Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects
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 teste...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Public Library of Science
2013
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| Online Access: | http://hdl.handle.net/1721.1/83401 |
| _version_ | 1826208159398625280 |
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| author | Patsopoulos, Nikolaos A. Barcellos, Lisa F. Hintzen, Rogier Q. Schaefer, Catherine van Duijn, Cornelia M. Noble, Janelle A. Raj, Towfique Gourraud, Pierre-Antoine Stranger, Barbara E. Oksenberg, Jorge Olsson, Tomas Taylor, Bruce V. Sawcer, Stephen Hafler, David A. Carrington, Mary De Jager, Philip L. de Bakker, Paul I. W. |
| author2 | Harvard University--MIT Division of Health Sciences and Technology |
| author_facet | Harvard University--MIT Division of Health Sciences and Technology Patsopoulos, Nikolaos A. Barcellos, Lisa F. Hintzen, Rogier Q. Schaefer, Catherine van Duijn, Cornelia M. Noble, Janelle A. Raj, Towfique Gourraud, Pierre-Antoine Stranger, Barbara E. Oksenberg, Jorge Olsson, Tomas Taylor, Bruce V. Sawcer, Stephen Hafler, David A. Carrington, Mary De Jager, Philip L. de Bakker, Paul I. W. |
| author_sort | Patsopoulos, Nikolaos A. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T14:01:10Z |
| format | Article |
| id | mit-1721.1/83401 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T14:01:10Z |
| publishDate | 2013 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | mit-1721.1/834012022-10-01T18:35:19Z Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects Patsopoulos, Nikolaos A. Barcellos, Lisa F. Hintzen, Rogier Q. Schaefer, Catherine van Duijn, Cornelia M. Noble, Janelle A. Raj, Towfique Gourraud, Pierre-Antoine Stranger, Barbara E. Oksenberg, Jorge Olsson, Tomas Taylor, Bruce V. Sawcer, Stephen Hafler, David A. Carrington, Mary De Jager, Philip L. de Bakker, Paul I. W. Harvard University--MIT Division of Health Sciences and Technology Hafler, David A. 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. R01NS049477 R01NS026799 NIH/NINDS R01NS049510 R01NS0495103 NIH/NIAID R01AI076544 2013-12-30T20:34:50Z 2013-12-30T20:34:50Z 2013-11 2013-04 Article http://purl.org/eprint/type/JournalArticle 1553-7404 1553-7390 http://hdl.handle.net/1721.1/83401 Patsopoulos, Nikolaos A., Lisa F. Barcellos, Rogier Q. Hintzen, Catherine Schaefer, Cornelia M. van Duijn, Janelle A. Noble, Towfique Raj, et al. “Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects.” Edited by Greg Gibson. PLoS Genetics 9, no. 11 (November 21, 2013): e1003926. en_US http://dx.doi.org/10.1371/journal.pgen.1003926 PLoS Genetics http://creativecommons.org/licenses/by/2.5/ application/pdf Public Library of Science PLoS |
| spellingShingle | Patsopoulos, Nikolaos A. Barcellos, Lisa F. Hintzen, Rogier Q. Schaefer, Catherine van Duijn, Cornelia M. Noble, Janelle A. Raj, Towfique Gourraud, Pierre-Antoine Stranger, Barbara E. Oksenberg, Jorge Olsson, Tomas Taylor, Bruce V. Sawcer, Stephen Hafler, David A. Carrington, Mary De Jager, Philip L. de Bakker, Paul I. W. Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects |
| title | Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects |
| title_full | Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects |
| title_fullStr | Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects |
| title_full_unstemmed | Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects |
| title_short | Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects |
| title_sort | fine mapping the genetic association of the major histocompatibility complex in multiple sclerosis hla and non hla effects |
| url | http://hdl.handle.net/1721.1/83401 |
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