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Risk Alleles for Multiple Sclerosis Identified by a Genomewide Study

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By DA Hafler, et al. • • July 31, 2007

Journal: New England Journal of Medicine. August 30 2007;357 [E-publication ahead of print July 29, 2007; full text available free online at]

Authors and affiliation: Hafler DA, Compston A, Sawcer S, et al. International Multiple Sclerosis Genetics Consortium

DOI: 10.1056/NEJMoa073493

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.

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