Dataset Information

Childhood-Onset Schizophrenia: A Systematic Overview of Its Genetic Heterogeneity From Classical Studies to the Genomic Era.

ABSTRACT: Childhood-onset schizophrenia (COS), a very rare and severe chronic psychiatric condition, is defined by an onset of positive symptoms (delusions, hallucinations and disorganized speech or behavior) before the age of 13. COS is associated with other neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit and hyperactivity disorder. Copy number variations (CNVs) represent well documented neurodevelopmental disorder risk factors and, recently, de novo single nucleotide variations (SNVs) in genes involved in brain development have also been implicated in the complex genetic architecture of COS. Here, we aim to review the genetic changes (CNVs and SNVs) reported for COS, going from previous studies to the whole genome sequencing era. We carried out a systematic review search in PubMed using the keywords "childhood(early)-onset schizophrenia(psychosis)" and "genetic(s) or gene(s) or genomic(s)" without language and date limitations. The main inclusion criteria are COS (onset before 13 years old) and all changes/variations at the DNA level (CNVs or SNVs). Thirty-six studies out of 205 met the inclusion criteria. Cytogenetic abnormalities (n = 72, including 66 CNVs) were identified in 16 autosomes and 2 sex chromosomes (X, Y), some with a higher frequency and clinical significance than others (e.g., 2p16.3, 3q29, 15q13.3, 22q11.21 deletions; 2p25.3, 3p25.3 and 16p11.2 duplications). Thirty-one single nucleotide mutations in genes principally involved in brain development and/or function have been found in 12 autosomes and one sex chromosome (X). We also describe five SNVs in X-linked genes inherited from a healthy mother, arguing for the X-linked recessive inheritance hypothesis. Moreover, ATP1A3 (19q13.2) is the only gene carrying more than one SNV in more than one patient, making it a strong candidate for COS. Mutations were distributed in various chromosomes illustrating the genetic heterogeneity of COS. More than 90% of CNVs involved in COS are also involved in ASD, supporting the idea that there may be genetic overlap between these disorders. Different mutations associated with COS are probably still unknown, and pathogenesis might also be explained by the association of different genetic variations (two or more CNVs or CNVs and SNVs) as well as association with early acquired brain lesions such as infection, hypoxia, or early childhood trauma.

SUBMITTER: Fernandez A

PROVIDER: S-EPMC6930680 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Childhood-Onset Schizophrenia: A Systematic Overview of Its Genetic Heterogeneity From Classical Studies to the Genomic Era.

Fernandez Arnaud A Drozd Malgorzata Marta MM Thümmler Susanne S Dor Emmanuelle E Capovilla Maria M Askenazy Florence F Bardoni Barbara B

Frontiers in genetics 20191218

Childhood-onset schizophrenia (COS), a very rare and severe chronic psychiatric condition, is defined by an onset of positive symptoms (delusions, hallucinations and disorganized speech or behavior) before the age of 13. COS is associated with other neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit and hyperactivity disorder. Copy number variations (CNVs) represent well documented neurodevelopmental disorder risk factors and, recently, <i>de novo</i> singl ...[more]

PMID: 31921276

Similar Datasets

Project description:BackgroundChildhood-onset and adult-onset asthma differ with respect to severity and comorbidities. Whether they also differ with respect to genetic risk factors has not been previously investigated in large samples. The goals of this study were to identify shared and distinct genetic risk loci for childhood-onset and adult-onset asthma, and to identify the genes that might mediate the effects of associated variation.MethodsWe did genome-wide and transcriptome-wide studies, using data from the UK Biobank, in individuals with asthma, including adults with childhood-onset asthma (onset before 12 years of age), adults with adult-onset asthma (onset between 26 and 65 years of age), and adults without asthma (controls; aged older than 38 years). We did genome-wide association studies (GWAS) for childhood-onset asthma and adult-onset asthma each compared with shared controls, and for age of asthma onset in all asthma cases, with a genome-wide significance threshold of p<5 × 10-8. Enrichment studies determined the tissues in which genes at GWAS loci were most highly expressed, and PrediXcan, a transcriptome-wide gene-based test, was used to identify candidate risk genes.FindingsOf 376 358 British white individuals from the UK Biobank, we included 37 846 with self-reports of doctor-diagnosed asthma: 9433 adults with childhood-onset asthma; 21 564 adults with adult-onset asthma; and an additional 6849 young adults with asthma with onset between 12 and 25 years of age. For the first and second GWAS analyses, 318 237 individuals older than 38 years without asthma were used as controls. We detected 61 independent asthma loci: 23 were childhood-onset specific, one was adult-onset specific, and 37 were shared. 19 loci were associated with age of asthma onset. The most significant asthma-associated locus was at 17q12 (odds ratio 1·406, 95% CI 1·365-1·448; p=1·45 × 10-111) in the childhood-onset GWAS. Genes at the childhood onset-specific loci were most highly expressed in skin, blood, and small intestine; genes at the adult onset-specific loci were most highly expressed in lung, blood, small intestine, and spleen. PrediXcan identified 113 unique candidate genes at 22 of the 61 GWAS loci. Single-nucleotide polymorphism-based heritability estimates were more than three times larger for childhood-onset asthma (0·327) than for adult-onset disease (0·098). The onset of disease in childhood was associated with additional genes with relatively large effect sizes, with the largest odds ratio observed at the FLG locus at 1q21.3 (1·970, 95% CI 1·823-2·129).InterpretationGenetic risk factors for adult-onset asthma are largely a subset of the genetic risk for childhood-onset asthma but with overall smaller effects, suggesting a greater role for non-genetic risk factors in adult-onset asthma. Combined with gene expression and tissue enrichment patterns, we suggest that the establishment of disease in children is driven more by dysregulated allergy and epithelial barrier function genes, whereas the cause of adult-onset asthma is more lung-centred and environmentally determined, but with immune-mediated mechanisms driving disease progression in both children and adults.FundingUS National Institutes of Health.

Dataset Information

Childhood-Onset Schizophrenia: A Systematic Overview of Its Genetic Heterogeneity From Classical Studies to the Genomic Era.

Publications

Childhood-Onset Schizophrenia: A Systematic Overview of Its Genetic Heterogeneity From Classical Studies to the Genomic Era.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets