The Genetics of Multiple Sclerosis: From 0 to 200 in 50 Years

More than 200 loci have been associated with MS susceptibility to date (half of them in the past 4 years alone). There is extensive sharing of genetic risk variants between MS and other autoimmune diseases. This suggests a model in which a general risk for autoimmunity is inherited. Additional genetic (and epigenetic) determinants and environmental exposures are compounded to ultimately define the target organ of the autodestructive process. Efforts to characterize the biological consequences of reported associations are ongoing. Cell-specific pathways are being developed to understand disease heterogeneity and individualized risk assessment. Multiple sclerosis (MS) is a common autoimmune disease that targets myelin in the central nervous system (CNS). Multiple genome-wide association studies (GWAS) over the past 10 years have uncovered more than 200 loci that independently contribute to disease pathogenesis. As with many other complex diseases, risk of developing MS is driven by multiple common variants whose biological effects are not immediately clear. Here, we present a historical perspective on the progress made in MS genetics and discuss current work geared towards creating a more complete model that accurately represents the genetic landscape of MS susceptibility. Such a model necessarily includes a better understanding of the individual contributions of each common variant to the cellular phenotypes, and interactions with other genes and with the environment. Future genetic studies in MS will likely focus on the role of rare variants and endophenotypes. Multiple sclerosis (MS) is a common autoimmune disease that targets myelin in the central nervous system (CNS). Multiple genome-wide association studies (GWAS) over the past 10 years have uncovered more than 200 loci that independently contribute to disease pathogenesis. As with many other complex diseases, risk of developing MS is driven by multiple common variants whose biological effects are not immediately clear. Here, we present a historical perspective on the progress made in MS genetics and discuss current work geared towards creating a more complete model that accurately represents the genetic landscape of MS susceptibility. Such a model necessarily includes a better understanding of the individual contributions of each common variant to the cellular phenotypes, and interactions with other genes and with the environment. Future genetic studies in MS will likely focus on the role of rare variants and endophenotypes. regions of the genome containing DNA sequence variants that influence the expression level of one or more genes. examination of a genome-wide set of genetic variants in different individuals to see whether any variant is associated with a trait. GWASs typically focus on associations between single-nucleotide polymorphisms (SNPs) and traits such as major human diseases, but can equally be applied to any other organism. a process leading to scars in the CNS that involves the production of a dense fibrous network of neuroglia (supporting cells) in areas of damage. In MS, gliosis ensues after axonal loss. a statistical term representing the proportion of phenotypic variance attributable to genetic variance. a genomic locus encoding the MHC proteins in humans. the entire set of molecular interactions of a cell or target protein. in population genetics, LD is the nonrandom association of alleles at different loci in a given population. in genetics, the OR is one way to quantify how strongly the presence or absence of a given phenotype is associated with the frequency of a particular allele in a specific population a set of cell surface proteins essential for the acquired immune system to recognize foreign molecules in vertebrates, which in turn determines histocompatibility. Failure to match HLA types between donor and recipient in an organ or tissue transplant can result in rejection. the study of genetic material recovered directly from environmental samples. Here, it refers to the genomes of bacteria and other microorganisms around or inhabiting the human body. an NIH-sponsored initiative to produce a public resource of human epigenomic data to catalyze basic biology and disease-oriented research. immunological tolerance is the failure to mount an immune response to an antigen. Self-tolerance refers to the (normal) failure to respond to one own’s antigens, thus avoiding avoid autoimmunity. in the splicing of RNA, the site at the 3′ end of an intron.