TitleComorbid Analysis of Genes Associated with Autism Spectrum Disorders Reveals Differential Evolutionary Constraints.
Publication TypeJournal Article
Year of Publication2016
AuthorsDavid MM, Enard D, Ozturk A, Daniels J, Jung J-Y, Diaz-Beltran L, Wall DP
JournalPLoS One
Volume11
Issue7
Paginatione0157937
Date Published2016
ISSN1932-6203
KeywordsAutism Spectrum Disorder, Cluster Analysis, Databases, Genetic, Humans, International Classification of Diseases
Abstract

The burden of comorbidity in Autism Spectrum Disorder (ASD) is substantial. The symptoms of autism overlap with many other human conditions, reflecting common molecular pathologies suggesting that cross-disorder analysis will help prioritize autism gene candidates. Genes in the intersection between autism and related conditions may represent nonspecific indicators of dysregulation while genes unique to autism may play a more causal role. Thorough literature review allowed us to extract 125 ICD-9 codes comorbid to ASD that we mapped to 30 specific human disorders. In the present work, we performed an automated extraction of genes associated with ASD and its comorbid disorders, and found 1031 genes involved in ASD, among which 262 are involved in ASD only, with the remaining 779 involved in ASD and at least one comorbid disorder. A pathway analysis revealed 13 pathways not involved in any other comorbid disorders and therefore unique to ASD, all associated with basal cellular functions. These pathways differ from the pathways associated with both ASD and its comorbid conditions, with the latter being more specific to neural function. To determine whether the sequence of these genes have been subjected to differential evolutionary constraints, we studied long term constraints by looking into Genomic Evolutionary Rate Profiling, and showed that genes involved in several comorbid disorders seem to have undergone more purifying selection than the genes involved in ASD only. This result was corroborated by a higher dN/dS ratio for genes unique to ASD as compare to those that are shared between ASD and its comorbid disorders. Short-term evolutionary constraints showed the same trend as the pN/pS ratio indicates that genes unique to ASD were under significantly less evolutionary constraint than the genes associated with all other disorders.

DOI10.1371/journal.pone.0157937
Alternate JournalPLoS ONE
PubMed ID27414027
PubMed Central IDPMC4945013
Grant ListR01 MH090611 / MH / NIMH NIH HHS / United States