Fine mapping major histocompatibility complex associations in psoriasis and its clinical subtypes

Yukinori Okada, Buhm Han, Lam C. Tsoi, Philip E. Stuart, Eva Ellinghaus, Trilokraj Tejasvi, Vinod Chandran, Fawnda Pellett, Remy Pollock, Anne M. Bowcock, Gerald G. Krueger, Michael Weichenthal, John J. Voorhees, Proton Rahman, Peter K. Gregersen, Andre Franke, Rajan P. Nair, Gonçalo R. Abecasis, Dafna D. Gladman, James T. ElderPaul I.W. De Bakker, Soumya Raychaudhuri

Research output: Contribution to journalArticle

103 Citations (Scopus)

Abstract

Psoriasis vulgaris (PsV) risk is strongly associated with variation within the major histocompatibility complex (MHC) region, but its genetic architecture has yet to be fully elucidated. Here, we conducted a large-scale fine-mapping study of PsV risk in the MHC region in 9,247 PsV-affected individuals and 13,589 controls of European descent by imputing class I and II human leukocyte antigen (HLA) genes from SNP genotype data. In addition, we imputed sequence variants for MICA, an MHC HLA-like gene that has been associated with PsV, to evaluate association at that locus as well. We observed that HLA-C*06:02 demonstrated the lowest p value for overall PsV risk (p = 1.7 × 10 -364). Stepwise analysis revealed multiple HLA-C*06: 02-independent risk variants in both class I and class II HLA genes for PsV susceptibility (HLA-C*12:03, HLA-B amino acid positions 67 and 9, HLA-A amino acid position 95, and HLA-DQα1 amino acid position 53; p < 5.0 × 10-8), but no apparent risk conferred by MICA. We further evaluated risk of two major clinical subtypes of PsV, psoriatic arthritis (PsA; n = 3,038) and cutaneous psoriasis (PsC; n = 3,098). We found that risk heterogeneity between PsA and PsC might be driven by HLA-B amino acid position 45 (pomnibus = 2.2 × 10-11), indicating that different genetic factors underlie the overall risk of PsV and the risk of specific PsV subphenotypes. Our study illustrates the value of high-resolution HLA and MICA imputation for fine mapping causal variants in the MHC.

Original languageEnglish
Pages (from-to)162-172
Number of pages11
JournalAmerican Journal of Human Genetics
Volume95
Issue number2
DOIs
StatePublished - 7 Aug 2014

Fingerprint

HLA Antigens
Major Histocompatibility Complex
Psoriasis
Amino Acids
HLA-D Antigens
Genes
Psoriatic Arthritis
Single Nucleotide Polymorphism
Genotype
Skin

Cite this

Okada, Yukinori ; Han, Buhm ; Tsoi, Lam C. ; Stuart, Philip E. ; Ellinghaus, Eva ; Tejasvi, Trilokraj ; Chandran, Vinod ; Pellett, Fawnda ; Pollock, Remy ; Bowcock, Anne M. ; Krueger, Gerald G. ; Weichenthal, Michael ; Voorhees, John J. ; Rahman, Proton ; Gregersen, Peter K. ; Franke, Andre ; Nair, Rajan P. ; Abecasis, Gonçalo R. ; Gladman, Dafna D. ; Elder, James T. ; De Bakker, Paul I.W. ; Raychaudhuri, Soumya. / Fine mapping major histocompatibility complex associations in psoriasis and its clinical subtypes. In: American Journal of Human Genetics. 2014 ; Vol. 95, No. 2. pp. 162-172.
@article{6aa125d942474b0e9ce36af010f7ede1,
title = "Fine mapping major histocompatibility complex associations in psoriasis and its clinical subtypes",
abstract = "Psoriasis vulgaris (PsV) risk is strongly associated with variation within the major histocompatibility complex (MHC) region, but its genetic architecture has yet to be fully elucidated. Here, we conducted a large-scale fine-mapping study of PsV risk in the MHC region in 9,247 PsV-affected individuals and 13,589 controls of European descent by imputing class I and II human leukocyte antigen (HLA) genes from SNP genotype data. In addition, we imputed sequence variants for MICA, an MHC HLA-like gene that has been associated with PsV, to evaluate association at that locus as well. We observed that HLA-C*06:02 demonstrated the lowest p value for overall PsV risk (p = 1.7 × 10 -364). Stepwise analysis revealed multiple HLA-C*06: 02-independent risk variants in both class I and class II HLA genes for PsV susceptibility (HLA-C*12:03, HLA-B amino acid positions 67 and 9, HLA-A amino acid position 95, and HLA-DQα1 amino acid position 53; p < 5.0 × 10-8), but no apparent risk conferred by MICA. We further evaluated risk of two major clinical subtypes of PsV, psoriatic arthritis (PsA; n = 3,038) and cutaneous psoriasis (PsC; n = 3,098). We found that risk heterogeneity between PsA and PsC might be driven by HLA-B amino acid position 45 (pomnibus = 2.2 × 10-11), indicating that different genetic factors underlie the overall risk of PsV and the risk of specific PsV subphenotypes. Our study illustrates the value of high-resolution HLA and MICA imputation for fine mapping causal variants in the MHC.",
author = "Yukinori Okada and Buhm Han and Tsoi, {Lam C.} and Stuart, {Philip E.} and Eva Ellinghaus and Trilokraj Tejasvi and Vinod Chandran and Fawnda Pellett and Remy Pollock and Bowcock, {Anne M.} and Krueger, {Gerald G.} and Michael Weichenthal and Voorhees, {John J.} and Proton Rahman and Gregersen, {Peter K.} and Andre Franke and Nair, {Rajan P.} and Abecasis, {Gon{\cc}alo R.} and Gladman, {Dafna D.} and Elder, {James T.} and {De Bakker}, {Paul I.W.} and Soumya Raychaudhuri",
year = "2014",
month = "8",
day = "7",
doi = "10.1016/j.ajhg.2014.07.002",
language = "English",
volume = "95",
pages = "162--172",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "2",

}

Okada, Y, Han, B, Tsoi, LC, Stuart, PE, Ellinghaus, E, Tejasvi, T, Chandran, V, Pellett, F, Pollock, R, Bowcock, AM, Krueger, GG, Weichenthal, M, Voorhees, JJ, Rahman, P, Gregersen, PK, Franke, A, Nair, RP, Abecasis, GR, Gladman, DD, Elder, JT, De Bakker, PIW & Raychaudhuri, S 2014, 'Fine mapping major histocompatibility complex associations in psoriasis and its clinical subtypes', American Journal of Human Genetics, vol. 95, no. 2, pp. 162-172. https://doi.org/10.1016/j.ajhg.2014.07.002

Fine mapping major histocompatibility complex associations in psoriasis and its clinical subtypes. / Okada, Yukinori; Han, Buhm; Tsoi, Lam C.; Stuart, Philip E.; Ellinghaus, Eva; Tejasvi, Trilokraj; Chandran, Vinod; Pellett, Fawnda; Pollock, Remy; Bowcock, Anne M.; Krueger, Gerald G.; Weichenthal, Michael; Voorhees, John J.; Rahman, Proton; Gregersen, Peter K.; Franke, Andre; Nair, Rajan P.; Abecasis, Gonçalo R.; Gladman, Dafna D.; Elder, James T.; De Bakker, Paul I.W.; Raychaudhuri, Soumya.

In: American Journal of Human Genetics, Vol. 95, No. 2, 07.08.2014, p. 162-172.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Fine mapping major histocompatibility complex associations in psoriasis and its clinical subtypes

AU - Okada, Yukinori

AU - Han, Buhm

AU - Tsoi, Lam C.

AU - Stuart, Philip E.

AU - Ellinghaus, Eva

AU - Tejasvi, Trilokraj

AU - Chandran, Vinod

AU - Pellett, Fawnda

AU - Pollock, Remy

AU - Bowcock, Anne M.

AU - Krueger, Gerald G.

AU - Weichenthal, Michael

AU - Voorhees, John J.

AU - Rahman, Proton

AU - Gregersen, Peter K.

AU - Franke, Andre

AU - Nair, Rajan P.

AU - Abecasis, Gonçalo R.

AU - Gladman, Dafna D.

AU - Elder, James T.

AU - De Bakker, Paul I.W.

AU - Raychaudhuri, Soumya

PY - 2014/8/7

Y1 - 2014/8/7

N2 - Psoriasis vulgaris (PsV) risk is strongly associated with variation within the major histocompatibility complex (MHC) region, but its genetic architecture has yet to be fully elucidated. Here, we conducted a large-scale fine-mapping study of PsV risk in the MHC region in 9,247 PsV-affected individuals and 13,589 controls of European descent by imputing class I and II human leukocyte antigen (HLA) genes from SNP genotype data. In addition, we imputed sequence variants for MICA, an MHC HLA-like gene that has been associated with PsV, to evaluate association at that locus as well. We observed that HLA-C*06:02 demonstrated the lowest p value for overall PsV risk (p = 1.7 × 10 -364). Stepwise analysis revealed multiple HLA-C*06: 02-independent risk variants in both class I and class II HLA genes for PsV susceptibility (HLA-C*12:03, HLA-B amino acid positions 67 and 9, HLA-A amino acid position 95, and HLA-DQα1 amino acid position 53; p < 5.0 × 10-8), but no apparent risk conferred by MICA. We further evaluated risk of two major clinical subtypes of PsV, psoriatic arthritis (PsA; n = 3,038) and cutaneous psoriasis (PsC; n = 3,098). We found that risk heterogeneity between PsA and PsC might be driven by HLA-B amino acid position 45 (pomnibus = 2.2 × 10-11), indicating that different genetic factors underlie the overall risk of PsV and the risk of specific PsV subphenotypes. Our study illustrates the value of high-resolution HLA and MICA imputation for fine mapping causal variants in the MHC.

AB - Psoriasis vulgaris (PsV) risk is strongly associated with variation within the major histocompatibility complex (MHC) region, but its genetic architecture has yet to be fully elucidated. Here, we conducted a large-scale fine-mapping study of PsV risk in the MHC region in 9,247 PsV-affected individuals and 13,589 controls of European descent by imputing class I and II human leukocyte antigen (HLA) genes from SNP genotype data. In addition, we imputed sequence variants for MICA, an MHC HLA-like gene that has been associated with PsV, to evaluate association at that locus as well. We observed that HLA-C*06:02 demonstrated the lowest p value for overall PsV risk (p = 1.7 × 10 -364). Stepwise analysis revealed multiple HLA-C*06: 02-independent risk variants in both class I and class II HLA genes for PsV susceptibility (HLA-C*12:03, HLA-B amino acid positions 67 and 9, HLA-A amino acid position 95, and HLA-DQα1 amino acid position 53; p < 5.0 × 10-8), but no apparent risk conferred by MICA. We further evaluated risk of two major clinical subtypes of PsV, psoriatic arthritis (PsA; n = 3,038) and cutaneous psoriasis (PsC; n = 3,098). We found that risk heterogeneity between PsA and PsC might be driven by HLA-B amino acid position 45 (pomnibus = 2.2 × 10-11), indicating that different genetic factors underlie the overall risk of PsV and the risk of specific PsV subphenotypes. Our study illustrates the value of high-resolution HLA and MICA imputation for fine mapping causal variants in the MHC.

UR - http://www.scopus.com/inward/record.url?scp=84905925233&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2014.07.002

DO - 10.1016/j.ajhg.2014.07.002

M3 - Article

C2 - 25087609

AN - SCOPUS:84905925233

VL - 95

SP - 162

EP - 172

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 2

ER -