Identifying Register-Based Severity Trajectories in Anorexia Nervosa: Associations with Polygenic Scores, Psychiatric and Somatic Conditions

Importance. Anorexia nervosa (AN) is a severe metabo-psychiatric disorder with heterogeneous outcomes and elevated mortality. Characterizing severity trajectories may improve early risk stratification and targeted intervention. Objective. To identify AN severity trajectories using a register-based severity index (AN-RSI) and examine their associations with polygenic scores (PGS), preceding (prior to AN diagnosis) as well as subsequent (5 years post AN diagnosis) psychiatric and somatic disorders. Design. Population-based cohort study. Setting. Nationwide study in Denmark. Participants. Individuals born between 1969 and 2013 with diagnosed AN (N = 9,534 individuals). Genetic data were available in a subsample comprising 5,126 individuals. Exposures. Forty-one PGS indexing traits relevant to AN, and psychiatric and somatic disorders prior to AN diagnosis. Main Outcomes and Measures. The main outcomes of interest were the AN-RSI trajectories and psychiatric and somatic disorders 5 years post AN diagnosis. Results. Three trajectories were identified: "low and stable" (32.6%), "medium and stable" (53.5%), and "high increasing" (14.0%). The "low and stable" group was used as the comparison group for all analyses. Each 1 standard deviation (SD) increase in AN PGS corresponded with 13% greater odds of following the "high increasing" trajectory. Increases in BMI and attention-deficit/hyperactivity disorder PGS corresponded with 15% and 14% lower odds of following the "high increasing" trajectory, respectively. No preceding psychiatric or somatic disorders were significantly associated with trajectory assignment. In contrast, psychiatric and somatic disorders were more likely to occur subsequent to an AN diagnosis in those in the "high increasing" trajectory with odds ratios (OR) ranging between 1.73 and 3.81 for psychiatric disorders and between 1.61 and 5.38 for somatic disorders with a notable exception of obesity which showed a lower OR of 0.27. Conclusions and Relevance. Our findings hold significant clinical relevance by demonstrating that individuals with AN follow distinct severity trajectories that have different genetic risk as measured by PGS and clear differences in post-diagnosis morbidity patterns but no discernable differences in pre-diagnosis psychiatric or somatic morbidity. As the eating disorders genetics field progresses, incorporating PGS into comprehensive assessments at first presentation may aid in early identification, personalized intervention, and resource allocation for individuals at higher risk of developing a severe illness trajectory.