Abstract

To identify susceptibility loci for visceral leishmaniasis, we undertook genome-wide association studies in two populations: 989 cases and 1,089 controls from India and 357 cases in 308 Brazilian families (1,970 individuals). The HLA-DRB1HLA-DQA1 locus was the only region to show strong evidence of association in both populations. Replication at this region was undertaken in a second Indian population comprising 941 cases and 990 controls, and combined analysis across the three cohorts for rs9271858 at this locus showed Pcombined = 2.76 × 10−17 and odds ratio (OR) = 1.41, 95% confidence interval (CI) = 1.30–1.52. A conditional analysis provided evidence for multiple associations within the HLA-DRB1HLA-DQA1 region, and a model in which risk differed between three groups of haplotypes better explained the signal and was significant in the Indian discovery and replication cohorts. In conclusion, the HLA-DRB1HLA-DQA1 HLA class II region contributes to visceral leishmaniasis susceptibility in India and Brazil, suggesting shared genetic risk factors for visceral leishmaniasis that cross the epidemiological divides of geography and parasite species.

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Acknowledgements

The principal funding for this study was provided by the Wellcome Trust, as part of the WTCCC2 project (085475/B/08/Z and 085475/Z/08/Z). We thank S. Bertrand, J. Bryant, S.L. Clark, J.S. Conquer, T. Dibling, J.C. Eldred, S. Gamble, C. Hind, M.L. Perez, C.R. Stribling, S. Taylor and A. Wilk of the Wellcome Trust Sanger Institute's Sample and Genotyping Facilities for technical assistance. We thank D. Davison for making available his Shellfish program for calculating principal components in large genetic data sets. C.C.A.S. is supported by a Wellcome Trust Fellowship (097364/Z/11/Z). H.J.C. is supported by a Wellcome Senior Fellowship in Basic Biomedical Science (087436/Z/10/Z). P. Donnelly is supported in part by a Royal Society Wolfson Merit Award, and work was supported in part by Wellcome Trust Centre for Human Genetics core grants 090532/Z/09/Z and 075491/Z/04/B. Collection of samples and epidemiological data, sample preparation and sequence-based HLA typing were supported by grants from the Wellcome Trust (074196/Z/04/Z and 085475/Z/08/Z to J.M.B., S.S., S.M.B.J. and M.E.W.) and the US National Institutes of Health (Tropical Medicine Research Center award P50AI074321 to S.S. in India; Tropical Medicine Research Center award P50 AI-30639 to E.M. Carvalho and S.M.B.J. in Brazil; and R01 AI076233 to M.E.W. and J.M.B.; R01 AI048822 to M.E.W., S.M.B.J. and J.M.B.). We give special thanks to all subjects who contributed samples and to clinicians and field staff in India and Brazil who helped with the recruitment of study subjects.

Author information

Author notes

    • E Nancy Miller
    •  & Leena Peltonen

    Deceased.

    • Michaela Fakiola
    •  & Amy Strange

    These authors contributed equally to this work.

    • Jenefer M Blackwell
    •  & Peter Donnelly

    These authors jointly directed this work.

Affiliations

  1. Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK.

    • Michaela Fakiola
    • , E Nancy Miller
    •  & Jenefer M Blackwell
  2. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Amy Strange
    • , Matti Pirinen
    • , Zhan Su
    • , Gavin Band
    • , Céline Bellenguez
    • , Colin Freeman
    • , Eleni Giannoulatou
    • , Richard Pearson
    • , Damjan Vukcevic
    • , Anna Rautanen
    • , Chris C A Spencer
    •  & Peter Donnelly
  3. Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.

    • Heather J Cordell
  4. Institute of Medical Sciences, Banaras Hindu University, Varanasi, India.

    • Anshuman Mishra
    • , Sanjana Mehrotra
    • , Madhukar Rai
    • , Shri P Singh
    •  & Shyam Sundar
  5. Department of Biochemistry, Center for Biosciences, Universidade Federal do Rio Grande do Norte, Natal, Brazil.

    • Gloria R Monteiro
    • , Núbia N Pontes
    • , Olivia Sousa
    •  & Selma M B Jeronimo
  6. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

    • Serge Dronov
    • , Sarah Edkins
    • , Emma Gray
    • , Sarah E Hunt
    • , Cordelia Langford
    • , Panos Deloukas
    •  & Leena Peltonen
  7. Department of Infectious Diseases, Universidade Federal do Rio Grande do Norte, Natal, Brazil.

    • Henio G Lacerda
  8. Department of Clinical Immunology, Royal Perth Hospital, Perth, Western Australia, Australia.

    • Linda Smith
    • , Frank Christiansen
    •  & Campbell Witt
  9. National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health at the South London and Maudsley National Health Service (NHS) Foundation Trust and Institute of Psychiatry King's College London, London, UK.

    • Elvira Bramon
  10. University of Queensland Diamantina Institute, Princess Alexandra Hospital, University of Queensland, Brisbane, Queensland, Australia.

    • Matthew A Brown
  11. Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK.

    • Juan P Casas
  12. Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland.

    • Aiden Corvin
  13. Molecular and Physiological Sciences, The Wellcome Trust, London, UK.

    • Audrey Duncanson
  14. Department of Oncology, University of Oxford, Oxford, UK.

    • Janusz Jankowski
  15. Stroke and Dementia Research Group, St George's University of London, London, UK.

    • Hugh S Markus
  16. Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London, UK.

    • Christopher G Mathew
  17. Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.

    • Colin N A Palmer
  18. Social, Genetic and Developmental Psychiatry Centre, King's College London Institute of Psychiatry, London, UK.

    • Robert Plomin
  19. Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.

    • Stephen J Sawcer
  20. Oxford Centre for Diabetes, Endocrinology and Metabolism (ICDEM), Churchill Hospital, Oxford, UK.

    • Richard C Trembath
  21. NIHR Biomedical Centre for Ophthalmology at Moorfields Eye Hospital NHS Foundation Trust, London, UK.

    • Ananth C Viswanathan
  22. University College London (UCL) Institute of Ophthalmology, London, UK.

    • Ananth C Viswanathan
  23. Department of Molecular Neuroscience, Institute of Neurology, London, UK.

    • Nicholas W Wood
  24. Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.

    • Mary E Wilson
  25. Veterans Affairs (VA) Medical Center, Iowa City, Iowa, USA.

    • Mary E Wilson
  26. Telethon Institute for Child Health Research, Centre for Child Health Research, The University of Western Australia, Subiaco, Western Australia, Australia.

    • Jenefer M Blackwell
  27. Department of Statistics, University of Oxford, Oxford, UK.

    • Peter Donnelly

Consortia

  1. LeishGEN Consortium

    A full list of members and affiliations is provided in the Supplementary Note.

  2. Wellcome Trust Case Control Consortium 2

    A full list of members and affiliations is provided in the Supplementary Note.

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Contributions

M.F., E.N.M., A.M., S.M., G.R.M., H.G.L., N.N.P., M.R., S.P.S., O.S., M.E.W., S.M.B.J., S.S. and J.M.B. oversaw cohort collections for LeishGEN. The WTCCC2 DNA, genotyping, data quality control and informatics group (S.D., S.E., E. Gray, S.E.H. and C.L.) executed GWAS sample handling, genotyping and quality control. The WTCCC2 Management Committee (P. Donnelly, J.M.B., E.B., M.A.B., J.P.C., A.C., P. Deloukas, A.D., J.J., H.S.M., C.G.M., C.N.A.P., R. Plomin, A.R., S.J.S., R.C.T., A.C.V., L.P. and N.W.W.) monitored the execution of the GWAS. A.S., M.F., H.J.C., M.P., Z.S., G.B., C.B., C.F., E. Giannoulatou, R. Pearson, D.V. and C.C.A.S. performed statistical analyses. L.S., F.C. and C.W. oversaw HLA typing and interpretation. A.S., M.F., H.J.C., C.C.A.S., J.M.B. and P. Donnelly contributed to writing the manuscript. All authors reviewed the final manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Jenefer M Blackwell or Peter Donnelly.

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https://doi.org/10.1038/ng.2518

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