Exploring the clinical consequences and genetic aetiology of adult weight trajectories

Background: Longitudinal weight trajectories may reflect individual health status. We examined the genetic aetiology and clinical consequences of adult weight trajectories in males and females leveraging genetic and phenotypic data in the electronic health records (EHR) of the BioMeTM Biobank. Methods: We constructed four longitudinal weight trajectories using annual EHR-recorded weights (stable weight, weight gain, weight loss, or weight cycle) (n=21,487). After validating the accuracy of the trajectories (n=100), we conducted a hypothesis-free phenome-wide association study (PheWAS), including sex-stratified PheWAS, to identify diseases associated with each weight trajectory. We then performed a hypothesis-driven polygenic risk score (PRS) analysis on these weight trajectories, focusing on anorexia nervosa (AN) and depression--both commonly associated with weight changes. Findings: Weight trajectory classification was highly accurate (accuracy, sensitivity, and specificity > 97% for all four trajectories). Hypothesis-free PheWAS analyses identified a significant association between depression and weight cycle (OR=1.4, p[≤]7.7x10-16) after Bonferroni correction, but not with weight gain or loss. Compared to other weight trajectories, we also observed a significant association of osteoporosis-related phecodes with weight loss in females only (ORfemale=1.4, pfemale[≤]1.4x10-7, ORmale=0.8, pmale[≥]0.18). AN-PRS was positively associated with weight loss trajectory among individuals without eating disorder diagnoses (ORtop vs. bottom 10% PRS=1.95, p=0.00035). Consistent effect direction was observed across three ancestry groups. The AN-PRS-weight loss association was not attenuated by obesity-PRS (ORtop vs. bottom 10% PRS=1.94). Interpretation: Adult weight trajectory is associated with disease both phenotypically and genetically. Our PheWAS reveals unique relationships between diseases and weight trajectory patterns, including the association of depression and weight cycle trajectory in both males and females, and osteoporosis-weight loss trajectory association in females only. In addition, our PRS analysis suggests that adults with higher AN genetic risk are more likely to have a weight loss trajectory, and this association may be independent of BMI/obesity-related genetic pathways.