Unveiling Multiple Sclerosis: The Impact of Early Environmental Exposure and Genetic Liability in Sardinian Families

Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system, characterized by inflammation, demyelination, gliosis, and neuronal loss. The etiology of MS involves both genetic and environmental factors, making heritability studies crucial for understanding its variability and identifying potential causal factors. In a recent study published in Genes, researchers Andrea Nova, Teresa Fazia, Valeria Saddi, Marialuisa Piras, and Luisa Bernardinelli estimated MS heritability using a Bayesian liability threshold model on extended families from the Sardinian province of Nuoro, Italy.

Heritability measures the proportion of trait variability explained by genetic variation. For complex diseases like MS, influenced by both genetic and environmental factors, quantifying heritability is essential. Previous studies mainly relied on twin designs, but the unique genetic background and environmental history of Sardinia presented an opportunity to explore MS heritability in a distinct population.

The study utilized a Bayesian liability threshold model to estimate MS heritability, addressing potential biases from ascertainment and shared environmental effects. The researchers sampled 89 MS-affected probands from a register of MS cases in Nuoro, reconstructing their genealogical trees to form 24 extended families. This sample included 790 individuals (118 MS cases and 672 healthy controls), with detailed demographic and MS-related data collected for analysis.

Key Findings
Environmental Factors Dominate MS Variability: The categorized year of birth (< 1946 or ≥ 1946) emerged as the primary explanatory factor, accounting for ~70% of MS liability variability. This suggests that early environmental exposures, such as post-World War II industrialization and changes in socioeconomic conditions, significantly influenced MS risk.

Genetic Contribution Varies by Birth Cohort: When stratifying the sample by year of birth, heritability estimates differed markedly. For individuals born before 1946, shared environmental effects and sex (female) were the main contributors. However, for those born on/after 1946, genetic factors became predominant, with heritability estimated at ~82%.

Sex and Shared Environment: For individuals born before 1946, sex (female vs. male) and shared environmental factors within families explained a significant portion of MS variability. This underscores the importance of considering both genetic and non-genetic factors in heritability studies.

Implications
The study highlights the dynamic interplay between genetic and environmental factors in MS etiology. The significant role of early environmental exposures in Sardinia suggests that changes post-1946, such as industrialization and improved healthcare, may have altered the landscape of MS risk. The high heritability in the post-1946 cohort indicates that genetic susceptibility became more prominent as environmental factors evolved.

Conclusion
This research underscores the importance of context-specific heritability studies, particularly for complex diseases like MS. The findings from Sardinia provide valuable insights into the genetic and environmental determinants of MS, emphasizing the need for further investigations into early environmental factors and their interaction with genetic susceptibility. Understanding these dynamics could inform prevention strategies and enhance our knowledge of MS etiology in diverse populations.

References
Nova, A., Fazia, T., Saddi, V., Piras, M., & Bernardinelli, L. (2023). Multiple Sclerosis Heritability Estimation on Sardinian Ascertained Extended Families Using Bayesian Liability Threshold Model. Genes, 14(8), 1579.