Disease similarity network analysis of Autism Spectrum Disorder and comorbid brain disorders

Background/Objectives: Autism Spectrum Disorder (ASD) is a clinically heterogeneous neurodevelopmental disorder , with variable severity and multiple comorbidities. Given the previous evidence of genetic overlap between ASD and several comorbid brain disorders, we sought to explore the genetic similarity with ASD across a range of brain disorders, using a genetic similarity disease network approach. Methods: We developed a genetic similarity disease network between ASD and Intellectual Disability, Attention-Deficit/Hyperactivity Disorder, Epilepsy, Schizophrenia and Bipolar Disease spectrum. Using gene-disease associations from the DisGeNET database, genetic similarities were estimated from the Jaccard coefficient between disease pairs. The Leiden algorithm identified network disease communities and shared biological pathways. Loss-of-function (LoF) rare de novo variants within shared genes underlying the disease communities were identified using the MSSNG whole-genome sequencing dataset. Results: We identified three disease communities. ASD is included in a heterogeneous community with Epilepsy, Bipolar Disorder, Attention-Deficit/Hyperactivity Disorder combined type, and some disorders in the Schizophrenia Spectrum. ASD and Intellectual Disability are in separate communities. The genes SHANK3, ASH1L, SCN2A, and CHD2, which are candidate genes for diseases in all communities, have a higher number of de novo rare LoF SNVs in ASD subjects. Conclusion: This approach enabled further clarification of genetic sharing between ASD and comorbid brain disorders, as we took advantage from a finer granularity in disease classification and multi-level evidence from DisGeNET, with important implications for disease nosology, pathophysiology, and personalized treatment. ; Fundação para a Ciência e a Tecnologia: BioSys PhD programme (Ref: PD/BD/131390/2017 from FCT (Portugal).; MEDPERSYST:PAC-POCI-01-0145-FEDER 016428;DeePer:(EXPL/CCI-BIO/0126/2021);National Institute of Health Doutor Ricardo Jorge. ...