A Mendelian randomisation study of the effect of body mass index on 52 causes of death among 125 000 Mexican adults with admixed ancestry

Background: Persistent hyperglycaemia in diabetes can cause weight loss, distorting the association of adiposity with mortality. We estimated the lifelong associations of genetically-predicted body-mass index (BMI) with 52 causes of death among 125 003 Mexican adults, in which persistent hyperglycaemia in diabetes was common. Methods: A trans-ancestry genetic instrument for BMI (from 724 BMI-associated SNPs) estimated the causal relevance of BMI to mortality before age 75 years, stratified by sex and adjusted for age and underlying ancestry structure using a one-sample Mendelian Randomization (MR) approach. Two-sample MR and other sensitivity analyses were also performed. Results: The instrument explained 3% of BMI variation and predicted BMI similarly in men and women. Each 5 kg/m2 higher genetically-predicted BMI was associated with nearly a doubling in all-cause mortality at ages 35-74 years (13 066 deaths; hazard ratio [HR] 1.80, 95% CI 1.63-2.00). Hazard ratios were greater for vascular-metabolic (n=7111; HR 2.15, 95% CI 1.87-2.48) than for non-vascular metabolic causes (n=5955; HR 1.47, 1.27-1.71), and particularly strong for renal (n=2034; HR 3.59, 2.76-4.67), acute diabetic crises (n=557; HR 2.70, 1.64-4.44), and infective deaths (n=811; HR 2.61, 1.73-3.92). For all-cause mortality, HRs were somewhat greater at younger ages compared with older ages, and slightly larger in those with a higher proportion of Indigenous American ancestry. The strength of the association with mortality was reduced by more than one half after simple adjustment for genetic-predisposition to diabetes. Sensitivity analyses supported the main conclusions. Conclusions: In this Mexican population, genetically-predicted lifelong BMI was strongly related to mortality and mediated substantially through diabetes.