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

Abstract

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 overtransmitted 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 < 0.001) and a similar strong correlation pattern between MDD and AS, but also extendable to another non-brain tissue such as lung (P < 0.001). Altogether, these results support the idea of AS being qualitatively distinct from Non_AS autism and consistently evidence the genetic overlap between AS and ADHD, MDD, or SCZ.

Genetic Overlap Among Autism Spectrum Disorders and Other Neuropsychiatric Disorders

“…They reported that the risk of schizophrenia, ADHD, and major depressive disorder is transmitted from parents to children with Asperger syndrome, but that this does not occur in the other ASD subtypes. Their results support the idea that Asperger syndrome is qualitatively different from the rest of the ASD subtypes, and indicates a genetic overlap between Asperger syndrome and ADHD, major depressive disorder, and schizophrenia (58). Furthermore, polygenic risk scores in a recent GWAS of multiple psychiatric disorders revealed a high correlation between schizophrenia and bipolar disorder, a moderate correlation between major depressive disorder and schizophrenia, major depressive disorder and bipolar disorder, major depressive disorder and ADHD, and a small but significant correlation between schizophrenia and ASD.…”

“…Using polygenic risk scores, it has been reported that alleles overexpressed in patients with schizophrenia are also overexpressed in patients with bipolar disorder and ADHD, but not ASD (55)(56)(57). Moreover, González-Peñas et al (58) reported genetic overlap among five disorders (schizophrenia, major depressive disorder, ADHD, obsessivecompulsive disorder, and anxiety disorders) and Asperger syndrome or other ASD subtypes using polygenic risk scores. They reported that the risk of schizophrenia, ADHD, and major depressive disorder is transmitted from parents to children with Asperger syndrome, but that this does not occur in the other ASD subtypes.…”

Gender Differences in Misdiagnosis and Delayed Diagnosis among Adults with Autism Spectrum Disorder with No Language or Intellectual Disability

“…The clinical heterogeneity of ASD is at least partially due to the high comorbidity with other mental disorders, especially when represented in high-functioning forms. While the comorbidity with other psychiatric conditions might be over-represented among patients with mild ASD compared to those with severe forms [ 5 ], lifetime estimates of overlapping disorders in this subgroup are quite large, ranging from 70 to about 80% [ 6 , 7 ]. It has been suggested that ASD might both share a common etiopathological root with other disorders and be itself the ground where other disorders flourish [ 8 , 9 ].…”

Exploring Polygenic Contributors to Subgroups of Comorbid Conditions in Atism Spectrum Disorder

“…[15] Finally, a recent study used polygenic risk scores (PRS) derived from five psychiatric disorders, such as schizophrenia, major depressive disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorders, and anxiety, and found that the polygenic contributions could distinguish Asperger syndrome (a diagnostic category in the Diagnostic and Statistical Manual (DSM) 4 th Edition although this term is no longer used in the updated DSM-5) from individuals with other non-Asperger subtypes of ASD. [16,17] Despite these advances in understanding the relationships between the genetic bases for ASD and associated comorbidities, it is clear that these approaches require further development to fully understand the role of comorbid genetic risk within ASD.…”