What is the inheritance pattern of Multiple Sclerosis (MS)?

Inheritance Pattern of Multiple Sclerosis

Multiple sclerosis (MS) follows a complex polygenic inheritance pattern rather than a simple Mendelian inheritance pattern, with both genetic and environmental factors contributing to disease susceptibility.

Genetic Architecture of MS

Non-Mendelian Inheritance

• MS is not a Mendelian disease with a simple inheritance pattern 1
• Multiple genes contribute to MS susceptibility, with no single major locus identified 2
• Genome screening studies provide strong evidence for exclusion of a major locus in MS 3

Family Patterns

• Higher incidence and prevalence in family members of affected individuals compared to the general population 1
• Increased relative risk of 20-40 times for siblings compared to general population 2
• Increased concordance rate in monozygotic compared to dizygotic twins, supporting genetic contribution 2
• Some families show MS cases across multiple generations, while others show cases only within a single generation 4

Key Genetic Factors

HLA Association

• The strongest and most consistently reported genetic association is with the Major Histocompatibility Complex (MHC) region on chromosome 6p 2
• HLA-DRB1*15 is particularly important as a risk modifier rather than an autosomal dominant acting gene 5
• In families with MS, HLA-DRB1*15 is frequently transmitted to affected offspring 5

Other Genetic Associations

• Over 200 genetic loci have been implicated in MS susceptibility through genome-wide association studies (GWAS) 1
• Associated genes include but are not limited to HLA classes I and II, T-cell receptor beta, CTLA4, ICAM1, and SH2D2A 3
• Each gene likely contributes a modest effect to overall risk 2

Environmental Factors

• Environmental factors are likely ubiquitous and act on a population basis rather than within family microenvironments 3
• The interplay between genetic and environmental factors complicates the inheritance pattern

Clinical Implications

Family Patterns

• Two distinct patterns may be observed in families with multiple MS cases 4:
  1. Families with MS across multiple generations: Higher annual relapse rate in second generation, higher frequency of progressive forms, and more patients with additional autoimmune diseases
  2. Families with MS in a single generation: Higher frequency of relapsing-remitting forms

Genetic Testing

• Due to the complex polygenic nature of MS, there is currently no clinically useful genetic test to predict MS risk
• Genetic screening has limited benefit due to the multifactorial nature of the disease

Conclusion

MS inheritance follows a complex pattern involving multiple genes of moderate effect combined with environmental factors. The HLA-DRB1*15 allele represents the strongest genetic association, but it acts as a risk modifier rather than a causative gene. The polygenic nature of MS makes it difficult to predict inheritance patterns with certainty, though family history remains an important risk factor.