NEW YORK (GenomeWeb) – Rare copy number alterations found in individuals from Japan with autism spectrum disorder (ASD) or schizophrenia overlap, new research suggests, lining up with results reported in Caucasian populations in the past.
As they reported in Cell Reports today, researchers from Nagoya University and elsewhere analyzed array comparative genomic hybridization (aCGH) data for more than 1,100 individuals with ASD, nearly 2,500 schizophrenia cases, and almost 2,100 unaffected controls, all from Japan. Their results highlighted 29 loci containing rare CNVs linked to both ASD and schizophrenia, spanning gene sets enriched for components of oxidative stress response, lipid metabolism, synapse/neuron projection, and other pathways.
The team's subsequent bioinformatic analysis, focused on eight loci linked to both conditions, led to dozens of shared candidate genes. Among them were synapse or neuron projection-related genes such as COMT, MAPK3 and other kinase-related genes, as well as genomic integrity genes such as CDC45.
"The identification of shared pathways and disease-relevant genes provides biological insights into autism spectrum disorder and schizophrenia," senior author Norio Ozaki, a researcher in the Department of Psychiatry at Nagoya University Graduate School of Medicine, said in a statement.
Although an abundance of rare CNVs has been reported in prior studies of individuals with ASD, schizophrenia, and other neurodevelopmental conditions, the team explained, most of the studies so far were done in individuals with European ancestry.
"[T]he majority of the previous CNV studies were carried out in Caucasian populations, limiting the generalization of pathogenic CNVs and relevant biological pathways to other populations," the authors wrote, adding that "clinical features of patients with pathogenic CNVs have not been fully examined in non-Caucasian populations."
Using Nimblegen or Agilent microarrays, the researchers profiled aCGH patterns in 1,132 Japanese individuals with ASD, 2,519 with schizophrenia, and 2,110 unaffected controls from the same population. Following quality control steps, they were left with data for 1,108 ASD cases, 2,458 schizophrenia cases, and 2,096 controls.
Starting from 14,959 copy number variants found at less than 1 percent frequency in the Japanese population, the team focused in on 89 clinically significant CNVs in the individuals with ASD, 210 in the schizophrenia cases, and 70 in unaffected controls. Of those, 29 CNV loci were shared between the ASD and schizophrenia groups, which both showed an overrepresentation of rare CNVs compared to the control group.
Along with their gene set analyses, candidate gene search, and assessment of new disease-linked loci, the researchers used phenotypic data for 74 individuals with ASD and 105 with schizophrenia to search for ties between CNV representation and specific symptoms. Their results showed, for example, that the presence of clinically significant CNVs tended to coincide with intellectual disability in both conditions.
"As phenotypic expressivity of clinically significant CNVs is age dependent, a prospective longitudinal study is required to obtain a more accurate picture of the associated phenotypic spectrum," the authors wrote. Still, they concluded that "the identification of shared pathways and disease-relevant genes provides biological insights into these disorders."