Genetic fine mapping of systemic lupus erythematosus MHC associations in Europeans and African Americans

Ken B. Hanscombe, David L. Morris, Janelle A. Noble, Alexander T. Dilthey, Philip Tombleson, Kenneth M. Kaufman, Mary Comeau, Carl D. Langefeld, Marta E. Alarcon-Riquelme, Patrick M. Gaffney, Chaim O. Jacob, Kathy L. Sivils, Betty P. Tsao, Graciela S. Alarcon, Elizabeth E. Brown, Jennifer Croker, Jeff Edberg, Gary Gilkeson, Judith A. James, Diane L. Kamen & 16 others Jennifer A. Kelly, Joseph McCune, Joan T. Merrill, Michelle Petri, Rosalind Ramsey-Goldman, John D. Reveille, Jane E. Salmon, Hal Scofield, Tammy Utset, Daniel J. Wallace, Michael H. Weisman, Robert P. Kimberly, John B. Harley, Cathryn M. Lewis, Lindsey A. Criswell, Timothy J. Vyse

Research output: Contribution to journalArticle

Abstract

Genetic variation within the major histocompatibility complex (MHC) contributes substantial risk for systemic lupus erythematosus, but high gene density, extreme polymorphism and extensive linkage disequilibrium (LD) have made fine mapping challenging. To address the problem, we compared two association techniques in two ancestrally diverse populations, African Americans (AAs) and Europeans (EURs). We observed a greater number of Human Leucocyte Antigen (HLA) alleles in AA consistent with the elevated level of recombination in this population. In EUR we observed 50 different A-C-B-DRB1-DQA-DQB multilocus haplotype sequences per hundred individuals; in the AA sample, these multilocus haplotypes were twice as common compared to Europeans. We also observed a strong narrow class II signal in AA as opposed to the long-range LD observed in EUR that includes class I alleles. We performed a Bayesian model choice of the classical HLA alleles and a frequentist analysis that combined both single nucleotide polymorphisms (SNPs) and classical HLA alleles. Both analyses converged on a similar subset of risk HLA alleles: in EUR HLA- B*08:01 + B*18:01 + (DRB1*15:01 frequentist only) + DQA*01:02 + DQB*02:01 + DRB3*02 and in AA HLA-C*17:01 + B*08:01 + DRB1*15:03 + (DQA*01:02 frequentist only) + DQA*02:01 + DQA*05:01+ DQA*05:05 + DQB*03:19 + DQB*02:02. We observed two additional independent SNP associations in both populations: EUR rs146903072 and rs501480; AA rs389883 and rs114118665. The DR2 serotype was best explained by DRB1*15:03 + DQA*01:02 in AA and by DRB1*15:01 + DQA*01:02 in EUR. The DR3 serotype was best explained by DQA*05:01 in AA and by DQB*02:01 in EUR. Despite some differences in underlying HLA allele risk models in EUR and AA, SNP signals across the extended MHC showed remarkable similarity and significant concordance in direction of effect for risk-associated variants.

Original languageEnglish (US)
Pages (from-to)3813-3824
Number of pages12
JournalHuman Molecular Genetics
Volume27
Issue number21
DOIs
StatePublished - Nov 1 2018

Fingerprint

Major Histocompatibility Complex
African Americans
Systemic Lupus Erythematosus
HLA Antigens
Alleles
Single Nucleotide Polymorphism
Linkage Disequilibrium
Haplotypes
Population
Genetic Recombination
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Hanscombe, K. B., Morris, D. L., Noble, J. A., Dilthey, A. T., Tombleson, P., Kaufman, K. M., ... Vyse, T. J. (2018). Genetic fine mapping of systemic lupus erythematosus MHC associations in Europeans and African Americans. Human Molecular Genetics, 27(21), 3813-3824. https://doi.org/10.1093/hmg/ddy280

Genetic fine mapping of systemic lupus erythematosus MHC associations in Europeans and African Americans. / Hanscombe, Ken B.; Morris, David L.; Noble, Janelle A.; Dilthey, Alexander T.; Tombleson, Philip; Kaufman, Kenneth M.; Comeau, Mary; Langefeld, Carl D.; Alarcon-Riquelme, Marta E.; Gaffney, Patrick M.; Jacob, Chaim O.; Sivils, Kathy L.; Tsao, Betty P.; Alarcon, Graciela S.; Brown, Elizabeth E.; Croker, Jennifer; Edberg, Jeff; Gilkeson, Gary; James, Judith A.; Kamen, Diane L.; Kelly, Jennifer A.; McCune, Joseph; Merrill, Joan T.; Petri, Michelle; Ramsey-Goldman, Rosalind; Reveille, John D.; Salmon, Jane E.; Scofield, Hal; Utset, Tammy; Wallace, Daniel J.; Weisman, Michael H.; Kimberly, Robert P.; Harley, John B.; Lewis, Cathryn M.; Criswell, Lindsey A.; Vyse, Timothy J.

In: Human Molecular Genetics, Vol. 27, No. 21, 01.11.2018, p. 3813-3824.

Research output: Contribution to journalArticle

Hanscombe, KB, Morris, DL, Noble, JA, Dilthey, AT, Tombleson, P, Kaufman, KM, Comeau, M, Langefeld, CD, Alarcon-Riquelme, ME, Gaffney, PM, Jacob, CO, Sivils, KL, Tsao, BP, Alarcon, GS, Brown, EE, Croker, J, Edberg, J, Gilkeson, G, James, JA, Kamen, DL, Kelly, JA, McCune, J, Merrill, JT, Petri, M, Ramsey-Goldman, R, Reveille, JD, Salmon, JE, Scofield, H, Utset, T, Wallace, DJ, Weisman, MH, Kimberly, RP, Harley, JB, Lewis, CM, Criswell, LA & Vyse, TJ 2018, 'Genetic fine mapping of systemic lupus erythematosus MHC associations in Europeans and African Americans', Human Molecular Genetics, vol. 27, no. 21, pp. 3813-3824. https://doi.org/10.1093/hmg/ddy280
Hanscombe KB, Morris DL, Noble JA, Dilthey AT, Tombleson P, Kaufman KM et al. Genetic fine mapping of systemic lupus erythematosus MHC associations in Europeans and African Americans. Human Molecular Genetics. 2018 Nov 1;27(21):3813-3824. https://doi.org/10.1093/hmg/ddy280
Hanscombe, Ken B. ; Morris, David L. ; Noble, Janelle A. ; Dilthey, Alexander T. ; Tombleson, Philip ; Kaufman, Kenneth M. ; Comeau, Mary ; Langefeld, Carl D. ; Alarcon-Riquelme, Marta E. ; Gaffney, Patrick M. ; Jacob, Chaim O. ; Sivils, Kathy L. ; Tsao, Betty P. ; Alarcon, Graciela S. ; Brown, Elizabeth E. ; Croker, Jennifer ; Edberg, Jeff ; Gilkeson, Gary ; James, Judith A. ; Kamen, Diane L. ; Kelly, Jennifer A. ; McCune, Joseph ; Merrill, Joan T. ; Petri, Michelle ; Ramsey-Goldman, Rosalind ; Reveille, John D. ; Salmon, Jane E. ; Scofield, Hal ; Utset, Tammy ; Wallace, Daniel J. ; Weisman, Michael H. ; Kimberly, Robert P. ; Harley, John B. ; Lewis, Cathryn M. ; Criswell, Lindsey A. ; Vyse, Timothy J. / Genetic fine mapping of systemic lupus erythematosus MHC associations in Europeans and African Americans. In: Human Molecular Genetics. 2018 ; Vol. 27, No. 21. pp. 3813-3824.
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T1 - Genetic fine mapping of systemic lupus erythematosus MHC associations in Europeans and African Americans

AU - Hanscombe, Ken B.

AU - Morris, David L.

AU - Noble, Janelle A.

AU - Dilthey, Alexander T.

AU - Tombleson, Philip

AU - Kaufman, Kenneth M.

AU - Comeau, Mary

AU - Langefeld, Carl D.

AU - Alarcon-Riquelme, Marta E.

AU - Gaffney, Patrick M.

AU - Jacob, Chaim O.

AU - Sivils, Kathy L.

AU - Tsao, Betty P.

AU - Alarcon, Graciela S.

AU - Brown, Elizabeth E.

AU - Croker, Jennifer

AU - Edberg, Jeff

AU - Gilkeson, Gary

AU - James, Judith A.

AU - Kamen, Diane L.

AU - Kelly, Jennifer A.

AU - McCune, Joseph

AU - Merrill, Joan T.

AU - Petri, Michelle

AU - Ramsey-Goldman, Rosalind

AU - Reveille, John D.

AU - Salmon, Jane E.

AU - Scofield, Hal

AU - Utset, Tammy

AU - Wallace, Daniel J.

AU - Weisman, Michael H.

AU - Kimberly, Robert P.

AU - Harley, John B.

AU - Lewis, Cathryn M.

AU - Criswell, Lindsey A.

AU - Vyse, Timothy J.

PY - 2018/11/1

Y1 - 2018/11/1

N2 - Genetic variation within the major histocompatibility complex (MHC) contributes substantial risk for systemic lupus erythematosus, but high gene density, extreme polymorphism and extensive linkage disequilibrium (LD) have made fine mapping challenging. To address the problem, we compared two association techniques in two ancestrally diverse populations, African Americans (AAs) and Europeans (EURs). We observed a greater number of Human Leucocyte Antigen (HLA) alleles in AA consistent with the elevated level of recombination in this population. In EUR we observed 50 different A-C-B-DRB1-DQA-DQB multilocus haplotype sequences per hundred individuals; in the AA sample, these multilocus haplotypes were twice as common compared to Europeans. We also observed a strong narrow class II signal in AA as opposed to the long-range LD observed in EUR that includes class I alleles. We performed a Bayesian model choice of the classical HLA alleles and a frequentist analysis that combined both single nucleotide polymorphisms (SNPs) and classical HLA alleles. Both analyses converged on a similar subset of risk HLA alleles: in EUR HLA- B*08:01 + B*18:01 + (DRB1*15:01 frequentist only) + DQA*01:02 + DQB*02:01 + DRB3*02 and in AA HLA-C*17:01 + B*08:01 + DRB1*15:03 + (DQA*01:02 frequentist only) + DQA*02:01 + DQA*05:01+ DQA*05:05 + DQB*03:19 + DQB*02:02. We observed two additional independent SNP associations in both populations: EUR rs146903072 and rs501480; AA rs389883 and rs114118665. The DR2 serotype was best explained by DRB1*15:03 + DQA*01:02 in AA and by DRB1*15:01 + DQA*01:02 in EUR. The DR3 serotype was best explained by DQA*05:01 in AA and by DQB*02:01 in EUR. Despite some differences in underlying HLA allele risk models in EUR and AA, SNP signals across the extended MHC showed remarkable similarity and significant concordance in direction of effect for risk-associated variants.

AB - Genetic variation within the major histocompatibility complex (MHC) contributes substantial risk for systemic lupus erythematosus, but high gene density, extreme polymorphism and extensive linkage disequilibrium (LD) have made fine mapping challenging. To address the problem, we compared two association techniques in two ancestrally diverse populations, African Americans (AAs) and Europeans (EURs). We observed a greater number of Human Leucocyte Antigen (HLA) alleles in AA consistent with the elevated level of recombination in this population. In EUR we observed 50 different A-C-B-DRB1-DQA-DQB multilocus haplotype sequences per hundred individuals; in the AA sample, these multilocus haplotypes were twice as common compared to Europeans. We also observed a strong narrow class II signal in AA as opposed to the long-range LD observed in EUR that includes class I alleles. We performed a Bayesian model choice of the classical HLA alleles and a frequentist analysis that combined both single nucleotide polymorphisms (SNPs) and classical HLA alleles. Both analyses converged on a similar subset of risk HLA alleles: in EUR HLA- B*08:01 + B*18:01 + (DRB1*15:01 frequentist only) + DQA*01:02 + DQB*02:01 + DRB3*02 and in AA HLA-C*17:01 + B*08:01 + DRB1*15:03 + (DQA*01:02 frequentist only) + DQA*02:01 + DQA*05:01+ DQA*05:05 + DQB*03:19 + DQB*02:02. We observed two additional independent SNP associations in both populations: EUR rs146903072 and rs501480; AA rs389883 and rs114118665. The DR2 serotype was best explained by DRB1*15:03 + DQA*01:02 in AA and by DRB1*15:01 + DQA*01:02 in EUR. The DR3 serotype was best explained by DQA*05:01 in AA and by DQB*02:01 in EUR. Despite some differences in underlying HLA allele risk models in EUR and AA, SNP signals across the extended MHC showed remarkable similarity and significant concordance in direction of effect for risk-associated variants.

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