A Mendelian randomization 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 whom persistent hyperglycaemia in diabetes was common.

Methods: A trans-ancestry genetic instrument for BMI (from 724 BMI-associated single-nucleotide polymorphisms) 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 genetic instrument explained 3% of the 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 the risk of all-cause mortality at ages 35-74 years [13 066 deaths; hazard ratio (HR) 1.80, 95% confidence interval (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, 95% CI 1.27-1.71) and particularly strong for renal (n =  2034; HR 3.59, 95% CI 2.76-4.67), acute diabetic crises (n =  557; HR 2.70, 95% CI 1.64-4.44), and infective deaths (n =  811; HR 2.61, 95% CI 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 half after simple adjustment for genetic predisposition to diabetes. Sensitivity analyses supported the main conclusions.

Conclusion: In this Mexican population, genetically predicted lifelong BMI was strongly related to mortality and mediated substantially through diabetes.