Parent-of-Origin Influence on Multiple Sclerosis Risk in Mixed-Ancestry Individuals

Multiple sclerosis (MS) is a complex neurological condition, often marked by inflammation and myelin loss in the central nervous system (CNS). This chronic disorder is more prevalent among individuals of European descent, especially those from Northern Europe, while lower incidence rates are seen in North American Indigenous populations. S.V. Ramagopalan and colleagues, in a 2009 study published in Neurology, investigated MS susceptibility in individuals with mixed ancestry from European and North American Indigenous backgrounds. This study sheds light on how parental origin might influence MS risk, an important consideration as genetic and environmental factors both play a role in the disease's onset.

Study Background
The Canadian Collaborative Project on Genetic Susceptibility to Multiple Sclerosis (CCPGSMS) collected data on over 30,000 Canadian families, each with at least one member diagnosed with MS. From this database, the researchers focused on 58 individuals who had one Caucasian and one Indigenous parent. This unique population allowed the researchers to explore how MS susceptibility might vary based on whether the mother or father was of European or Indigenous descent, contributing to the broader understanding of maternal versus paternal effects in MS risk.

Methodology
The study classified individuals based on their maternal and paternal ethnic backgrounds, creating two primary groups: those with a Caucasian mother and an Indigenous father, and those with an Indigenous mother and a Caucasian father. Statistical analyses were conducted to compare the MS occurrence, sex ratio, and sib recurrence risk between these groups. Each participant provided consent, and ethical approvals were obtained for the data collection process across collaborating Canadian institutions.

Key Findings
Increased MS Risk with Caucasian Mothers: The study revealed a notable difference in MS risk related to the parent of origin. Individuals with a Caucasian mother and Indigenous father exhibited a higher sib recurrence risk (7.2%) compared to those with an Indigenous mother and Caucasian father (4.1%). This maternal effect supports previous findings that maternal lineage may play a role in MS susceptibility.

Sex Ratio Disparities: Among MS-affected offspring, there was a distinct difference in sex ratios. In the group with a Caucasian mother and Indigenous father, the female-to-male ratio was significantly skewed at 7:1. In contrast, those with an Indigenous mother and Caucasian father had a lower female-to-male ratio of 2:1. This gender disparity suggests that maternal factors may influence susceptibility to MS in females more strongly than in males, aligning with other studies that report a female predominance in MS cases.

Environmental Interactions and Maternal Influence: The authors propose that environmental exposures and interactions specific to mothers of European descent may contribute to MS risk, particularly in female offspring. Possible environmental influences include diet, lifestyle, and other maternal factors that differ between Caucasian and Indigenous populations.

Implications of the Findings
This study highlights the importance of parent-of-origin effects in MS and opens pathways to explore how maternal and paternal influences could affect disease risk differently. These findings also suggest that, beyond purely genetic contributions, environmental exposures specific to the maternal lineage may play a critical role. This could have implications for understanding gene-environment interactions in MS and developing targeted prevention strategies based on maternal environmental factors.

Conclusion
The study by Ramagopalan and colleagues provides valuable insights into the parent-of-origin effects on MS risk in mixed-ancestry populations, underscoring the complex interplay between genetics and environment in this disease. As research advances, understanding these maternal and paternal influences will be crucial in unraveling MS etiology, ultimately contributing to more personalized approaches in MS risk assessment and intervention strategies.

This work is a step forward in recognizing that, beyond genetic risk factors, epigenetic and environmental factors specific to parental origin are pivotal in understanding MS, especially in the context of diverse populations and mixed ancestries​.

References:
Ramagopalan, S. V., Yee, I. M., Dyment, D. A., Orton, S. M., Marrie, R. A., Sadovnick, A. D., & Ebers, G. C. (2009). Parent-of-origin effect in multiple sclerosis: observations from interracial matings. Neurology, 73(8), 602-605.