Psychiatric comorbidities in Asperger syndrome are related with polygenic overlap and differ from other Autism subtypes

• Published in: Translational psychiatry 2020-07, Vol.10 (1), p.258-258, Article 258
• Main Authors: González-Peñas, Javier, Costas, Javier Costas, García-Alcón, Alicia, Penzol, María José, Rodríguez, Julio, Rodríguez-Fontenla, Cristina, Alonso-González, Aitana, Fernández-Prieto, Montse, Carracedo, Ángel, Arango, Celso, Parellada, Mara
• Format: Article
• Language: English
• Subjects: 631/208/212/2166; 692/699/476/1373; Asperger Syndrome - epidemiology; Asperger Syndrome - genetics; Attention Deficit Disorder with Hyperactivity - epidemiology; Attention Deficit Disorder with Hyperactivity - genetics; Attention deficit hyperactivity disorder; Autism; Autism Spectrum Disorder - epidemiology; Autism Spectrum Disorder - genetics; Autistic Disorder - epidemiology; Autistic Disorder - genetics; Behavioral Sciences; Biological Psychology; Child; Consortia; Gene expression; Genome-Wide Association Study; Humans; Medicine; Medicine & Public Health; Multifactorial Inheritance; Neurosciences; Obsessive compulsive disorder; Pharmacotherapy; Psychiatry
• ISSN: 2158-3188; 2158-3188
• DOI: 10.1038/s41398-020-00939-7

There is great phenotypic heterogeneity within autism spectrum disorders (ASD), which has led to question their classification into a single diagnostic category. The study of the common genetic variation in ASD has suggested a greater contribution of other psychiatric conditions in Asperger syndrome (AS) than in the rest of the DSM-IV ASD subtypes (Non_AS). Here, using available genetic data from previously performed genome-wide association studies (GWAS), we aimed to study the genetic overlap between five of the most related disorders (schizophrenia (SCZ), major depression disorder (MDD), attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorders (OCD) and anxiety (ANX)), and AS, comparing it with the overlap in Non_AS subtypes. A Spanish cohort of autism trios ( N  = 371) was exome sequenced as part of the Autism Sequencing Consortium (ASC) and 241 trios were extensively characterized to be diagnosed with AS following DSM-IV and Gillberg’s criteria ( N  = 39) or not ( N  = 202). Following exome imputation, polygenic risk scores (PRS) were calculated for ASD, SCZ, ADHD, MDD, ANX, and OCD (from available summary data from Psychiatric Genomic Consortium (PGC) repository) in the Spanish trios’ cohort. By using polygenic transmission disequilibrium test (pTDT), we reported that risk for SCZ ( P scz  = 0.008, corrected- P SCZ  = 0.0409), ADHD ( P ADHD  = 0.021, corrected-P ADHD  = 0.0301), and MDD ( P MDD  = 0.039, corrected-P MDD  = 0.0501) is over-transmitted to children with AS but not to Non_AS. Indeed, agnostic clustering procedure with deviation values from pTDT tests suggested two differentiated clusters of subjects, one of which is significantly enriched in AS ( P  = 0.025). Subsequent analysis with S-Predixcan, a recently developed software to predict gene expression from genotype data, revealed a clear pattern of correlation between cortical gene expression in ADHD and AS ( P