Using large-scale genome-wide genetic data on millions of individuals to understand causal inference and shared genetic basis between modifiable environmental exposures and multiple sclerosis

Multiple sclerosis (MS) is a progressive neurodegenerative autoimmune disorder. The estimated incidence and prevalence of MS in Sweden are among the highest globally.

Despite several MS-associated environmental factors have been identified, it remains difficult to pinpoint which of the many lifestyle changes that have occurred during the past are responsible for MS onset later on, as the observational nature of conventional epidemiological design hinders causal interpretation.Mendelian randomization (MR) is a novel statistical tool which incorporates genetic variants as instruments to make causal inference between exposures and outcomes (if all model assumptions are met).

Using this approach, the evidence on a causal role of vitamin D and obesity has been considerably strengthened in MS.

Current genetic discoveries for the many heritable/modifiable human complex traits (i.e. smoking, alcohol drinking, coffee consumption, physical activity, diet etc.) have provided an exceptional opportunity to evaluate a putative causal role of these exposures in MS, which have not been adequately studied.Therefore, to better understand disease mechanisms and inform intervention strategy, we propose to integrate extensive GWAS summary data on 47,429 MS cases and 68,374 controls, as well as publicly available large-scale GWAS summary data on a wide variety of modifiable exposures covering lifestyle, nutritional and psychosocial factors based on millions of individuals, to conduct MR analysis.

We will also calculate pairwise genetic correlations to understand causal overlap.

For 19,000 of the 47,429/68,374 participants, we also have access to individual-level genetic and questionnaire data, which provides a good opportunity to check model assumptions and validity of results.We anticipate the knowledge gained from this work could shed new lights on the mechanistic developmental process of MS, as well as facilitate patient care by providing a list of actionable prevention strategies.