Background Autism is a neurodevelopmental disorder largely attributable to rare and common genetic variants. Additionally, environmental factors such as maternal immune activation and air pollution exposure can also increase the risk of autism. Genetic heterogeneity of autism has been well-recognized from gene discovery efforts over the past decade; however, genetic substrates of endophenotypes that constitute phenotypic heterogeneity are not known yet.
Methods Whole-genome sequencing (WGS) data and a set of phenotype scores that represent neurocognitive development and the severity of core symptoms of autism were collected from the iHART and MSSNG databases and the phenotype database of Autism Speaks. Endophenotype-wide association analysis was performed with genome-wide genotype and 29 phenotype scores.
Results One or more genetic loci were associated with each of phenotype scores at a genome-wide significance threshold ( P =5×10 -8 ) except for a total score of the Social Responsiveness Scale-2. An intergenic locus on chromosome 15q26.1 was significant for three core symptom domain scores of ADOS Module 1 while each phenotype score was associated with a unique set of genetic loci. The Repetitive Behaviors Scale total score was associated with the largest number of loci (N=132) including the loci that overlapped with the genes involved in brain development and neurodegenerative disorders. Among the significant genotype-endophenotype associations, verbal intelligence and the OSTN gene was notable. The secretory peptide osteocrin—encoded by OSTN —is implicated in activity dependent dendritic growth in human and has potential for a biomarker of autism and an endophenotype marker for verbal intelligence.
Limitations Validation of our findings in another cohort is required. Several associations involving the ADI-R and ADOS scores may indicate inherited allelic differences between affected and unaffected individuals since unaffected siblings were included in our analysis.
Conclusions Our results suggest that autism candidate genes discovered by case-control GWAS may include trait-associated genes for core symptoms.