Decoding the Genetic and Familial Landscape of Multiple Sclerosis

Multiple sclerosis (MS) is a complex disease that arises from the interplay between genetic and environmental factors. Over the past few decades, genetic epidemiological studies have provided significant insights into the genetic architecture of MS, with a focus on familial recurrence rates and genetic models. The heritability of MS has been estimated to be around 50%, with the genes involved mainly located within the major histocompatibility complex (MHC).

Genetic Associations:
Recent genome-wide association studies (GWAS) have revolutionized the genetics of MS, uncovering more than 200 implicated genetic loci. These studies have confirmed the role of the MHC region, with HLA-DRB1*15 being the most significant risk allele. Additionally, non-MHC loci, such as IL2RA, IL7R, and CD40, have been identified as playing a role in the susceptibility to MS.

Parent-of-Origin Effects:
Parent-of-origin effects, a phenomenon where the same allele from different parents has different effects on the offspring, have also been observed in MS. A study by Kantarci et al. found that men transmit MS more often to their children than women, suggesting a paternal parent-of-origin effect, or the Carter effect. This effect is thought to be caused by an interaction of genetic and environmental factors, with the possibility of epigenetic mechanisms playing a role.

Familial MS:
Familial MS represents 12.6% of all MS cases, with the risk depending on the degree of genetic proximity to the index case. Familial cases seem to have a different clinical presentation from sporadic cases, such as earlier worsening of disability and more severe long-term disability. Clinical correlations between different members of a family with MS have also been described, such as a similar age of onset between siblings.

Conclusion:
The genetic contribution to the risk of developing MS is now estimated to be about 50%, with the genes involved mainly located within the MHC. Familial MS represents 12.6% of all MS cases, with the risk depending on the degree of genetic proximity to the index case. Furthermore, these familial cases seem to have a different clinical presentation from sporadic cases such as earlier worsening of disability and more severe long-term disability. Clinical correlations between different members of a family with MS have also been described, such as a similar age of onset between siblings. These findings highlight the importance of understanding the genetic and familial aspects of MS in order to improve diagnosis, prognosis, and treatment strategies.

References:
Hoppenbrouwers, I. A. (2004). Genetic Epidemiological Studies of Multiple Sclerosis. The Lancet, 363(9423), 1773-1774.
Genetics of Multiple Sclerosis: An Overview and New Directions. (2019). NCBI.
Genetics and familial distribution of multiple sclerosis: A review. (2022). PubMed.
Multigenerational family with multiple sclerosis. (1999). Brain - Oxford Academic.
Elevated genetic risk for multiple sclerosis emerged in steppe populations during the Bronze Age. (2023). Nature.