Does the Swedish Registry slay a fact, or two?

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Wow; what else that we think we know about MS is wrong? #MSBlog #MSResearch

“The great tragedy of science – the slaying of a beautiful hypothesis by an ugly fact.” Thomas Huxley


“The higher transmission rate of MS down the maternal (mother), compared to the paternal (father), line has been used as an argument to support many theories about the cause of MS. For example, the vertical transmission (mother-to-child) of an infectious agent or epigenetics* due to an intrauterine environmental effect. The large Swedish registry study below refutes this finding and suggests there is no increased maternal transmission of the disease. Who do you believe? The Swedish study is a population level study and is less likely to affected by recall bias.”

*Epigenetics are changes to the control of the genome or DNA, independent of the genetic code, that affect how the genome is controlled. Epigenetics is one way how the environment interacts with our genes. 

“This study therefore casts doubt on the intrauterine effect, and hence the epigenetic model of MS causation. I am in shock. I will need to step back and reconsider my position on a lot of things. This study also suggests that the familial risk has been overplayed in the past. Again this challenges current dogma  that is probably based on flawed ascertainment in other studies, i.e. people with a positive family history of MS are more likely to be diagnosed with MS and volunteer for studies. I can imagine somebody with a family member who has MS being more likely to have symptoms investigated, and hence being diagnosed with MS, and volunteering for research.”

“I think we need to get Professor Jan Hillert and Professor George Ebers to debate this paper and the implications of its findings on their thinking. Believe me the issues this paper raises are not trivial.”


“I must congratulate the Swedes on a wonderful paper. Well done.”

Epub: Westerlind H, Ramanujam R, Uvehag D, Kuja-Halkola R, Boman M, Bottai M, Lichtenstein P, Hillert J. Modest familial risks for multiple sclerosis: a registry-based study of the population of Sweden. Brain. 2014 Jan.

Background: Data on familial recurrence rates of complex diseases such as MS give important hints to aetiological factors such as the importance of genes and environment. By linking national registries, we sought to avoid common limitations of clinic-based studies such as low numbers, poor representation of the population and selection bias. 


Methods: Through the Swedish Multiple Sclerosis Registry and a nationwide hospital registry, a total of 28 396 MSers were identified. We used the national Multi-Generation Registry to identify first and second degree relatives as well as cousins, and the Swedish Twin Registry to identify twins of MSer. 

Results: Crude and age corrected familial risks were estimated for cases and found to be in the same range as previously published figures. Matched population-based controls were used to calculate relative risks, revealing lower estimates of familial multiple sclerosis risks than previously reported, with a sibling recurrence risk (λs = 7.1; 95% confidence interval: 6.42-7.86). Surprisingly, despite a well-established lower prevalence of MS among males, the relative risks were equal among maternal and paternal relations. A previously reported increased risk in maternal relations could thus not be replicated. An observed higher transmission rate from fathers to sons compared with mothers to sons suggested a higher transmission to offspring from the less prevalent sex; therefore, presence of the so-called ‘Carter effect’ could not be excluded. We estimated the heritability of  MS using 74 757 twin pairs with known zygosity, of which 315 were affected with MS, and added information from 2.5 million sibling pairs to increase power. The heritability was estimated to be 0.64 (0.36-0.76), whereas the shared environmental component was estimated to be 0.01 (0.00-0.18). 

Conclusion: In summary, whereas MS is to a great extent an inherited trait, the familial relative risks may be lower than usually reported.

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

7 comments

  • Does this change the estimated MS risk in siblings?
    In the past you have said there is a 4% chance of MS in siblings of MSers

  • These papers kill a maternal effect in MS. No month of birth, no increased risk for dizygotic twins as compared to full siblings and no increased risk for maternal half sibs. Therefore no effect of vitamin D?

    • I think Vit D is related to metabolism which has nothing to do with maternal genes etc.

      Everyone know that the month of birth effect is mumbo-jumbo!

      From my observation Vit D levels are related to the disease ACTIVITY in the body in general (my levels are notoriously low despite supplementation but even lower during attacks).

      I would recommend to read this study (quite recent one) where they found out that Vit D levels were low in healthy controls undergoing an operation so NOT MS-related.

  • I agree that this study challenges a lot of dogma that has crept into the MS literature and questions the role of epigenetics in MS pathogenesis. I agree low vD levels may be a chicken or egg and we need more hard science to understand the role of vD in MS pathogenesis. However, there is a very close correlation between MS prevalence (number of cases per 100,000 population) and ultraviolet exporsure. This is a consistent finding and therefore I think vD is involved in the MS causal pathway and is the reason why I make sure all the MSers I look after tell their families about the association and get them to take adequate vD levels.

    By the way there are large number of genetic factors that control vD levels; if you have low constitutional levels of vD despite adequate UV exposure and/or supplementation you are likely to have genes that cause low levels.

  • By the way I have emailed Prof. George Ebers for his thoughts on this paper. I am not sure he would agree with you about the month-of-birth effect being mumbo-jumbo.

    • Unless Prof George Ebers re-does his studies with the epidemiological accuracy conducted by Jan Hillert and Stephen Sawcer and colleagues it doesn't really matter what he says; his studies were flawed.

By Prof G

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