Does the influence of low body-mass index on diagnosis complicate genetic studies of the role of cardiometabolic traits in liability to anorexia nervosa?

Anorexia nervosa (AN) is an eating disorder for which the underlying aetiology remains mostly uncharacterised. Large-scale genetic studies of AN suggest a relationship between AN liability and cardiometabolic traits, such as lipid and glycaemic biology, which may reveal novel treatment targets through pharmacological or nutritional interventions. However, the role of body mass index (BMI) in the diagnosis of AN presents a challenge in the interpretation of these genetic studies. Specifically, BMI is a heritable trait with a genetic architecture that is related to cardiometabolic traits. This becomes particularly salient with the emergence of an "atypical" AN diagnosis whereby individuals display behaviours consistent with AN, but their BMI remains within normal or higher ranges. In this review, we outline the evidence from genetic studies that support a role of cardiometabolic traits in risk for AN, as well as the unmet need to study cardiometabolic factors in atypical AN. The influence of selection for individuals with low BMI, particularly from large, international studies that rely on cohorts that used older diagnostic criteria, will be discussed, along with efforts from the literature to disentangle these relationships. We conclude that there is at least some evidence that genetic susceptibility to lower BMI may impact the inferred cardiometabolic relationships with AN genetic liability; however, there remains genetic support for a role of metabolic factors in AN risk beyond what is directly attributable to weight related diagnostic considerations alone. Finally, we provide recommendations for future genetic studies exploring cardiometabolic traits across the spectrum of eating disorders.