Causal Effect of Genetic Variants Associated With Body Mass Index on Multiple Sclerosis Susceptibility

Abstract

Multiple sclerosis (MS) is an autoimmune disease with both genetic and environmental risk factors. Recent studies indicate that childhood and adolescent obesity double the risk of MS, but this association may reflect unmeasured confounders rather than causal effects of obesity. We used separate-sample Mendelian randomization to estimate the causal effect of body mass index (BMI) on susceptibility to MS. Using data from non-Hispanic white members of the Kaiser Permanente Medical Care Plan of Northern California (KPNC) (2006-2014; 1,104 cases of MS and 10,536 controls) and a replication data set from Sweden (the Epidemiological Investigation of MS (EIMS) and the Genes and Environment in MS (GEMS) studies, 2005-2013; 5,133 MS cases and 4,718 controls), we constructed a weighted genetic risk score using 97 variants previously established to predict BMI. Results were adjusted for birth year, sex, education, smoking status, ancestry, and genetic predictors of MS. Estimates in KPNC and Swedish data sets suggested that higher genetically induced BMI predicted greater susceptibility to MS (odds ratio = 1.13, 95% confidence interval: 1.04, 1.22 for the KPNC sample; odds ratio = 1.09, 95% confidence interval: 1.03, 1.15 for the Swedish sample). Although the mechanism remains unclear, to our knowledge, these findings support a causal effect of increased BMI on susceptibility to MS for the first time, and they suggest a role for inflammatory pathways that characterize both obesity and the MS disease process.

Paediatric multiple sclerosis: a new era in diagnosis and treatment

“…The association with obesity and vitamin D levels may also have an underlying genetic basis. Obesity risk alleles identified by a genome‐wide association study demonstrated a causal association with paediatric multiple sclerosis after adjustment for age, sex, ancestry, the HLA‐DRB1*15:01 allele, and over 100 non‐HLA multiple sclerosis risk variants . The same study used three genetic variants known to affect serum concentrations of 25‐hydroxy‐vitamin D levels to compute a genetic risk score which estimated the effect of each risk variant.…”

“…Obesity risk alleles identified by a genome-wide association study 56 demonstrated a causal association with paediatric multiple sclerosis after adjustment for age, sex, ancestry, the HLA-DRB1*15:01 allele, and over 100 non-HLA multiple sclerosis risk variants. 57 The same study used three genetic variants known to affect serum concentrations of 25-hydroxy-vitamin D levels to compute a genetic risk score which estimated the effect of each risk variant. The genetic risk score associated with increasing serum concentrations of 25-hydroxy-vitamin D decreased the odds of paediatric-onset multiple sclerosis.…”

Oleic acid Induces Tissue Resident FoxP3 Regulatory T cell Lineage Stability and Suppressive Functions

“…However, Th1-like T regs have also been described in models of chronic infection ( 86–88 ) and patients with type one diabetes (T1D) ( 26 ). Furthermore, childhood obesity has been linked as a risk factor for the development of MS ( 89–92 ). Therefore, using MS as our model, we used single cell RNA-sequencing to profile 1,334 T regs from peripheral blood and 805 T regs from adipose tissue of eight healthy donors and eight MS patients, two of whom are untreated (> ~1.5yrs at the time of the procedure), and the rest had previously received disease modifying treatments (DMTs) (> 6 months prior to the procedure, but were currently off treatment) (Supplemental Figure 10, Supplemental Figure 12, and Supplementary Table 3).…”

Obesity and Multiple Sclerosis Susceptibility: A Review

“…Attempts to determine a causal association between obesity and MS susceptibility have recently been conducted 41,42 . Mendelian randomization is a type of instrumental variable (IV) analysis that uses genetic variants strongly associated with an exposure, rather than a direct measure of the exposure, to estimate the effect of the exposure on an outcome.…”

“…One study indicated that obesity is causally associated with MS onset using an IV composed of 97 genetic variants associated with BMI 42 . Authors confirmed the results in two populations, and also found evidence that five BMI-associated genes had a direct effect on MS susceptibility.…”