Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects

Nikolaos A. Patsopoulos; Lisa F. Barcellos; Rogier Q. Hintzen; Catherine Schaefer; Cornelia M. van Duijn; Janelle A. Noble; Towfique Raj; Pierre Antoine Gourraud; Barbara E. Stranger; Jorge Oksenberg; Tomas Olsson; Bruce V. Taylor; Stephen Sawcer; David A. Hafler; Mary Carrington; Philip L. De Jager; Paul I.W. de Bakker; Luisa Bernardinelli; David Booth; Manuel Comabella; Alastair Compston; Sandra D'Alfonso; Bertrand Fontaine; An Goris; Jonathan Haines; Hanne Harbo; Steve Hauser; Clive Hawkins; Bernhard Hemmer; Adrian Ivinson; Christina Lill; Roland Martin; Filippo Martinelli-Boneschi; Annette Oturai; Aarno Palotie; Margaret PericakVance; Janna Saarela; Graeme Stewart; Frauke Zipp; Rodney J. Scott; Jeannette Lechner-Scott; Pablo Moscato; David R. Booth; Graeme J. Stewart; Robert N. Heard; Deborah Mason; Lyn Griffiths; Simon Broadley; Matthew A. Brown; Mark Slee; Simon J. Foote; Jim Stankovich; James Wiley; Melanie Bahlo; Victoria Perreau; Judith Field; Helmut Butzkueven; Trevor J. Kilpatrick; Justin Rubio; Mark Marriott; William M. Carroll1; Allan G. Kermode

doi:10.1371/journal.pgen.1003926

Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects

Nikolaos A. Patsopoulos, Lisa F. Barcellos, Rogier Q. Hintzen, Catherine Schaefer, Cornelia M. van Duijn, Janelle A. Noble, Towfique Raj, Pierre Antoine Gourraud, Barbara E. Stranger, Jorge Oksenberg, Tomas Olsson, Bruce V. Taylor, Stephen Sawcer, David A. Hafler, Mary Carrington, Philip L. De Jager, Paul I.W. de Bakker, Luisa Bernardinelli, David Booth, Manuel ComabellaAlastair Compston, Sandra D'Alfonso, Bertrand Fontaine, An Goris, Jonathan Haines, Hanne Harbo, Steve Hauser, Clive Hawkins, Bernhard Hemmer, Adrian Ivinson, Christina Lill, Roland Martin, Filippo Martinelli-Boneschi, Annette Oturai, Aarno Palotie, Margaret PericakVance, Janna Saarela, Graeme Stewart, Frauke Zipp, Rodney J. Scott, Jeannette Lechner-Scott, Pablo Moscato, David R. Booth, Graeme J. Stewart, Robert N. Heard, Deborah Mason, Lyn Griffiths, Simon Broadley, Matthew A. Brown, Mark Slee, Simon J. Foote, Jim Stankovich, James Wiley, Melanie Bahlo, Victoria Perreau, Judith Field, Helmut Butzkueven, Trevor J. Kilpatrick, Justin Rubio, Mark Marriott, William M. Carroll1, Allan G. Kermode

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Abstract

The major histocompatibility complex (MHC) region is strongly associated with multiple sclerosis (MS) susceptibility. HLA-DRB1*15:01 has the strongest effect, and several other alleles have been reported at different levels of validation. Using SNP data from genome-wide studies, we imputed and tested classical alleles and amino acid polymorphisms in 8 classical human leukocyte antigen (HLA) genes in 5,091 cases and 9,595 controls. We identified 11 statistically independent effects overall: 6 HLA-DRB1 and one DPB1 alleles in class II, one HLA-A and two B alleles in class I, and one signal in a region spanning from MICB to LST1. This genomic segment does not contain any HLA class I or II genes and provides robust evidence for the involvement of a non-HLA risk allele within the MHC. Interestingly, this region contains the TNF gene, the cognate ligand of the well-validated TNFRSF1A MS susceptibility gene. The classical HLA effects can be explained to some extent by polymorphic amino acid positions in the peptide-binding grooves. This study dissects the independent effects in the MHC, a critical region for MS susceptibility that harbors multiple risk alleles.

Original language	English
Article number	e1003926
Journal	PLoS Genetics
Volume	9
Issue number	11
DOIs	https://doi.org/10.1371/journal.pgen.1003926
State	Published - 1 Nov 2013

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Patsopoulos, N. A., Barcellos, L. F., Hintzen, R. Q., Schaefer, C., van Duijn, C. M., Noble, J. A., Raj, T., Gourraud, P. A., Stranger, B. E., Oksenberg, J., Olsson, T., Taylor, B. V., Sawcer, S., Hafler, D. A., Carrington, M., De Jager, P. L., de Bakker, P. I. W., Bernardinelli, L., Booth, D., ... Kermode, A. G. (2013). Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects. PLoS Genetics, 9(11), Article e1003926. https://doi.org/10.1371/journal.pgen.1003926

@article{6e2fcc1758424823a543ccc86d1b4e58,

title = "Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects",

abstract = "The major histocompatibility complex (MHC) region is strongly associated with multiple sclerosis (MS) susceptibility. HLA-DRB1*15:01 has the strongest effect, and several other alleles have been reported at different levels of validation. Using SNP data from genome-wide studies, we imputed and tested classical alleles and amino acid polymorphisms in 8 classical human leukocyte antigen (HLA) genes in 5,091 cases and 9,595 controls. We identified 11 statistically independent effects overall: 6 HLA-DRB1 and one DPB1 alleles in class II, one HLA-A and two B alleles in class I, and one signal in a region spanning from MICB to LST1. This genomic segment does not contain any HLA class I or II genes and provides robust evidence for the involvement of a non-HLA risk allele within the MHC. Interestingly, this region contains the TNF gene, the cognate ligand of the well-validated TNFRSF1A MS susceptibility gene. The classical HLA effects can be explained to some extent by polymorphic amino acid positions in the peptide-binding grooves. This study dissects the independent effects in the MHC, a critical region for MS susceptibility that harbors multiple risk alleles.",

author = "Patsopoulos, {Nikolaos A.} and Barcellos, {Lisa F.} and Hintzen, {Rogier Q.} and Catherine Schaefer and {van Duijn}, {Cornelia M.} and Noble, {Janelle A.} and Towfique Raj and Gourraud, {Pierre Antoine} and Stranger, {Barbara E.} and Jorge Oksenberg and Tomas Olsson and Taylor, {Bruce V.} and Stephen Sawcer and Hafler, {David A.} and Mary Carrington and {De Jager}, {Philip L.} and {de Bakker}, {Paul I.W.} and Luisa Bernardinelli and David Booth and Manuel Comabella and Alastair Compston and Sandra D'Alfonso and Bertrand Fontaine and An Goris and Jonathan Haines and Hanne Harbo and Steve Hauser and Clive Hawkins and Bernhard Hemmer and Adrian Ivinson and Christina Lill and Roland Martin and Filippo Martinelli-Boneschi and Annette Oturai and Aarno Palotie and Margaret PericakVance and Janna Saarela and Graeme Stewart and Frauke Zipp and Scott, {Rodney J.} and Jeannette Lechner-Scott and Pablo Moscato and Booth, {David R.} and Stewart, {Graeme J.} and Heard, {Robert N.} and Deborah Mason and Lyn Griffiths and Simon Broadley and Brown, {Matthew A.} and Mark Slee and Foote, {Simon J.} and Jim Stankovich and James Wiley and Melanie Bahlo and Victoria Perreau and Judith Field and Helmut Butzkueven and Kilpatrick, {Trevor J.} and Justin Rubio and Mark Marriott and Carroll1, {William M.} and Kermode, {Allan G.}",

year = "2013",

month = nov,

day = "1",

doi = "10.1371/journal.pgen.1003926",

language = "English",

volume = "9",

journal = "PLoS Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "11",

}

Patsopoulos, NA, Barcellos, LF, Hintzen, RQ, Schaefer, C, van Duijn, CM, Noble, JA, Raj, T, Gourraud, PA, Stranger, BE, Oksenberg, J, Olsson, T, Taylor, BV, Sawcer, S, Hafler, DA, Carrington, M, De Jager, PL, de Bakker, PIW, Bernardinelli, L, Booth, D, Comabella, M, Compston, A, D'Alfonso, S, Fontaine, B, Goris, A, Haines, J, Harbo, H, Hauser, S, Hawkins, C, Hemmer, B, Ivinson, A, Lill, C, Martin, R, Martinelli-Boneschi, F, Oturai, A, Palotie, A, PericakVance, M, Saarela, J, Stewart, G, Zipp, F, Scott, RJ, Lechner-Scott, J, Moscato, P, Booth, DR, Stewart, GJ, Heard, RN, Mason, D, Griffiths, L, Broadley, S, Brown, MA, Slee, M, Foote, SJ, Stankovich, J, Wiley, J, Bahlo, M, Perreau, V, Field, J, Butzkueven, H, Kilpatrick, TJ, Rubio, J, Marriott, M, Carroll1, WM & Kermode, AG 2013, 'Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects', PLoS Genetics, vol. 9, no. 11, e1003926. https://doi.org/10.1371/journal.pgen.1003926

TY - JOUR

T1 - Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis

T2 - HLA and Non-HLA Effects

AU - Patsopoulos, Nikolaos A.

AU - Barcellos, Lisa F.

AU - Hintzen, Rogier Q.

AU - Schaefer, Catherine

AU - van Duijn, Cornelia M.

AU - Noble, Janelle A.

AU - Raj, Towfique

AU - Gourraud, Pierre Antoine

AU - Stranger, Barbara E.

AU - Oksenberg, Jorge

AU - Olsson, Tomas

AU - Taylor, Bruce V.

AU - Sawcer, Stephen

AU - Hafler, David A.

AU - Carrington, Mary

AU - De Jager, Philip L.

AU - de Bakker, Paul I.W.

AU - Bernardinelli, Luisa

AU - Booth, David

AU - Comabella, Manuel

AU - Compston, Alastair

AU - D'Alfonso, Sandra

AU - Fontaine, Bertrand

AU - Goris, An

AU - Haines, Jonathan

AU - Harbo, Hanne

AU - Hauser, Steve

AU - Hawkins, Clive

AU - Hemmer, Bernhard

AU - Ivinson, Adrian

AU - Lill, Christina

AU - Martin, Roland

AU - Martinelli-Boneschi, Filippo

AU - Oturai, Annette

AU - Palotie, Aarno

AU - PericakVance, Margaret

AU - Saarela, Janna

AU - Stewart, Graeme

AU - Zipp, Frauke

AU - Scott, Rodney J.

AU - Lechner-Scott, Jeannette

AU - Moscato, Pablo

AU - Booth, David R.

AU - Stewart, Graeme J.

AU - Heard, Robert N.

AU - Mason, Deborah

AU - Griffiths, Lyn

AU - Broadley, Simon

AU - Brown, Matthew A.

AU - Slee, Mark

AU - Foote, Simon J.

AU - Stankovich, Jim

AU - Wiley, James

AU - Bahlo, Melanie

AU - Perreau, Victoria

AU - Field, Judith

AU - Butzkueven, Helmut

AU - Kilpatrick, Trevor J.

AU - Rubio, Justin

AU - Marriott, Mark

AU - Carroll1, William M.

AU - Kermode, Allan G.

PY - 2013/11/1

Y1 - 2013/11/1

N2 - The major histocompatibility complex (MHC) region is strongly associated with multiple sclerosis (MS) susceptibility. HLA-DRB1*15:01 has the strongest effect, and several other alleles have been reported at different levels of validation. Using SNP data from genome-wide studies, we imputed and tested classical alleles and amino acid polymorphisms in 8 classical human leukocyte antigen (HLA) genes in 5,091 cases and 9,595 controls. We identified 11 statistically independent effects overall: 6 HLA-DRB1 and one DPB1 alleles in class II, one HLA-A and two B alleles in class I, and one signal in a region spanning from MICB to LST1. This genomic segment does not contain any HLA class I or II genes and provides robust evidence for the involvement of a non-HLA risk allele within the MHC. Interestingly, this region contains the TNF gene, the cognate ligand of the well-validated TNFRSF1A MS susceptibility gene. The classical HLA effects can be explained to some extent by polymorphic amino acid positions in the peptide-binding grooves. This study dissects the independent effects in the MHC, a critical region for MS susceptibility that harbors multiple risk alleles.

AB - The major histocompatibility complex (MHC) region is strongly associated with multiple sclerosis (MS) susceptibility. HLA-DRB1*15:01 has the strongest effect, and several other alleles have been reported at different levels of validation. Using SNP data from genome-wide studies, we imputed and tested classical alleles and amino acid polymorphisms in 8 classical human leukocyte antigen (HLA) genes in 5,091 cases and 9,595 controls. We identified 11 statistically independent effects overall: 6 HLA-DRB1 and one DPB1 alleles in class II, one HLA-A and two B alleles in class I, and one signal in a region spanning from MICB to LST1. This genomic segment does not contain any HLA class I or II genes and provides robust evidence for the involvement of a non-HLA risk allele within the MHC. Interestingly, this region contains the TNF gene, the cognate ligand of the well-validated TNFRSF1A MS susceptibility gene. The classical HLA effects can be explained to some extent by polymorphic amino acid positions in the peptide-binding grooves. This study dissects the independent effects in the MHC, a critical region for MS susceptibility that harbors multiple risk alleles.

UR - http://www.scopus.com/inward/record.url?scp=84888231843&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1003926

DO - 10.1371/journal.pgen.1003926

M3 - Article

C2 - 24278027

AN - SCOPUS:84888231843

SN - 1553-7390

VL - 9

JO - PLoS Genetics

JF - PLoS Genetics

IS - 11

M1 - e1003926

ER -

Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects

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