Abstract
BACKGROUND: There is limited evidence on the causal associations of life-course adiposity with the risk of respiratory diseases. This study aimed to elucidate these associations. METHODS: Two-sample Mendelian randomization was conducted using genetic instruments of life-course adiposity (including birth weight, childhood BMI, and adulthood adiposity) to estimate their causal effect on respiratory diseases in participants of European ancestry from the UK Biobank, the FinnGen consortium, and other large consortia. RESULTS: Genetically predicted higher birth weight was associated with decreased risk of acute upper respiratory infections and increased risk of pulmonary embolism, sleep apnea, and lung cancer. Genetically predicted high childhood BMI was associated with increased risk of asthma, COPD, pulmonary embolism, and sleep apnea. However, most of these observed associations were no longer significant after adjusting for adult BMI. Genetically predicted higher adult BMI and WHR were associated with 10 and 4 respiratory diseases, respectively. High adult body fat percentage and visceral adiposity were genetically associated with increased risk of 9 and 11 respiratory diseases, respectively. Consistently, genetically predicted higher whole-body fat mass was associated with increased risk of 8 respiratory diseases. CONCLUSIONS: This study provides genetic evidence that greater adiposity in childhood and adulthood has a causal effect in increasing the risk of a wide range of respiratory diseases. Furthermore, the effects of childhood obesity on respiratory outcomes may be mediated by adult obesity.