{"doi":"10.1177/1352458521995484","title":"The relative contributions of obesity, vitamin D, leptin, and adiponectin to multiple sclerosis risk: A Mendelian randomization mediation analysis","abstract":"BACKGROUND: Obesity is associated with increased risk of multiple sclerosis (MS); however, the underlying mechanisms remain unclear. OBJECTIVE: To determine the extent to which decreased vitamin D bioavailability and altered levels of adiponectin and leptin mediate the association between obesity and MS. METHODS: We performed Mendelian randomization (MR) analyses to estimate the effects on MS of body mass index (BMI), 25-hydroxyvitamin D (25OHD), adiponectin, and leptin levels in a cohort of 14,802 MS cases and 26,703 controls. We then estimated the proportion of the effect of obesity on MS explained by these potential mediators. RESULTS: Genetic predisposition to higher BMI was associated with increased MS risk (odds ratio (OR) = 1.33 per standard deviation (SD), 95% confidence interval (CI) = 1.09-1.63), while higher 25OHD levels reduced odds of MS (OR = 0.72 per SD, 95% CI = 0.60-0.87). In contrast, we observed no effect of adiponectin or leptin. In MR mediation analysis, 5.2% of the association between BMI and MS was attributed to obesity lowering 25OHD levels (95% CI = 0.3%-31.0%). CONCLUSIONS: This study found that a minority of the increased risk of MS conferred by obesity is mediated by lowered vitamin D levels, while leptin and adiponectin had no effect. Consequently, vitamin D supplementation would only modestly reverse the effect of obesity on MS.","journal":"Multiple Sclerosis Journal","year":2021,"id":157371,"datarank":1.4738562417314047,"base_score":3.9318256327243257,"endowment":3.9318256327243257,"self_citation_contribution":0.5897738449086489,"citation_network_contribution":0.8840823968227558,"self_endowment_contribution":0.5897738449086489,"citer_contribution":0.8840823968227558,"corpus_percentile":null,"corpus_rank":null,"citation_count":50,"citer_count":47,"citers_with_citation_signal":34,"citers_with_endowment":34,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.954,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":663909,"name":"Despoina Manousaki","orcid":"0000-0002-4133-0618","position":1,"is_corresponding":false},{"id":267234,"name":"Guillaume Butler‐Laporte","orcid":"0000-0001-5388-0396","position":2,"is_corresponding":false},{"id":614742,"name":"Ruth E. Mitchell","orcid":"0000-0002-3506-160X","position":3,"is_corresponding":false},{"id":1528,"name":"George Davey Smith","orcid":"0000-0002-1407-8314","position":4,"is_corresponding":false},{"id":37303,"name":"J. Brent Richards","orcid":"0000-0002-3746-9086","position":5,"is_corresponding":false},{"id":1310,"name":"Sergio E. Baranzini","orcid":"0000-0003-0067-194X","position":6,"is_corresponding":false},{"id":267236,"name":"Adil Harroud","orcid":"0000-0003-2616-7274","position":0,"is_corresponding":true}],"reference_count":35,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:44:17.471040Z","pmid":"33605807","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}