The genetics of multiple sclerosis: SNPs to pathways to pathogenesis

• Published in: Nature reviews. Genetics Vol. 9; no. 7; pp. 516 - 526
• Main Authors: Oksenberg, Jorge R, Hauser, Stephen L, Baranzini, Sergio E, Sawcer, Stephen
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-07-2008; Nature Publishing Group
• Subjects: Agriculture; Animal Genetics and Genomics; Animals; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Classical genetics, quantitative genetics, hybrids; Disease; DNA sequencing; Epidemiology; Fundamental and applied biological sciences. Psychology; Gene Function; Genes; Genetic aspects; Genetic disorders; Genetic Predisposition to Disease; Genetics of eukaryotes. Biological and molecular evolution; Genome, Human; Genomes; Health aspects; Health risk assessment; HLA Antigens - genetics; Human; Human Genetics; Humans; Medical sciences; Multiple sclerosis; Multiple Sclerosis - genetics; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis; Neurology; Nucleotide sequencing; Pathogenesis; Polymorphism, Single Nucleotide; review-article; Risk factors; Single nucleotide polymorphisms; United Kingdom; United States > US; San Francisco California; California; Human; Nervous system diseases; Genome organization; Multiple sclerosis; Pathogenesis; Susceptibility locus; Central nervous system disease; Genotype; Genetics; Single nucleotide polymorphism; Inflammatory disease
• ISSN: 1471-0056; 1471-0064
• DOI: 10.1038/nrg2395

Key Points
Multiple sclerosis (MS) clusters with the so-called complex genetic diseases, a group of common disorders characterized by modest disease-risk heritability and multifaceted gene–environment interactions.
The genetic component of MS is reflected in the co-occurrence of cases within families and the high prevalence in some ethnic populations (particularly those of northern European origin) compared with others (African and Asian groups), irrespective of geographic location.
Concordance in families for early and late clinical features indicates that genes influence age of onset, disease course and other aspects of the clinical phenotype in addition to susceptibility.
The
HLA-DRB1
gene on chromosome 6p21 is the strongest genetic factor identified as influencing MS susceptibility. However, recent studies suggest the possibility that complex
trans
-allelic interactions across the human leukocyte antigen (HLA) locus could determine the balance between susceptibility and resistance.
The power of genome-wide association (GWA) studies to isolate modest genetic variation associated with central nervous system autoimmunity was recently demonstrated with the confirmation of
IL2R
and
IL7R
as true MS disease genes.
Based on the allele-sharing date, common susceptibility alleles (that is, those with a frequency of >10%) are unlikely to increase the risk by more than a factor of 2.0. A 10,000–15,000 case GWA study would be a reasonable next step in the genetic analysis of MS.
Because of the redundancy and complexity inherent to the molecular, cellular and physiological pathways leading to disease, genetic studies in MS should move from the reductionist, single gene strategy to a multi-disciplinary, integrative and system-level research approach.
Progress in understanding the genetic basis of susceptibility to multiple sclerosis — a debilitating and genetically complex disease — is being obtained by a combination of advances in genome studies (through genome-wide association studies) and powerful systems-level approaches.
Multiple sclerosis (MS) is an autoimmune demyelinating disease and a common cause of neurological disability in young adults. The modest heritability of MS reflects complex genetic effects and multifaceted gene–environment interactions. The human leukocyte antigen (HLA) region is the strongest susceptibility locus for MS, but a genome-wide association study recently identified new susceptibility genes. Progress in high-throughput genotyping and sequencing technologies and a better understanding of the structural organization of the human genome, together with powerful brain-imaging techniques that refine the phenotype, suggest that the tools could finally exist to identify the full set of genes influencing the pathogenesis of MS.