Risk alleles for multiple sclerosis identified by a genomewide study

David A. Hafler, Alastair Compston, Stephen Sawcer, Eric S. Lander, Mark J. Daly, Philip L. De Jager, Paul I W De Bakker, Stacey B. Gabriel, Daniel B. Mirel, Adrian J. Ivinson, Margaret A Pericak-Vance, Simon G. Gregory, John D. Rioux, Jacob L McCauley, Jonathan L. Haines, Lisa F. Barcellos, Bruce Cree, Jorge R. Oksenberg, Stephen L. Hauser

Research output: Contribution to journalArticle

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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<1×10-4); 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 α gene (IL2RA) were strongly associated with multiple sclerosis (P = 2.96×10 -8), as were a nonsynonymous SNP in the interleukin-7 receptor α gene (IL7RA) (P = 2.94×10-7) and multiple SNPs in the HLA-DRA locus (P = 8.94×10-81). CONCLUSIONS: Alleles of IL2RA and IL7RA and those in the HLA locus are identified as heritable risk factors for multiple sclerosis.

Original languageEnglish
Pages (from-to)851-862
Number of pages12
JournalNew England Journal of Medicine
Volume357
Issue number9
DOIs
StatePublished - Aug 30 2007

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Multiple Sclerosis
Single Nucleotide Polymorphism
Alleles
HLA-DR alpha-Chains
Interleukin-7 Receptors
Interleukin-2 Receptors
Oligonucleotide Array Sequence Analysis
Genes
Parents
Technology

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Hafler, D. A., Compston, A., Sawcer, S., Lander, E. S., Daly, M. J., De Jager, P. L., ... Hauser, S. L. (2007). Risk alleles for multiple sclerosis identified by a genomewide study. New England Journal of Medicine, 357(9), 851-862. https://doi.org/10.1056/NEJMoa073493

Risk alleles for multiple sclerosis identified by a genomewide study. / Hafler, David A.; Compston, Alastair; Sawcer, Stephen; Lander, Eric S.; Daly, Mark J.; De Jager, Philip L.; De Bakker, Paul I W; Gabriel, Stacey B.; Mirel, Daniel B.; Ivinson, Adrian J.; Pericak-Vance, Margaret A; Gregory, Simon G.; Rioux, John D.; McCauley, Jacob L; Haines, Jonathan L.; Barcellos, Lisa F.; Cree, Bruce; Oksenberg, Jorge R.; Hauser, Stephen L.

In: New England Journal of Medicine, Vol. 357, No. 9, 30.08.2007, p. 851-862.

Research output: Contribution to journalArticle

Hafler, DA, Compston, A, Sawcer, S, Lander, ES, Daly, MJ, De Jager, PL, De Bakker, PIW, Gabriel, SB, Mirel, DB, Ivinson, AJ, Pericak-Vance, MA, Gregory, SG, Rioux, JD, McCauley, JL, Haines, JL, Barcellos, LF, Cree, B, Oksenberg, JR & Hauser, SL 2007, 'Risk alleles for multiple sclerosis identified by a genomewide study', New England Journal of Medicine, vol. 357, no. 9, pp. 851-862. https://doi.org/10.1056/NEJMoa073493
Hafler DA, Compston A, Sawcer S, Lander ES, Daly MJ, De Jager PL et al. Risk alleles for multiple sclerosis identified by a genomewide study. New England Journal of Medicine. 2007 Aug 30;357(9):851-862. https://doi.org/10.1056/NEJMoa073493
Hafler, David A. ; Compston, Alastair ; Sawcer, Stephen ; Lander, Eric S. ; Daly, Mark J. ; De Jager, Philip L. ; De Bakker, Paul I W ; Gabriel, Stacey B. ; Mirel, Daniel B. ; Ivinson, Adrian J. ; Pericak-Vance, Margaret A ; Gregory, Simon G. ; Rioux, John D. ; McCauley, Jacob L ; Haines, Jonathan L. ; Barcellos, Lisa F. ; Cree, Bruce ; Oksenberg, Jorge R. ; Hauser, Stephen L. / Risk alleles for multiple sclerosis identified by a genomewide study. In: New England Journal of Medicine. 2007 ; Vol. 357, No. 9. pp. 851-862.
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T1 - Risk alleles for multiple sclerosis identified by a genomewide study

AU - Hafler, David A.

AU - Compston, Alastair

AU - Sawcer, Stephen

AU - Lander, Eric S.

AU - Daly, Mark J.

AU - De Jager, Philip L.

AU - De Bakker, Paul I W

AU - Gabriel, Stacey B.

AU - Mirel, Daniel B.

AU - Ivinson, Adrian J.

AU - Pericak-Vance, Margaret A

AU - Gregory, Simon G.

AU - Rioux, John D.

AU - McCauley, Jacob L

AU - Haines, Jonathan L.

AU - Barcellos, Lisa F.

AU - Cree, Bruce

AU - Oksenberg, Jorge R.

AU - Hauser, Stephen L.

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N2 - 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<1×10-4); 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 α gene (IL2RA) were strongly associated with multiple sclerosis (P = 2.96×10 -8), as were a nonsynonymous SNP in the interleukin-7 receptor α gene (IL7RA) (P = 2.94×10-7) and multiple SNPs in the HLA-DRA locus (P = 8.94×10-81). CONCLUSIONS: Alleles of IL2RA and IL7RA and those in the HLA locus are identified as heritable risk factors for multiple sclerosis.

AB - 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<1×10-4); 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 α gene (IL2RA) were strongly associated with multiple sclerosis (P = 2.96×10 -8), as were a nonsynonymous SNP in the interleukin-7 receptor α gene (IL7RA) (P = 2.94×10-7) and multiple SNPs in the HLA-DRA locus (P = 8.94×10-81). CONCLUSIONS: Alleles of IL2RA and IL7RA and those in the HLA locus are identified as heritable risk factors for multiple sclerosis.

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