Cell-type–specific eQTL of primary melanocytes facilitates identification of melanoma susceptibility genes

  1. Kevin M. Brown1,8
  1. 1Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;
  2. 2Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;
  3. 3Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;
  4. 4Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, LS9 7TF, United Kingdom;
  5. 5Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia;
  6. 6Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
  7. 11Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia;
  8. 12Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, LS9 7TF, UK;
  9. 13Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA;
  10. 14INSERM, UMR 946, Genetic Variation and Human Diseases Unit, 75013 Paris, France;
  11. 15Institut Universitaire d'Hématologie, Université Paris Diderot, Sorbonne Paris Cité, 75013 Paris, France;
  12. 16Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia;
  13. 17Centre for Genetic Origins of Health and Disease, Faculty of Medicine, Dentistry and Health Sciences, University of Western Australia, Perth, Western Australia, 6009, Australia;
  14. 18Department of Epidemiology and Biostatistics, Key Laboratory of Cancer Prevention and Therapy, Tianjin, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China;
  15. 19Division of Molecular Genetic Epidemiology, German Cancer Research Center, 69120 Heidelberg, Germany;
  16. 20Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB2 1TN, UK;
  17. 21Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB2 1TN, UK;
  18. 22Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW3 6JB, UK;
  19. 23Division of Breast Cancer Research, The Institute of Cancer Research, London SW3 6JB, UK;
  20. 24Department of Dermatology, University of Athens School of Medicine, Andreas Sygros Hospital, Athens 161 21, Greece;
  21. 25Centre for Cancer Biomarkers (CCBIO), Department of Clinical Medicine, University of Bergen, 5007 Bergen, Norway;
  22. 26Department of Pathology, Haukeland University Hospital, 5021 Bergen, Norway;
  23. 27Department of Pathology, Molecular Pathology, Oslo University Hospital, Rikshospitalet, 0372 Oslo, Norway;
  24. 28Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Service de Dermatologie, Université Paris Descartes, 75006 Paris, France;
  25. 29Department of Dermatology, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv 6997801, Israel;
  26. 30Oncogenetics Unit, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel;
  27. 31Department of Internal Medicine and Medical Specialties, University of Genoa, 16126 Genova GE, Italy;
  28. 32Laboratory of Genetics of Rare Cancers, Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria (IRCCS AOU) San Martino l'Istituto Scientifico Tumori Istituto Nazionale per la Ricerca sul Cancro, 16132 Genova GE, Italy;
  29. 33Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Bethesda, MD 20892, USA;
  30. 34International Hereditary Cancer Center, Pomeranian Medical University, 70-204 Szczecin, Poland;
  31. 35Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA;
  32. 36Université Paris 13, Equipe de Recherche en Epidémiologie Nutritionnelle (EREN), Centre de Recherche en Epidémiologie et Statistiques, INSERM U1153, Institut National de la Recherche Agronomique (INRA) U1125, Conservatoire National des Arts et Métiers, Communauté d'Université Sorbonne Paris Cité, 93000 Bobigny, France;
  33. 37Inherited Disease Research Branch, National Human Genome Research Institute, US National Institutes of Health, Baltimore, MD 21224, USA;
  34. 38Department of Dermatology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands;
  35. 39Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, 171 76 Solna, Sweden;
  36. 40Department of Dermatology, Oslo University Hospital, Rikshospitalet, 0372 Oslo, Norway;
  37. 41Department of Surgical Oncology, Institute of Oncology Ljubljana, 1000 Ljubljana, Slovenia;
  38. 42Department of Surgery, Clinical Sciences, Lund University, P663+Q9 Lund, Sweden;
  39. 43Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612 USA;
  40. 44Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
  41. 45Department of Medical Genetics, University of Glasgow, Glasgow G12 8QQ, UK;
  42. 46McGill University and Génome Québec Innovation Centre, Montreal, QC H3A 0G1, Canada;
  43. 47Department of Public Health, University of Glasgow, Glasgow G12 8QQ, UK;
  44. 48Centre for Cancer Research, University of Sydney at Westmead, Millennium Institute for Medical Research and Melanoma Institute Australia, Sydney, NSW 2145, Australia;
  45. 49Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, 5007 Bergen, Norway;
  46. 50Molecular Biology, the University of Queensland, Brisbane, QLD 4072, Australia;
  47. 51Department of Molecular Diagnostics, Institute of Oncology Ljubljana, 1000 Ljubljana, Slovenia;
  48. 52Department of Oncology/Pathology, Clinical Sciences, Lund University, P663+Q9 Lund, Sweden;
  49. 53Department of Cancer Epidemiology, Clinical Sciences, Lund University, P663+Q9 Lund, Sweden;
  50. 54Melanoma Unit, Departments of Dermatology, Biochemistry and Molecular Genetics, Hospital Clinic, Institut d'Investigacions Biomèdica August Pi Suñe, Universitat de Barcelona, 08007 Barcelona, Spain;
  51. 55Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Raras, Instituto de Salud Carlos III, Planta 0 28029 Madrid, Spain;
  52. 56Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN 46202, USA;
  53. 57Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, IN 46202, USA;
  54. 58Department of Dermatology, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA;
  55. 59Inflammatory Bowel Diseases, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia;
  56. 60Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane, QLD 4029, Australia;
  57. 61University of Queensland School of Medicine, Herston Campus, Brisbane, QLD 4072, Australia;
  58. 62Department of Clinical Genetics, Center of Human and Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands;
  59. 63Cancer Control Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia;
  60. 64Department of Ophthalmology, Flinders University, Adelaide, SA 5042, Australia;
  61. 65Department of Dermatology, University Hospital Essen, 45147 Essen, Germany;
  62. 66German Consortium for Translational Cancer Research (DKTK), 69120 Heidelberg, Germany;
  63. 67Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7005, Australia;
  64. 68Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD 4000, Australia;
  65. 69Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London SM2 5NG, UK;
  66. 70Cancer Epidemiology and Services Research, Sydney School of Public Health, University of Sydney, Sydney, NSW 2006, Australia;
  67. 71Oncogenomics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia;
  68. 72Department of Dermatology, Fachklinik Hornheide, Institute for Tumors of the Skin at the University of Münster, 48149 Münster, Germany;
  69. 73Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA;
  70. 74NIH Intramural Sequencing Center, Bethesda, MD 20892, USA

    1. ↵7 These authors are co-first authors and contributed equally to this work.

    2. ↵8 These authors are co-senior authors and contributed equally to this work.

  1. Corresponding authors: bpavan{at}mail.nih.gov, kevin.brown3{at}nih.gov

    2. Abstract

    Most expression quantitative trait locus (eQTL) studies to date have been performed in heterogeneous tissues as opposed to specific cell types. To better understand the cell-type–specific regulatory landscape of human melanocytes, which give rise to melanoma but account for <5% of typical human skin biopsies, we performed an eQTL analysis in primary melanocyte cultures from 106 newborn males. We identified 597,335 cis-eQTL SNPs prior to linkage disequilibrium (LD) pruning and 4997 eGenes (FDR < 0.05). Melanocyte eQTLs differed considerably from those identified in the 44 GTEx tissue types, including skin. Over a third of melanocyte eGenes, including key genes in melanin synthesis pathways, were unique to melanocytes compared to those of GTEx skin tissues or TCGA melanomas. The melanocyte data set also identified trans-eQTLs, including those connecting a pigmentation-associated functional SNP with four genes, likely through cis-regulation of IRF4. Melanocyte eQTLs are enriched in cis-regulatory signatures found in melanocytes as well as in melanoma-associated variants identified through genome-wide association studies. Melanocyte eQTLs also colocalized with melanoma GWAS variants in five known loci. Finally, a transcriptome-wide association study using melanocyte eQTLs uncovered four novel susceptibility loci, where imputed expression levels of five genes (ZFP90, HEBP1, MSC, CBWD1, and RP11-383H13.1) were associated with melanoma at genome-wide significant P-values. Our data highlight the utility of lineage-specific eQTL resources for annotating GWAS findings, and present a robust database for genomic research of melanoma risk and melanocyte biology.

    Footnotes

    • ↵9 A complete list of the NISC Comparative Sequencing Program authors appears at the end of this paper.

    • ↵10 A complete list of the Melanoma Meta-Analysis Consortium authors appears at the end of this paper.

    • [Supplemental material is available for this article.]

    • Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.233304.117.

    • Received December 7, 2017.
    • Accepted September 21, 2018.

    This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

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    1. Published in Advance October 17, 2018, doi: 10.1101/gr.233304.117 Genome Res. 28: 1621-1635 © 2018 Zhang et al.; Published by Cold Spring Harbor Laboratory Press

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    1. Profile for Brown, K. M.http://orcid.org/0000-0002-8558-6711

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