Toggle Health Problems and D

Multiple Sclerosis 40% more likely in obese than in overweight (Mendelian randomization) Jan 2018

Mendelian randomization in multiple sclerosis: A causal role for vitamin D and obesity?

Multiple Sclerosis Journal, January 8, 2018
Adil Harroud, J Brent Richards


Not a surprise

  • Obese have lower levels of vitamin D
  • Lower level of vitamin D (for any reason) increases the risk of Multiple Sclerosis

Items in both categories Multiple Sclerosis and Obesity are listed here:

 Download the PDF from VitaminDWiki

The etiology of multiple sclerosis (MS) involves a complex interplay of genetic and environmental factors. Epidemiologic studies have furthered our understanding of these risk factors but remain limited by residual confounding and potential for reverse causation, particularly in MS where time of disease onset is not known. Mendelian randomization (MR) uses genetic variants to study the causal effect of modifiable exposures on an outcome. This method avoids some of the limitations of classical epidemiology and can strengthen causal inference. Here, we introduce the basic concepts of MR and review its contributions to the field of MS. Indeed, several studies using MR have now provided support for a causal role for low vitamin D level and obesity in the development of MS.

Table 1. Limitations of MR and how to address them



  • 1. Olsson, T, Barcellos, LF, Alfredsson, L. Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis. Nat Rev Neurol 2017; 13: 25–36. Google Scholar, Crossref, Medline
  • 2. Van der Mei, I, Lucas, RM, Taylor, BV. Population attributable fractions and joint effects of key risk factors for multiple sclerosis. Mult Scler 2016; 22: 461–469. Google Scholar, Link
  • 3. International Multiple Sclerosis Genetics Consortium, Beecham, AH, Patsopoulos, NA. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat Genet 2013; 45: 1353–1360. Google Scholar, Crossref, Medline
  • 4. Smith, GD, Lawlor, DA, Harbord, R. Clustered environments and randomized genes: A fundamental distinction between conventional and genetic epidemiology. PLoS Med 2007; 4: e352. Google Scholar, Crossref, Medline
  • 5. Marrie, RA, Yu, N, Wei, Y. High rates of physician services utilization at least five years before multiple sclerosis diagnosis. Mult Scler 2013; 19: 1113–1119. Google Scholar, Link
  • 6. Hughes, AM, Lucas, RM, McMichael, AJ. Early-life hygiene-related factors affect risk of central nervous system demyelination and asthma differentially. Clin Exp Immunol 2013; 172: 466–474. Google Scholar, Crossref, Medline
  • 7. Magyari, M, Koch-Henriksen, N, Pfleger, CC. Reproduction and the risk of multiple sclerosis. Mult Scler 2013; 19: 1604–1609. Google Scholar, Link
  • 8. Hedstrom, AK, Hillert, J, Olsson, T. Reverse causality behind the association between reproductive history and MS. Mult Scler 2014; 20: 406–411. Google Scholar, Link
  • 9. Lawlor, DA, Harbord, RM, Sterne, JA. Mendelian randomization: Using genes as instruments for making causal inferences in epidemiology. Stat Med 2008; 27: 1133–1163. Google Scholar, Crossref, Medline
  • 10. Mokry, LE, Ahmad, O, Forgetta, V. Mendelian randomisation applied to drug development in cardiovascular disease: A review. J Med Genet 2015; 52: 71–79. Google Scholar, Crossref, Medline
  • 11. Nielsen, NM, Munger, KL, Koch-Henriksen, N. Neonatal vitamin D status and risk of multiple sclerosis: A population-based case-control study. Neurology 2017; 88: 44–51. Google Scholar, Crossref, Medline
  • 12. Davey Smith, G, Hemani, G. Mendelian randomization: Genetic anchors for causal inference in epidemiological studies. Hum Mol Genet 2014; 23: R89–98. Google Scholar, Crossref, Medline
  • 13. Bowden, J, Davey Smith, G, Burgess, S. Mendelian randomization with invalid instruments: Effect estimation and bias detection through Egger regression. Int J Epidemiol 2015; 44: 512–525. Google Scholar, Crossref, Medline
  • 14. Interleukin-6 Receptor Mendelian Randomisation Analysis Consortium, Swerdlow, DI, Holmes, MV. The interleukin-6 receptor as a target for prevention of coronary heart disease: A Mendelian randomisation analysis. Lancet 2012; 379: 1214–1224. Google Scholar, Crossref, Medline
  • 15. Kleveland, O, Kunszt, G, Bratlie, M. Effect of a single dose of the interleukin-6 receptor antagonist tocilizumab on inflammation and troponin T release in patients with non-ST-elevation myocardial infarction: A double-blind, randomized, placebo-controlled phase 2 trial. Eur Heart J 2016; 37: 2406–2413. Google Scholar, Crossref, Medline
  • 16. Burgess, S, Timpson, NJ, Ebrahim, S. Mendelian randomization: Where are we now and where are we going? Int J Epidemiol 2015; 44: 379–388. Google Scholar, Crossref, Medline
  • 17. Noyce, AJ, Nalls, MA. Mendelian randomization–The key to understanding aspects of Parkinson’s disease causation? Mov Disord 2016; 31: 478–483. Google Scholar, Crossref, Medline
  • 18. Looker, AC, Pfeiffer, CM, Lacher, DA. Serum 25-hydroxyvitamin D status of the US population: 1988–1994 compared with 2000–2004. Am J Clin Nutr 2008; 88: 1519–1527. Google Scholar, Crossref, Medline
  • 19. Flegal, KM, Kruszon-Moran, D, Carroll, MD. Trends in obesity among adults in the United States, 2005 to 2014. JAMA 2016; 315: 2284–2291. Google Scholar, Crossref, Medline
  • 20. Salzer, J, Hallmans, G, Nystrom, M. Vitamin D as a protective factor in multiple sclerosis. Neurology 2012; 79: 2140–2145. Google Scholar, Crossref, Medline
  • 21. Munger, KL, Levin, LI, Hollis, BW. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 2006; 296: 2832–2838. Google Scholar, Crossref, Medline
  • 22. Munger, KL, Zhang, SM, O’Reilly, E. Vitamin D intake and incidence of multiple sclerosis. Neurology 2004; 62: 60–65. Google Scholar, Crossref, Medline
    in VitaminDWiki Multiple Sclerosis risk reduced 40% in 92,000 women taking more than 400 IU of vitamin D – 2004
  • 23. Mokry, LE, Ross, S, Ahmad, OS. Vitamin D and risk of multiple sclerosis: A Mendelian randomization Study. PLoS Med 2015; 12: e1001866. Google Scholar, Crossref, Medline
  • 24. International Multiple Sclerosis Genetics Consortium, Wellcome Trust Case Control Consortium, Sawcer, S. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 2011; 476: 214–219. Google Scholar, Crossref, Medline
  • 25. Rhead, B, Baarnhielm, M, Gianfrancesco, M. Mendelian randomization shows a causal effect of low vitamin D on multiple sclerosis risk. Neurol Genet 2016; 2: e97. Google Scholar, Crossref, Medline
  • 26. Gianfrancesco, MA, Stridh, P, Rhead, B. Evidence for a causal relationship between low vitamin D, high BMI, and pediatric-onset MS. Neurology 2017; 88: 1623–1629. Google Scholar, Crossref, Medline
  • 27. Munger, KL, Chitnis, T, Ascherio, A. Body size and risk of MS in two cohorts of US women. Neurology 2009; 73: 1543–1550. Google Scholar, Crossref, Medline
  • 28. Langer-Gould, A, Brara, SM, Beaber, BE. Childhood obesity and risk of pediatric multiple sclerosis and clinically isolated syndrome. Neurology 2013; 80: 548–552. Google Scholar, Crossref, Medline
  • 29. Munger, KL, Bentzen, J, Laursen, B. Childhood body mass index and multiple sclerosis risk: A long-term cohort study. Mult Scler 2013; 19: 1323–1329. Google Scholar, Link
  • 30. Hedstrom, AK, Olsson, T, Alfredsson, L. Body mass index during adolescence, rather than childhood, is critical in determining MS risk. Mult Scler 2016; 22: 878–883. Google Scholar, Link
  • 31. Mokry, LE, Ross, S, Timpson, NJ. Obesity and multiple sclerosis: A Mendelian randomization study. PLoS Med 2016; 13: e1002053. Google Scholar, Crossref, Medline
  • 32. Locke, AE, Kahali, B, Berndt, SI. Genetic studies of body mass index yield new insights for obesity biology. Nature 2015; 518: 197–206. Google Scholar, Crossref, Medline
  • 33. Gianfrancesco, MA, Glymour, MM, Walter, S. Causal effect of genetic variants associated with Body Mass Index on multiple sclerosis susceptibility. Am J Epidemiol 2017; 185: 162–171. Google Scholar, Medline
  • 34. Felix, JF, Bradfield, JP, Monnereau, C. Genome-wide association analysis identifies three new susceptibility loci for childhood Body Mass Index. Hum Mol Genet 2016; 25: 389–403. Google Scholar, Crossref, Medline
  • 35. Pierce, BL, Ahsan, H, Vanderweele, TJ. Power and instrument strength requirements for Mendelian randomization studies using multiple genetic variants. Int J Epidemiol 2011; 40: 740–752. Google Scholar, Crossref, Medline
  • 36. Sovio, U, Mook-Kanamori, DO, Warrington, NM. Association between common variation at the FTO locus and changes in body mass index from infancy to late childhood: The complex nature of genetic association through growth and development. PLoS Genet 2011; 7: e1001307. Google Scholar, Crossref, Medline
  • 37. Pakpoor, J, Pakpoor, J. Childhood obesity and risk of pediatric multiple sclerosis and clinically isolated syndrome. Neurology 2013; 81: 1366. Google Scholar, Crossref, Medline
  • 38. Vimaleswaran, KS, Berry, DJ, Lu, C. Causal relationship between obesity and vitamin D status: Bi-directional Mendelian randomization analysis of multiple cohorts. PLoS Med 2013; 10: e1001383. Google Scholar, Crossref, Medline
  • 39. Kraszula, L, Jasinska, A, Eusebio, M. Evaluation of the relationship between leptin, resistin, adiponectin and natural regulatory T cells in relapsing-remitting multiple sclerosis. Neurol Neurochir Pol 2012; 46: 22–28. Google Scholar, Crossref, Medline
  • 40. Piccio, L, Cantoni, C, Henderson, JG. Lack of adiponectin leads to increased lymphocyte activation and increased disease severity in a mouse model of multiple sclerosis. Eur J Immunol 2013; 43: 2089–2100. Google Scholar, Crossref, Medline
  • 41. Devorak, J, Mokry, LE, Morris, JA. Large differences in adiponectin levels have no clear effect on multiple sclerosis risk: A Mendelian randomization study. Mult Scler 2016: 1352458516681196. Google Scholar
  • 42. Hedstrom, AK, Lima Bomfim, I, Barcellos, L. Interaction between adolescent obesity and HLA risk genes in the etiology of multiple sclerosis. Neurology 2014; 82: 865–872. Google Scholar, Crossref, Medline

Created by admin. Last Modification: Saturday April 7, 2018 22:29:40 GMT-0000 by admin. (Version 6)

Attached files

ID Name Comment Uploaded Size Downloads
9171 MS MR Table 1.jpg admin 13 Jan, 2018 11:11 84.57 Kb 364
9170 Mendelian randomization in multiple sclerosis.pdf PDF 2018 admin 13 Jan, 2018 11:11 79.36 Kb 425
See any problem with this page? Report it (FINALLY WORKS)