FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 357:851-862 August 30, 2007 Number 9 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Supplementary Material Editorial by Peltonen, L. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

ABSTRACT

Background Multiple sclerosis has a clinically significant heritable component. We conducted a genomewide association study to identify alleles associated with the risk of multiple sclerosis.

Methods We used DNA microarray technology to identify common DNA sequence variants in 931 family trios (consisting of an affected child and both parents) and tested them for association. For replication, we genotyped another 609 family trios, 2322 case subjects, and 789 control subjects and used genotyping data from two external control data sets. A joint analysis of data from 12,360 subjects was performed to estimate the overall significance and effect size of associations between alleles and the risk of multiple sclerosis.

Results A transmission disequilibrium test of 334,923 single-nucleotide polymorphisms (SNPs) in 931 family trios revealed 49 SNPs having an association with multiple sclerosis (P<1x10^–4); of these SNPs, 38 were selected for the second-stage analysis. A comparison between the 931 case subjects from the family trios and 2431 control subjects identified an additional nonoverlapping 32 SNPs (P<0.001). An additional 40 SNPs with less stringent P values (<0.01) were also selected, for a total of 110 SNPs for the second-stage analysis. Of these SNPs, two within the interleukin-2 receptor gene (IL2RA) were strongly associated with multiple sclerosis (P=2.96x10^–8), as were a nonsynonymous SNP in the interleukin-7 receptor gene (IL7RA) (P=2.94x10^–7) and multiple SNPs in the HLA-DRA locus (P=8.94x10^–81).

Conclusions Alleles of IL2RA and IL7RA and those in the HLA locus are identified as heritable risk factors for multiple sclerosis.

Source Information

The writing group (David A. Hafler, M.D., Alastair Compston, F.Med.Sci., Ph.D., Stephen Sawcer, M.B., Ch.B., Ph.D., Eric S. Lander, Ph.D., Mark J. Daly, Ph.D., Philip L. De Jager, M.D., Ph.D., Paul I.W. de Bakker, Ph.D., Stacey B. Gabriel, Ph.D., Daniel B. Mirel, Ph.D., Adrian J. Ivinson, Ph.D., Margaret A. Pericak-Vance, Ph.D., Simon G. Gregory, Ph.D., John D. Rioux, Ph.D., Jacob L. McCauley, Ph.D., Jonathan L. Haines, Ph.D., Lisa F. Barcellos, Ph.D., Bruce Cree, M.D., Ph.D., Jorge R. Oksenberg, Ph.D., and Stephen L. Hauser, M.D.) assumes responsibility for the overall content and integrity of the article.

This article (10.1056/NEJMoa073493) was published at www.nejm.org on July 29, 2007.

Full Text of this Article

Related Letters:

Genomewide Study of Multiple Sclerosis
Ramagopalan S. V., Anderson C., Sadovnick A. D., Ebers G. C., Matesanz F., Fernández O., Alcina A., Chaudhuri A., Behan P. O., Hafler D. A., Compston A., Hauser S. L., the International Multiple Sclerosis Genetics Consortium
Extract | Full Text | PDF  
N Engl J Med 2007; 357:2199-2201, Nov 22, 2007. Correspondence

This article has been cited by other articles:

• Venken, K., Hellings, N., Broekmans, T., Hensen, K., Rummens, J.-L., Stinissen, P. (2008). Natural Naive CD4+CD25+CD127low Regulatory T Cell (Treg) Development and Function Are Disturbed in Multiple Sclerosis Patients: Recovery of Memory Treg Homeostasis during Disease Progression. J. Immunol. 180: 6411-6420 [Abstract] [Full Text]  
• Yang, L., Anderson, D. E., Kuchroo, J., Hafler, D. A. (2008). Lack of TIM-3 Immunoregulation in Multiple Sclerosis. J. Immunol. 180: 4409-4414 [Abstract] [Full Text]  
• Pearson, T. A., Manolio, T. A. (2008). How to Interpret a Genome-wide Association Study. JAMA 299: 1335-1344 [Abstract] [Full Text]  
• Rosenberg, R. N. (2008). Neuromics and Neurological Disease. Arch Neurol 65: 307-308 [Full Text]  
• O'Doherty, C., Kantarci, O., Vandenbroeck, K. (2008). IL7RA Polymorphisms and Susceptibility to Multiple Sclerosis. NEJM 358: 753-754 [Full Text]  
• Hegele, R. A., Dichgans, M. (2008). Update on the Genetics of Stroke and Cerebrovascular Disease 2007. Stroke 39: 252-254 [Full Text]  
• Banwell, B. L. (2008). Through the eyes of a child: research insights gained through the study of childhood multiple sclerosis. Mult Scler 14: 4-5  
• DeLuca, G. C., Ramagopalan, S. V., Herrera, B. M., Dyment, D. A., Lincoln, M. R., Montpetit, A., Pugliatti, M., Barnardo, M. C. N., Risch, N. J., Sadovnick, A. D., Chao, M., Sotgiu, S., Hudson, T. J., Ebers, G. C. (2007). An extremes of outcome strategy provides evidence that multiple sclerosis severity is determined by alleles at the HLA-DRB1 locus. Proc. Natl. Acad. Sci. USA 104: 20896-20901 [Abstract] [Full Text]  
• Serafini, B., Rosicarelli, B., Franciotta, D., Magliozzi, R., Reynolds, R., Cinque, P., Andreoni, L., Trivedi, P., Salvetti, M., Faggioni, A., Aloisi, F. (2007). Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain. J. Exp. Med. 204: 2899-2912 [Abstract] [Full Text]  
• Ramagopalan, S. V., Anderson, C., Sadovnick, A. D., Ebers, G. C., Matesanz, F., Fernandez, O., Alcina, A., Chaudhuri, A., Behan, P. O., Hafler, D. A., Compston, A., Hauser, S. L., the International Multiple Sclerosis Genetics Cons, (2007). Genomewide Study of Multiple Sclerosis. NEJM 357: 2199-2201 [Full Text]  
• Maier, L. M., Anderson, D. E., De Jager, P. L., Wicker, L. S., Hafler, D. A. (2007). Allelic variant in CTLA4 alters T cell phosphorylation patterns. Proc. Natl. Acad. Sci. USA 104: 18607-18612 [Abstract] [Full Text]  
• Millichap, J. G. (2007). Multinational Study of Childhood Multiple Sclerosis: Risk Factors and Outcome. AAP Grand Rounds 18: 58-58 [Full Text]  
• Friese, M. A., Fugger, L. (2007). T cells and microglia as drivers of multiple sclerosis pathology. Brain 130: 2755-2757 [Full Text]  
• Peltonen, L. (2007). Old Suspects Found Guilty -- The First Genome Profile of Multiple Sclerosis. NEJM 357: 927-929 [Full Text]