Sex- and time-specific associations of obesity with glycaemic traits: A two-step multivariate Mendelian randomization study

Abstract

Aim: To assess the sex- and time-specific causal effects of obesity-related anthropometric traits on glycaemic traits.

Materials and methods: We used univariate and multivariate Mendelian randomization to assess the causal associations of anthropometric traits (gestational variables, birth weight, childhood body mass index [BMI], BMI, waist-to-hip ratio [WHR], BMI-adjusted WHR [WHR_adj BMI]) with fasting glucose and insulin in Europeans from the Early Growth Genetics Consortium (n ≤ 298 142), the UK Biobank, the Genetic Investigation of Anthropometric Traits Consortium (n ≤ 697 734; females: n ≤ 434 794; males: n ≤ 374 754) and the Meta-Analyses of Glucose and Insulin-related traits Consortium (n ≤ 151 188; females: n ≤ 73 089; males: n ≤ 67 506), adjusting for maternal genetic effects, smoking, alcohol consumption, and age at menarche.

Results: We observed a null association for gestational variables, a negative association for birth weight, and positive associations for childhood BMI and adult traits (BMI, WHR, and WHR_adj BMI). In female participants, increased birth weight causally decreased fasting insulin (beta_IVW , -0.07, 95% confidence interval [CI] -0.11 to -0.03; p = 1.92 × 10^-3 ), but not glucose levels, which was annulled by adjusting for age at menarche. In male participants, increased birth weight causally decreased fasting glucose (beta_{inverse-variance-weighted (IVW)} , -0.07, 95% CI -0.11 to -0.03; p = 3.22 × 10^-4 ), but not insulin levels. In time-specific analyses, independent effects of birth weight were absent in female participants, and were more pronounced in male participants. Independent effects of childhood BMI were attenuated in both sexes; independent effects of adult traits differed by sex.

Conclusions: Our findings provide evidence for causal and independent effects of sex- and time-specific anthropometric traits on glycaemic variables, and highlight the importance of considering multiple obesity exposures at different time points in the life course.

Keywords: age at menarche; birth weight; causal inference; childhood body mass index; fasting glucose level; fasting insulin level; obesity; sex-stratified analysis; waist-to-hip ratio.