Genetic Association in the HLA Region

  • Loukas MoutsianasEmail author
  • Javier Gutierrez-Achury
Part of the Methods in Molecular Biology book series (MIMB, volume 1793)


The MHC/HLA region has been consistently associated with a large number of complex traits, including but not limited to, most immune-mediated ones. Efforts to pinpoint drivers of this commonly encountered association peak at the short arm of chromosome 6, however, have been challenging, owing to the high density of genes and the long and extended linkage disequilibrium that are characteristic of this region.

The development of methods to impute classical HLA alleles and amino acids from SNP genotyping data has offered an important additional layer of information to the investigators seeking to fine map the signal in the region. As a result, imputation-aided association analyses are now typically employed to shed light on the relationship of this locus with disease susceptibility and response to drugs.

In this chapter we discuss how the signal in the HLA region can be interrogated in practice, from performing the imputation to understanding its output and to incorporating it into downstream analysis. In addition, we recount some of the analytical approaches that are commonly used and suggest ways in which the findings from such imputation-aided analyses can be interpreted.

Key words

HLA MHC Imputation Association studies Immune-mediated diseases Autoimmunity HLA*IMP:02 SNP2HLA HIBAG 


  1. 1.
    Trowsdale J, Knight JC (2013) Major histocompatibility complex genomics and human disease. Annu Rev Genomics Hum Genet 14:301–323. CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Moon J, Kim TJ, Lim JA et al (2016) HLA-B*40:02 and DRB1*04:03 are risk factors for oxcarbazepine-induced maculopapular eruption. Epilepsia 57:1879. CrossRefPubMedGoogle Scholar
  3. 3.
    Sousa-Pinto B, Correia C, Gomes L et al (2016) HLA and delayed drug-induced hypersensitivity. Int Arch Allergy Immunol 170(3):163–179. CrossRefPubMedGoogle Scholar
  4. 4.
    Stamp LK, Day RO, Yun J (2016) Allopurinol hypersensitivity: investigating the cause and minimizing the risk. Nat Rev Rheumatol 12(4):235–242. CrossRefPubMedGoogle Scholar
  5. 5.
    Voorter CE, Palusci F, Tilanus MG (2014) Sequence-based typing of HLA: an improved group-specific full-length gene sequencing approach. Methods Mol Biol 1109:101–114. CrossRefPubMedGoogle Scholar
  6. 6.
    Ehrenberg PK, Geretz A, Baldwin KM et al (2014) High-throughput multiplex HLA genotyping by next-generation sequencing using multi-locus individual tagging. BMC Genomics 15:864. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Hosomichi K, Jinam TA, Mitsunaga S et al (2013) Phase-defined complete sequencing of the HLA genes by next-generation sequencing. BMC Genomics 14:355. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    de Bakker PI, McVean G, Sabeti PC et al (2006) A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. Nat Genet 38(10):1166–1172. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Dilthey AT, Moutsianas L, Leslie S et al (2011) HLA*IMP – an integrated framework for imputing classical HLA alleles from SNP genotypes. Bioinformatics 27(7):968–972. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Dilthey A, Leslie S, Moutsianas L et al (2013) Multi-population classical HLA type imputation. PLoS Comput Biol 9(2):e1002877. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Jia X, Han B, Onengut-Gumuscu S et al (2013) Imputing amino acid polymorphisms in human leukocyte antigens. PLoS One 8(6):e64683. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Zheng X, Shen J, Cox C et al (2014) HIBAG – HLA genotype imputation with attribute bagging. Pharmacogenomics J 14(2):192–200. CrossRefPubMedGoogle Scholar
  13. 13.
    Erlich RL, Jia X, Anderson S et al (2011) Next-generation sequencing for HLA typing of class I loci. BMC Genomics 12:42. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Leslie S, Donnelly P, McVean G (2008) A statistical method for predicting classical HLA alleles from SNP data. Am J Hum Genet 82(1):48–56. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Li N, Stephens M (2003) Modeling linkage disequilibrium and identifying recombination hotspots using single-nucleotide polymorphism data. Genetics 165(4):2213–2233PubMedPubMedCentralGoogle Scholar
  16. 16.
    Okada Y, Momozawa Y, Ashikawa K et al (2015) Construction of a population-specific HLA imputation reference panel and its application to Graves' disease risk in Japanese. Nat Genet 47(7):798–802. CrossRefPubMedGoogle Scholar
  17. 17.
    Zhou F, Cao H, Zuo X et al (2016) Deep sequencing of the MHC region in the Chinese population contributes to studies of complex disease. Nat Genet 48(7):740–746. CrossRefPubMedGoogle Scholar
  18. 18.
    Kim K, Bang SY, Lee HS et al (2014) Construction and application of a Korean reference panel for imputing classical alleles and amino acids of human leukocyte antigen genes. PLoS One 9(11):e112546. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Marsh SG, Albert ED, Bodmer WF et al (2010) Nomenclature for factors of the HLA system, 2010. Tissue Antigens 75(4):291–455. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Robinson J, Soormally AR, Hayhurst JD et al (2016) The IPD-IMGT/HLA database - new developments in reporting HLA variation. Hum Immunol 77(3):233–237. CrossRefPubMedGoogle Scholar
  21. 21.
    Anderson CA, Pettersson FH, Clarke GM et al (2010) Data quality control in genetic case-control association studies. Nat Protoc 5(9):1564–1573. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Moutsianas L, Jostins L, Beecham AH et al (2015) Class II HLA interactions modulate genetic risk for multiple sclerosis. Nat Genet 47(10):1107–1113. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Marchini J, Howie B (2010) Genotype imputation for genome-wide association studies. Nat Rev Genet 11(7):499–511. CrossRefPubMedGoogle Scholar
  24. 24.
    Wellcome Trust Case Control Consortium (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447(7145):661–678. CrossRefGoogle Scholar
  25. 25.
    Chang CC, Chow CC, Tellier LC et al (2015) Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience 4:7. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Evans DM, Spencer CC, Pointon JJ et al (2011) Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nat Genet 43(8):761–767. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Genetic Analysis of Psoriasis Consortium and the Wellcome Trust Case Control Consortium, Strange A, Capon F et al (2010) A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nat Genet 42(11):985–990. CrossRefGoogle Scholar
  28. 28.
    Todd JA, Bell JI, McDevitt HO (1987) HLA-DQ beta gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature 329(6140):599–604. CrossRefPubMedGoogle Scholar
  29. 29.
    Gutierrez-Achury J, Zhernakova A, Pulit SL et al (2015) Fine mapping in the MHC region accounts for 18% additional genetic risk for celiac disease. Nat Genet 47(6):577–578. CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Patsopoulos NA, Barcellos LF, Hintzen RQ et al (2013) Fine-mapping the genetic association of the major histocompatibility complex in multiple sclerosis: HLA and non-HLA effects. PLoS Genet 9(11):e1003926. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    McMahon G, Ring SM, Davey-Smith G et al (2015) Genome-wide association study identifies SNPs in the MHC class II loci that are associated with self-reported history of whooping cough. Hum Mol Genet 24(20):5930–5939. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Moutsianas L, Enciso-Mora V, Ma YP et al (2011) Multiple Hodgkin lymphoma-associated loci within the HLA region at chromosome 6p21.3. Blood 118(3):670–674. CrossRefPubMedGoogle Scholar
  33. 33.
    Goyette P, Boucher G, Mallon D et al (2015) High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis. Nat Genet 47(2):172–179. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Oksenberg JR, Barcellos LF, Cree BA et al (2004) Mapping multiple sclerosis susceptibility to the HLA-DR locus in African Americans. Am J Hum Genet 74(1):160–167. CrossRefPubMedGoogle Scholar
  35. 35.
    Han F, Lin L, Li J et al (2012) HLA-DQ association and allele competition in Chinese narcolepsy. Tissue Antigens 80(4):328–335. CrossRefPubMedGoogle Scholar
  36. 36.
    Mignot E, Kimura A, Lattermann A et al (1997) Extensive HLA class II studies in 58 non-DRB1*15 (DR2) narcoleptic patients with cataplexy. Tissue Antigens 49(4):329–341CrossRefPubMedGoogle Scholar
  37. 37.
    Liu C, Yang X, Duffy B et al (2013) ATHLATES: accurate typing of human leukocyte antigen through exome sequencing. Nucleic Acids Res 41(14):e142. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Szolek A, Schubert B, Mohr C et al (2014) OptiType: precision HLA typing from next-generation sequencing data. Bioinformatics 30(23):3310–3316. CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Dilthey AT, Gourraud PA, Mentzer AJ et al (2016) High-accuracy HLA type inference from whole-genome sequencing data using population reference graphs. PLoS Comput Biol 12(10):e1005151. CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Boegel S, Scholtalbers J, Lower M et al (2015) In silico HLA typing using standard RNA-Seq sequence reads. Methods Mol Biol 1310:247–258. CrossRefPubMedGoogle Scholar
  41. 41.
    Browning BL, Browning SR (2009) A unified approach to genotype imputation and haplotype-phase inference for large data sets of trios and unrelated individuals. Am J Hum Genet 84(2):210–223. CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Wissemann WT, Hill-Burns EM, Zabetian CP et al (2013) Association of Parkinson disease with structural and regulatory variants in the HLA region. Am J Hum Genet 93(5):984–993. CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Chen D, Gaborieau V, Zhao Y et al (2015) A systematic investigation of the contribution of genetic variation within the MHC region to HPV seropositivity. Hum Mol Genet 24(9):2681–2688. CrossRefPubMedGoogle Scholar
  44. 44.
    Hu X, Deutsch AJ, Lenz TL et al (2015) Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk. Nat Genet 47(8):898–905. CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Lenz TL, Deutsch AJ, Han B et al (2015) Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases. Nat Genet 47(9):1085–1090. CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Field J, Browning SR, Johnson LJ et al (2010) A polymorphism in the HLA-DPB1 gene is associated with susceptibility to multiple sclerosis. PLoS One 5(10):e13454. CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Sekar A, Bialas AR, de Rivera H et al (2016) Schizophrenia risk from complex variation of complement component 4. Nature 530(7589):177–183. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.The Wellcome Trust Sanger InstituteCambridgeshireUK

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