Overlapping copy number variations underlie autism and schizophrenia in Japanese patients

September 11, 2018, Cell Press
This visual abstract depicts the comparative analyses of CNV in autism and schizophrenia. Credit: Itaru Kushima, Nagoya University Graduate School of Medicine

Common genetic variants may underlie autism spectrum disorder and schizophrenia across human populations, according to a study appearing September 11th in the journal Cell Reports. In line with previous studies in Caucasians, the researchers found that Japanese individuals with autism spectrum disorder and schizophrenia have overlapping copy number variations (CNVs)—inter-individual variations in the number of copies of a particular gene.

"The strength of our study is the systematic head-to-head comparison of pathogenic CNVs and biological pathways between and ," says senior study author Norio Ozaki of Nagoya University Graduate School of Medicine. "Previous studies in Caucasian populations found overlap in pathogenic CNVs between the two disorders, but their analyses were limited to a small number of genes and CNV loci."

Autism spectrum disorder and schizophrenia have complex inheritance patterns, with multiple genetic and environmental factors influencing disease risk. Available evidence points to genetic overlap between the two clinically distinct disorders. For example, they tend to co-occur at a higher rate than would be expected in the general population, and a large epidemiological study showed that a family history of schizophrenia in first-degree relatives is a risk factor for spectrum disorder. In particular, previous studies have revealed that these two disorders are associated with an increased burden of CNVs, and that rare CNVs in specific loci are shared risk factors for both disorders.

However, the majority of the previous CNV studies were carried out in Caucasian populations, limiting the generalization of pathogenic CNVs and relevant biological pathways. Studies in populations other than Caucasians may also provide additional biological insights into the disorders. Moreover, the clinical features of patients with pathogenic CNVs have not been fully examined in non-Caucasian populations. Until now, no studies have directly compared pathogenic CNVs and biological pathways between autism spectrum disorder and schizophrenia in non-Caucasian populations.

To address this gap in knowledge, Ozaki and his team performed comparative CNV analyses of 1,108 cases of autism spectrum disorder, 2,458 individuals with schizophrenia, and 2,095 controls in a Japanese population using a high-resolution technique called array comparative genomic hybridization. They confirmed an increased genome-wide burden of rare CNVs in autism spectrum disorder and schizophrenia and observed an overlap in pathogenic CNVs between the two disorders. Pathogenic CNVs, including those at 29 loci common to both disorders, were found in about 8% of the two types of patients, which was significantly higher than in controls.

"Genetic overlap has been suggested in epidemiological and molecular genetic studies," says first author Itaru Kushima of Nagoya University Graduate School of Medicine. "In line with this, our systematic and comprehensive investigation confirmed a significant overlap of pathogenic CNVs between autism spectrum disorder and schizophrenia in a Japanese population."

Additional analysis revealed that both disorders are associated overlapping biological pathways involved in the oxidative stress response, lipid metabolism, and genomic integrity. The researchers also identified 12 CNV loci potentially associated with these disorders in a Japanese . Moreover, intellectual disability was strongly associated with pathogenic CNVs in both patient groups. "The identification of shared pathways and disease-relevant genes provides biological insights into autism spectrum disorder and schizophrenia," Ozaki says.

Moving forward, the researchers plan to investigate CNVs in bipolar disorder and examine the overlap of pathogenic CNVs and biological pathways among the three disorders. In the near future, they will also conduct studies using CNV-based animal models, as well as induced pluripotent stem cells (iPSCs) derived from patients with pathogenic CNVs.

Explore further: Genomic copy number variants contribute to cognitive impairment in the UK

More information: Cell Reports, Kushima et al.: "Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights" https://www.cell.com/cell-reports/fulltext/S2211-1247(18)31293-2 , DOI: 10.1016/j.celrep.2018.08.022

Related Stories

Genomic copy number variants contribute to cognitive impairment in the UK

June 28, 2017
Genetic alterations of rare deletions or duplications of small DNA segments, called copy number variants (CNVs), have been known to increase risk of neurodevelopmental disorders such as schizophrenia, autism spectrum disorder, ...

Analysis of genetic repeats suggests role for DNA instability in schizophrenia

June 24, 2016
International researchers centered at Nagoya University use a highly sensitive technique to identify significantly more DNA sequence repeats in patients with schizophrenia than in control individuals, and outline a possible ...

25 new autism-related gene variants discovered

January 14, 2013
Genetics researchers have identified 25 additional copy number variations (CNVs)—missing or duplicated stretches of DNA—that occur in some patients with autism. These CNVs, say the researchers, are "high impact": although ...

Researchers uncover impact of mutations in the human genome on cognitive ability

December 19, 2013
deCODE genetics reported today in the journal Nature that mutations associated with an increased risk of schizophrenia and autism also affect cognition in individuals without the disease or intellectual disability. The research ...

Researchers develop new type of genetic test for identifying developmental disorders

September 15, 2014
(Medical Xpress)—A large team of researchers with members from a host of countries across the globe has conducted an exhaustive study that has resulted in the development of a new genetic test to help identify development ...

Rare genetic mutations linked to bipolar disorder

December 21, 2011
An international team of scientists, led by researchers at the University of California, San Diego School of Medicine, reports that abnormal sequences of DNA known as rare copy number variants, or CNVs, appear to play a significant ...

Recommended for you

Music improves social communication in autistic children

November 5, 2018
Engaging in musical activities such as singing and playing instruments in one-on-one therapy can improve autistic children's social communication skills, improve their family's quality of life, as well as increase brain connectivity ...

Unraveling a genetic network linked to autism

November 2, 2018
Donnelly Centre researchers have uncovered a genetic network linked to autism. The findings, described in the journal Molecular Cell, will facilitate developing new therapies for this common neurological disorder.

Study links gene mutation to neurodevelopmental disorders

November 2, 2018
A new model created by UCLA scientists reveals how the alteration of a specific gene increases the risk for neurodevelopmental problems in mice. When the researchers mutated the gene, it produced symptoms at specific ages ...

Common medications taken during pregnancy are not associated with risk for autism

October 31, 2018
Babies exposed in the womb to the majority of medications that target neurotransmitter systems, including typical targets of antidepressants and antipsychotic drugs, are not any more likely to develop autism than non-exposed ...

Brainwave activity reveals potential biomarker for autism in children

October 29, 2018
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that can impair communication ability, socialization, and verbal and motor skills. It generally starts in early childhood and is diagnosed through behavior observation. ...

In kids with autism, short questionnaire may detect GI disorders

October 22, 2018
Anger, aggression, and other troubling behavior problems in kids with autism are often treated as psychological issues, but in many cases the problems can be traced to gastrointestinal distress.

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

Anonym518498
1 / 5 (1) Sep 11, 2018
old news, these ideas have been around for a long time

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.