inclusion probabilities. We first show through simulation that the method correctly identifies truly colocalising genes. We then test the method in two positive control scenarios, showing colocalisation between hepatitis B and liver disease at HLA-DPB1, and between Epstein-Barr virus and multiple sclerosis at HLA-DRB1 and HLA-DQB1. Finally, we perform a large colocalisation scan between multiple viruses and auto-immune diseases, demonstrating that the method is well calibrated and uncovering multiple biologically plausible novel causal associations, such as cytomegalovirus and ulcerative colitis. To our knowledge, HLA-colocalisation is the first accurate genetic colocalisation method for the HLA locus (github: https://github.com/DrGBL/hlacoloc).

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Authors+Show Affiliations

Butler-Laporte G0000-0001-5388-0396Centre for Human Genetics, University of Oxford, Oxford, UK. Lady Davis Institute, Jewish General Hospital, McGill University, Québec, Canada. Division of Infectious Diseases, McGill University Health Centre, Québec, Canada.
Lu T0000-0002-5664-5698Department of Statistical Sciences, University of Toronto, Toronto, Ontario, Canada. Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin, USA. Department of Population Health Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Morris SClinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
Zhang WMontreal Heart Institute, Montreal, Quebec, Canada.
Band GCentre for Human Genetics, University of Oxford, Oxford, UK.
Hamilton FMRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Infection Sciences, North Bristol NHS Trust, Bristol, UK.
Chong ACentre for Human Genetics, University of Oxford, Oxford, UK.
Lin KClinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
Nanjala RKennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
Richards JBLady Davis Institute, Jewish General Hospital, McGill University, Québec, Canada. Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montréal, Québec, Canada. Department of Human Genetics, McGill University, Montréal, Québec, Canada. Department of Twin Research, King's College London, London, UK. 5 Prime Sciences Inc, Montreal, Quebec, Canada.
Lee MHInstitute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
Yang L0000-0001-5750-6588Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
Yao PClinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
Li LDepartment of Epidemiology & Biostatistics, School of Public Health, Peking University, Beijing, China. Peking University Center for Public Health and Epidemic Preparedness and Response, Beijing, China. Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, China.
Chen ZClinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
Luo YKennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
Millwood IYClinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
Walters RGClinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
Mentzer AJCentre for Human Genetics, University of Oxford, Oxford, UK. Chinese Academy of Medical Science Oxford Institute, University of Oxford, Oxford, UK.

MeSH

HumansLinkage DisequilibriumBayes TheoremAlgorithmsAllelesHLA-DRB1 ChainsHLA-DQ beta-ChainsHLA-DP beta-ChainsMultiple SclerosisHepatitis BHerpesvirus 4, HumanGenetic Predisposition to DiseaseModels, Genetic

Pub Type(s)

Journal Article

Language

eng

PubMed ID

42174329