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Nature vs nurture: are environmental influences or genetic risk factors the prime driver in MS?


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The role of heritability and genetics in the development of MS has long been investigated and explored, with genetic analyses from the 1970s [1] and 1980s [2] indicating that single locus inheritance as an underlying risk factor is unlikely. Environmental factors, therefore, may also play a role in the underlying aetiology of MS and twin studies have provided science with the unique opportunity to unravel the relative contributions of nature and nurture to the pathogenesis of this disease.

As we continue to increase our knowledge around MS, it is valuable to consider some of the learnings that have emerged from recently published studies conducted in populations of monozygotic twins who are discordant for MS, that is where the occurrence or severity of MS differs between the two twins.

Twin studies offer a unique window into the underlying aetiology of MS

Studies conducted using populations of monozygotic twins are unique among epidemiological designs, permitting quantitative variations in a disease or trait to be attributed to genetic or environmental factors whilst removing potential bias owing to the shared family environment. However, such studies may be confounded when a volunteer approach is employed, leading to an over-representation of female and monozygotic twins. A review of six large population-based twin studies [3] published in 2009 concluded that, although a genetic contribution to the development of MS was evident, the magnitude of the genetic effect could not be definitively measured, in part due to the relative rarity of MS. Similarly, a meta-analysis of twin studies in MS [4] that attempted to clarify the relative contributions of genetic and environmental factors to disease aetiology concluded that MS is a complex disease originating from heterogeneous genetic and environmental factors, with further research required to fully elucidate heritable and non-heritable disease components.

More recent studies have examined factors such as the DNA methylation signatures [5] of monozygotic twins clinically discordant for MS, taking the first steps towards identifying epigenetic mechanisms that may underlie the pathogenesis of MS and provide the means of monitoring treatment effects. Similarly, a German study examining differences in plasma lipidomics [6] in monozygotic twins discordant for MS noted a potential role for altered lipid signalling in the disease. In addition, a case study examining deep DNA metagenomic sequencing [7] revealed a divergence in the oral microbiome of one set of monozygotic twins with discordant MS severity. Although the findings of this study are limited, the authors suggest that further research may be warranted to examine whether microbiome analysis could provide a useful tool for diagnosis or monitoring of treatment effects in individuals with MS. The observation of a potential role for the oral microbiome in MS is particularly interesting given the influences of the gut microbiome on inflammation noted in April’s ECTRIMS Insights article [8]

Immune signatures of MS in monozygotic twins

The role of the immune system in the pathogenesis of MS has also been explored using studies involving monozygotic twins. One study examined a relatively small population of six pairs of twins, where one twin had received an MS diagnosis whilst the co-twin was considered to carry a maximal familial risk for MS [9]. Subclinical neuroinflammation was observed in these ‘healthy’ twins, with sequencing of cells in the cerebrospinal fluid revealing clonal expansion of CD8+ T-cells, plasmablasts and CD4+ T-cells similar to that seen in the partner twin with a diagnosis of MS. A further study in a group of 43 twin pairs [10] confirmed distinct immune signatures of MS in both the twin with a diagnosis of MS, and seemingly healthy co-twins who were demonstrated to have subclinical neuroinflammation.

A more recent study by Ingelfinger and colleagues [11] investigated the peripheral immune signatures of 61 pairs of monozygotic twins who were discordant for MS. In this study, the authors aimed to further elucidate the influences of genetic and environmental factors in the pathogenesis of MS. An inflammatory shift in a monocyte cluster was identified in the twin partner with a diagnosis of MS, together with the emergence of interleukin-2 hyper-responsive transitional naïve helper T-cells and a variance in CD25 expression. These immune signatures were also observed in non-twin individuals with MS, further validating their potential usefulness as an MS-associated immune signature.

Promoting continued advances in research

ECTRIMS welcomes this increased knowledge around the roles of environmental and genetic factors in the aetiology of MS and applauds the efforts of the scientific community to constantly improve our understanding of the pathogenesis of MS. We remain optimistic that ongoing research, including the unique insights provided by twin studies, will bring with it greater advances to further improve our knowledge of how to best care for individuals with MS.

 

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ECTRIMS Insights articles are produced with an intent of being a neutral source of information sharing and objective analysis for the MS and neuroscience community. Unless otherwise stated, cited information in our articles does equivocate official endorsement from ECTRIMS. 

 

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REFERENCES

[1] Roberts DF, et al. J Epidemiol Community Health. 1979 Dec;33(4):229–235.

[2] Roberts DF, et al. J Neurol Sci. 1982 May;54(2):287–293.

[3] Hawkes CH, et al. Mult Scler. 2009 Jun;15(6):661–667.

[4] Fagnani C, et al. Mult Scler. 2015 Oct;21(11):1404–1413.

[5] Souren NY, et al. Nat Commun. 2019 May 7;10(1):2094.

[6] Penkert H, et al. Ann Clin Transl Neurol. 2020 Dec;7(12):2461–2466.

[7] Boullerne AI, et al. J Neuroimmunol. 2020 Jun 15;343:577237.

[8] ECTRIMS Insights: A Closer Look at How Diet and Lifestyle Can Impact MS. April 2022. Available at: https://www.ectrims.eu/insights/a-closer-look-at-how-diet-and-lifestyle-can-impact-ms/

[9] Beltrán E, et al. J Clin Invest. 2019 Nov 1;129(11):4758–4768.

[10] Gerdes LA, et al. Proc Natl Acad Sci USA. 2020 Sep 1;117(35):21546–21556.

[11] Ingelfinger F, et al. Nature. 2022 Mar;603(7899):152–158.