5HTTLPR Polymorphism, stressful events, neuropsychological performance and brain connectivity in eating disorders

Abstract Introduction. Low functioning variants of 5HTTLPR have been associated to an increased risk of depression in subjects who experienced stressful events, to altered cognitive functioning and decisional processes, and functional and structural neural patterns. Contrasting evidence is available up to now in Eating Disorders (ED), and no study has evaluated the polymorphism effect on brain connectivity according to graph theory in Anorexia Nervosa (AN). Methods. We recruited up to 735 patients with life-time history of AN or bulimia nervosa (BN) according to DSM-IV criteria and up to 241 healthy controls (HC) for the assessment of the association between 5HTTLPR polymorphism and ED. We merged our Biobank data from BIO.Ve.D.A. and meta-analyzed 22 former studies. Patients underwent a structured diagnostic interview for present or life-time ED, an interview for presence and severity of stressful events, Edinburgh Handedness Inventory, Wisconsin Card Sorting Test, Trail A making test, Trail B making test, Iowa Gambling Task, Cognitive Bias Task, psychopathology rating scales for ED and general symptoms. Finally patients with AN and HCs underwent a Magnetic Resonance; their brains’ connectivity integration and segregation measures were then measured with Graph Analysis Toolbox, according to 5HTTLPR polymorpshim. Results. Our results from a meta-analysis including data from BIO.Ve.D.A. and 22 previous studies, suggest that 5HTTLPR polymorphism does not have a role per se in determing ED onset. However it may moderate the effect of SEs in increasing the risk of ED onset, and the influence of SEs on ED severity, anxious, depressive and obsessive symptoms. When we tested both a multiplicative and an additive model, which is considered to be more representative of a real-world gene by environment interaction, such a 5HTTLPR by SE interaction was not confirmed instead. S allele was associated with worse performance at Cognitive Bias Task and Trail Making B, and with increased ED psychopathology, general psychopathology, anxious, depressive, and obsessive symptoms. Finally S allele was associated with decreased segregation measures at brain connectivity analysis according to graph theory compared with L allele in AN; this was an opposite association compared with healthy controls who had higher modularity associated with S allele instead. Conclusions. 5HTTLPR polymorphism does not seem to be a causal factor of ED per se, but it seems to play a role in moderating the role of stressful events in increasing ED risk. Such a moderation however did not reflect a gene by environment interaction according to either a multiplicative or additive model. S allele was associated with higher psychopathology scores, and worse neuropsychological functions in AN, and with a disrupted segregation measures of brain signal connectivity compared to HCs.

Nella tesi si evidenzia come il polimorfismo 5HTTLPR non causi di per se alcun disturbo dell'alimentazione (DA), come possa moderare l'effetto degli eventi stressanti sul rischio di DA, ma come non interagisca secondo modello moltiplicativo o additivo con gli eventi stressanti nel predisporre a DA. Inoltre in pazienti con anoressia nervosa in presenza di un allele S si associa ad una peggiora performance neurocognitiva, e ad una connettività cerebrale alterata rispetto a quanto accade nei controlli sani in presenza dello stesso allele.