A paper published last March in the Journal of Molecular Psychiatry confirmed the complexity of the genetics of these diseases, but also supported the concept that common biological themes “underlie this complexity.” Study results suggested several new candidate genes and genomic variants as contributors to autism, and the research team concluded that many more remain to be discovered.
Further evidence for the role of genomic aberrations in autism is found in the fact that the disorder occurs concurrently with diseases associated with known cytogenetic etiologies such as Fragile X syndrome. These account for <10% of cases, though. The remainder, often referred to as idiopathic autism, are considered highly heritable with a 5–10% recurrence rate in siblings and a 60–90% concordance rate in monozygotic twins.
Genome-wide studies of autistic individuals have implicated numerous minor risk alleles but few common variants, according to the researchers. This suggests a complex genetic model with many contributing loci. Genetic linkage and association studies have reportedly had limited success with pinpointing risk loci.
Studies of genome copy-number variations (CNVs), on the other hand, have identified several candidate loci, the scientists added. The researchers focused their analysis on rare inherited structural variants in autistic individuals and looked for potential enrichment of any functional categories assigned to genes overlapping the CNVs.
“We identified a set of genes that were over-represented for structural variations in our autism cases, and then we asked whether these genes were preferentially associated with biological functions such as brain development, or with similar phenotypes observed in mouse models of these genes,” Peter White, Ph.D., director of the Center for Biomedical Informatics at The Children’s Hospital of Philadelphia and lead author of the paper, explained to GEN. “It turned out that these genes were enriched in processes consistent with brain development, including regulation of synaptic function, synapse development, and neurotransmission.”
Dr. White’s analysis was based on the AGRE (autism genetic resource exchange) cohort of 5,431 affected and parental samples from 1,000 families, grouped into four sets based on the time when they were recruited. After applying various exclusion criteria, the final discovery cohort, which comprised set 4, included 1,793 subjects, and the replication cohort, composed of sets 1–3, included 1,702 subjects.
Of the genes they identified as enriched for inherited CNVs in ASD subjects, the ionotropic glutamate receptor GRIN2A and CNVs spanning both the islet cell autoantigen (ICA1) and the adjacent α-neurexin ligand NXPH1 were of particular interest. These genes were disrupted by CNVs in subjects from both autism cohorts and had no evidence of structural variation in healthy controls.
Their results, according to the authors, were consistent with the hypothesis that inherited autism risk is genetically highly heterogeneous, both from “our failure to find even a moderate frequency of autism-specific CNVs overlapping any single gene in our analysis and the lack of overlap between gene sets represented by the same autism-enriched functional terms in our two cohorts.”