Study Finds Obesity May Worsen Multiple Sclerosis: Genetic Analysis Points to Causal Link

A new study links obesity to an increased severity of multiple sclerosis.

Image Credit: BMI - Olivier Le Moal

A new study led by researchers at McGill University links obesity to an increased severity of multiple sclerosis (MS). The study, published in Annals of Neurology, aimed to build on findings from the largest genome-wide association study (GWAS) of MS severity to date, which provided extensive data but initially found no confirmed link between body mass index (BMI) and MS severity.¹

“Results showed a significant association between higher genetically-determined body mass index and increased MS severity (P = .02),” the researchers noted, adding that “The convergence of this genetic evidence with prior observational studies strengthens the association between obesity and adverse long-term disability in MS.”

For this study, researchers updated the statistical power and expanded the analysis of the original GWAS of MS severity data to incorporate a range of obesity measures beyond BMI, providing a more comprehensive view of how different aspects of obesity might impact disease progression in patients with MS .²

A larger GWAS with 806,834 participants was used to identify relevant genetic variants associated with obesity traits, which served as proxies for obesity in the analysis.³ “Mendelian randomization (MR), a technique that uses genetic variants as proxies for risk factors, allowed us to overcome confounding factors and reverse causality,” the authors explained. The original GWAS of 12,584 individuals with MS was then examined using MR to determine the effects of various obesity measures, including adipose distribution, on MS severity and progression.¹

The primary analysis showed that each standard deviation increase in BMI was associated with a 0.08-point increase in MS severity scores (P = .02). This association was measured using the Age-Related Multiple Sclerosis Severity Score (ARMSS). In addition to BMI, other measures of obesity, such as whole-body fat mass (WBF), body fat percentage (BFP), trunk fat percentage (TFP), and trunk fat mass (TFM), showed a positive correlation with MS severity. However, only WBF had a significant association (β = 0.08, P = .04). “Similar to BMI, we observed no heterogeneity, a null MR-Egger intercept, and a significant RAPS estimate (β = 0.08, P = .039),” the authors noted. The study found no significant association between MS severity and measures of fat distribution, such as waist-hip ratio adjusted for BMI and visceral adipose tissue.

While the study offers additional insights into the link between obesity and MS severity, the authors note several limitations. First, despite the robust MR approach, the analysis cannot fully eliminate the risk of pleiotropy, where genetic variants may influence MS severity through pathways other than obesity. Additionally, the genetic associations with MS severity were derived from data that did not stratify participants by sex, limiting the ability to examine potential sex-based differences. Collider bias, where obesity influences both MS onset and severity, remains a potential confounding factor despite efforts to account for it.

Obesity, which is a well-known risk factor for several autoimmune and inflammatory diseases, has been associated with MS onset in past research, with adolescent obesity nearly doubling the risk of developing the disease.⁴ However, the effect of obesity on MS prognosis and progression has remained less clear.⁵ The data from this study aligns with a previous prospective longitudinal study of 1,066 MS patients with a BMI ≥30 kg/m² at onset, which linked obesity to higher EDSS scores and a shorter time to reach EDSS 3.⁶

“This study provides MR evidence that strengthens the association between obesity and greater long-term disability in MS, identifying obesity as a potentially modifiable risk factor whose management could alleviate the severity of MS," the original authors wrote.¹ "To this end, the emergence of drug therapies targeting obesity presents a potential strategy for people with MS and co-morbid obesity."

References

1. Alzamanan F, Ding Y, Harroud A. Obesity and multiple sclerosis severity: a Mendelian randomization study. Ann Neurol. Published online October 21, 2024. doi:10.1002/ana.27112

2. International Multiple Sclerosis Genetics Consortium; MultipleMS Consortium. Locus for severity implicates CNS resilience in progression of multiple sclerosis. Nature. 2023;619(7969):323-331. doi:10.1038/s41586-023-06250-x

3. Pulit SL, Stoneman C, Morris AP, et al; GIANT Consortium. Meta-analysis of genome-wide association studies for body fat distribution in 694,649 individuals of European ancestry. Hum Mol Genet. 2019;28(1):166-174. doi:10.1093/hmg/ddy327

4. Munger KL, Chitnis T, Ascherio A. Body size and risk of MS in two cohorts of US women. Neurology. 2009;73:1543-1550. doi:10.1212/WNL.0b013e3181c0d6e0

5. Manuel Escobar J, Cortese M, Edan G, et al. Body mass index as a predictor of MS activity and progression among participants in BENEFIT. Mult Scler. 2022;28(8):1277-1285. doi:10.1177/13524585211061861

6. Lutfullin I, Eveslage M, Bittner S, et al. Association of obesity with disease outcome in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2023;94(1):57-61. doi:10.1136/jnnp-2022-329685