The effect of FTO rs9939609 on major depression differs across MDD subtypes

Recently, Samaan et al.1 reported in this journal that the fat mass and obesity-associated protein (FTO) rs9939609 A variant was associated with a lower risk of major depressive disorder (MDD) independently from BMI. However, clinical heterogeneity may contribute to variability of results in association studies investigating the biologic and genetic underpinnings of MDD. Using data from the Netherlands Study of Depression and Anxiety (NESDA) we showed2 in a previous issue of the journal that depressed patients can be divided using data-driven techniques into a ‘typical’ (termed also ‘melancholic’) and an ‘atypical’ subtype differentiated mainly by the direction of change in vegetative symptoms (that is, appetite, weight and sleep) and associated with distinct biological correlates, pointing to a partially distinct pathophysiological and genetic liability. Therefore, considering our prior observations that obesity and increased appetite are more prevalent in atypical depression, and obesity rates are not different or even less prevalent as compared with controls in typical depression,2, 3, it can be expected that the FTO variant shows different associations across MDD subtypes. As an exemplification of our hypothesis, we performed the same association test between rs9939609 and MDD as in the paper of Samaan et al.1 In addition, we explored whether this association differed across clinical subtypes.