Body shape from birth to adulthood is associated with skeletal development: A Mendelian randomization study.

Abstract

Observational studies have shown that childhood obesity is associated with adult bone health but yield inconsistent results. We aimed to explore the potential causal association between body shape and skeletal development. We used two-sample Mendelian randomization (MR) to estimate causal relationships between body shape from birth to adulthood and skeletal phenotypes, with exposures including placental weight, birth weight, childhood obesity, BMI, lean mass, fat mass, waist circumference, and hip circumference. Independent genetic instruments associated with the exposures at the genome-wide significance level (P < 5 × 10^-8) were selected from corresponding large-scale genome-wide association studies. The inverse-variance weighted analysis was chosen as the primary method, and complementary MR analyses included the weighted median, MR-Egger, weighted mode, and simple mode. The MR analysis shows strong evidence that childhood (β = -1.29 × 10^-3, P = 8.61 × 10^-5) and adulthood BMI (β = -1.28 × 10^-3, P = 1.45 × 10^-10) were associated with humerus length. Tibiofemoral angle was negatively associated with childhood BMI (β = -3.60 × 10^-1, P = 3.00 × 10^-5) and adolescent BMI (β = -3.62 × 10^-1, P = 2.68 × 10^-3). In addition, genetically predicted levels of appendicular lean mass (β = 1.16 × 10^-3, P = 1.49 × 10^-13), whole body fat mass (β = 1.66 × 10^-3, P = 1.35 × 10^-9), waist circumference (β = 1.72 × 10^-3, P = 6.93 × 10^-8) and hip circumference (β =1.28 × 10^-3, P = 4.34 × 10^-6) were all associated with tibia length. However, we found no causal association between placental weight, birth weight and bone length/width. This large-scale MR analysis explores changes in growth patterns in the length/width of major bone sites, highlighting the important role of childhood body shape in bone development and providing insights into factors that may drive bone maturation.