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Pericak-Vance, Margaret A.

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Genetic Epidemiology of Multiple Sclerosis

Haines, Jonathan L

1 August 1995 - 31 August 2011
NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
Total Funding: $ 11,623,718

FY 2010
5R01NS032830-16
$ 1,177,223
FY 2009
2R01NS032830-15
$ 1,214,223
FY 2008
5R01NS032830-14
$ 846,841
FY 2007
5R01NS032830-13
$ 850,918
FY 2006
5R01NS032830-12
$ 850,979
FY 2005
5R01NS032830-11
$ 815,033
FY 2004
2R01NS032830-10A1
$ 840,557
FY 2003
3R01NS032830-09S1
$ 25,000
FY 2003
5R01NS032830-09
$ 601,223
FY 2002
5R01NS032830-08
$ 586,382
FY 2001
5R01NS032830-07
$ 567,898
FY 2000
5R01NS032830-06
$ 550,103
FY 1999
2R01NS032830-05
$ 720,367
FY 1998
5R01NS032830-04
$ 494,228
FY 1997
7R01NS032830-03
$ 476,236
FY 1996
5R01NS032830-02
$ 489,051
FY 1995
1R01NS032830-01A2
$ 517,456
 
 
$ 11,623,718
Abstract

Multiple sclerosis (MS) is a debilitating neuroimmunological and neurodegenerative disorder affecting more than 400,000 individuals in the United States. Epidemiological and genetic studies have produced overwhelming evidence for a genetic influence on the risk of MS. While the first confirmed MS genetic association (with the HLA-DRB1*1501 allele) was identified in the early 1970's, additional success was not forthcoming using the then available molecular and statistical tools. In 2007, and as a direct result of the current funding, we identified the first new genetic association in MS in over 30 years;we demonstrated that a common non-synonymous functional SNP in the IL7RA gene was associated with an increased risk of MS. Since making this discovery, we and others have identified and confirmed associations to several other genes, including IL2RA, CLEC16A, CD58, TYK2, TNFRSF1A, IRF8, CD6, and CD226. However, there are very significant genetic questions that remain unanswered in MS. First, these genes explain only a small fraction of the overall genetic influence on MS. Numerous additional genes of modest yet important effect remain to be found. Second, all this work has assumed the common-disease/common-variant hypothesis, which we contend is only part of the story. Detailed examination for rarer variants of stronger effect in both the nuclear and mitochondrial genomes has yet to be performed and may well explain a measurable proportion of the genetic influence on MS. We are in an excellent position to further examine the genetic role in both severity and type of progression of MS. Our specific aims are to: 1). Confirm additional important genes in the IL7RA pathway;2). Confirm additional important genes identified in the top 5% of SNPs from the original MS GWAS analysis;3). Identify all variants in the confirmed non-MHC genes (currently IL7RA, IL2RA, CLEC16A, CD58, CD226) using high-throughput sequencing techniques. We will take advantage of our unique large multiplex family dataset to sequence MS cases most likely to carry rare variants of strong effect.

30 Resulting Publications

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