Multiple Sclerosis CS295 Final Presentation Yongxing Guo Dec. 18, 2007
Outlines • Introduction to Multiple Sclerosis (MS) • Genomewide Association Study of MS • IL2RA & IL7RA and MS risk • Comments
What’s Multiple Sclerosis (MS) • First described by Charcot in 1868. • A chronic inflammatory disease of the central nervous system (CNS), the brain and the spinal cord. • A malfunction of the immune system which leads to attacks against, and causes destruction of the myelin sheath. • Symptoms range from mild muscle weakness to partial or complete paralysis. • Widely considered an autoimmune disease
Epidemiology of Multiple Sclerosis • Monozygotic twins: concordance rate is nearly 30% • Siblings or dizygotic twins: 2% • Average Northern European population: 0.1% • Both genetic predisposition and largely unknown environmental factors are required to cause the disease
Association between MS and the HLA MHC Complex • In 1972, the association between multiple sclerosis and the HLA region of the genome was established. • HLA-DRB1 gene on chromosome 6p21 was identified. The human leukocyte antigen system (HLA) is the name of the human major histocompatibility complex (MHC). This group of genes resides on chromosome 6, and encodes cell-surface antigen-presenting proteins and many other genes. The major HLA antigens are essential elements in immune function
Other Studies of MS • No other loci with a definitive association with the disease have been found. • Early efforts to screen the genome for linkage with the use of low-density maps of microsatellites were unsuccessful. • These results indicate that in multiple sclerosis, linkage studies lack the statistical power to detect susceptibility loci that may reside outside the HLA-MHC region.
Overview • A genomewide association study • A transmission disequilibrium test of 334,923 single-nucleotide polymorphisms (SNPs) was performed • A joint analysis of data from 12,360 subjects was performed • Alleles of IL2RA and IL7RA and those in the HLA locus are identified as heritable risk factors for multiple sclerosis
Quality Control of Genotyping MAF: Minor Allele Frequency HW: Hardy Weinberg Equilibrium ME: Mendelian Errors
ScreeningAnalysis WTCCC: Wellcome Trust Case Control Consortium NIMH: National Institute of Mental Health IMSGC: International Multiple Sclerosis Genetics Consortium
Overview of the Primary Genomewide Association Scan Involving 931 Family Trios P values (shown as –log10 values) for results of transmission disequilibrium testing are plotted across the genome. The classic HLA-DR risk locus on chromosome 6p21 stands out with strong statistical significance (P<1×10−81).
Observed and Expected Distributions for the Results of Transmission Disequilibrium Testing Red: The expected null distribution Gray: P values for all 334,923 SNPs Black: The observed distributionafter exclusion of the SNPs across the extended HLA region
What’s IL2RA & IL7RA • Both are important in are important in T-cell mediated immunity • IL2RA • The interleukin-2 receptor (IL-2R) is heterotrimeric protein expressed on the surface of certain immune cells, such as lymphocytes, that binds and responds to a cytokine called interleukin 2. • Linked to two other autoimmune diseases: type 1 diabetes and autoimmune thyroid disease. • IL7RA • The protein encoded by this gene is a receptor for interleukine 7 (IL7) • Helps to control the activity of a class of immune cells called regulatory T cells. • IL7RA variant indicate an effect on gene expression with a change in the ratio of soluble to cell-bound interleukin-7 receptor
Comments • This is a “hypothesis free” association study. • The increased risk contributed by IL2RA and IL7RA is very low and that these two alleles explain only a very small proportion of the variance (0.2%) in the risk of MS. • Complex disease association studies need a massive number of study samples and the collaboration of large consortia because of the small effect of common alleles. • No clues to new pathways emerged from among the top-scoring associations, in contrast to the results of some genomewide studies involving other complex diseases, such as type 2 diabetes. • The best-associated variants in the combined data analysis were actually not among the best hits in the initial screen • Genomewide association studies that rely on common SNPs monitor only common alleles