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The impact of clinical heterogeneity in schizophrenia on genomic analyses.

ABSTRACT: Though clinically useful, the diagnostic systems currently employed are not well equipped to capture the substantial clinical heterogeneity observed for most psychiatric disorders, as exemplified by the complex psychotic disorder(s) that Bleuler aptly labeled the "Group of Schizophrenias". The clinical heterogeneity associated with schizophrenia has likely frustrated decades of attempts to illuminate the underlying genetic architecture, although recent genome-wide association studies have begun to provide valuable insight into the role of common genetic risk variants. Here we demonstrate the importance of using diagnostic information to identify a core form of the disorder and to eliminate potential comorbidities in genetic studies. We also demonstrate why applying a diagnostic screening procedure to the control dataset to remove individuals with potentially related disorders is critical. Additionally, subjects may participate in multiple studies at different institutions or may have genotype data released by more than one research group. It is thus good practice to verify that no identical subjects exist within or between samples prior to conducting any type of genetic analysis to avoid potential confounding of results. While the availability of genomic data for large collections of subjects has facilitated many investigations that would otherwise not have been possible, we clearly show why one must use caution when acquiring data from publicly available sources. Although the broad vs. narrow debate in terms of phenotype definition in genetic analyses will remain, it is likely that both approaches will yield different results and that both will have utility in resolving the genetic architecture of schizophrenia.

SUBMITTER: Liang SG

PROVIDER: S-EPMC4308487 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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The impact of clinical heterogeneity in schizophrenia on genomic analyses.

Liang Sherri G SG Greenwood Tiffany A TA

Schizophrenia research 20141210 2-3

Though clinically useful, the diagnostic systems currently employed are not well equipped to capture the substantial clinical heterogeneity observed for most psychiatric disorders, as exemplified by the complex psychotic disorder(s) that Bleuler aptly labeled the "Group of Schizophrenias". The clinical heterogeneity associated with schizophrenia has likely frustrated decades of attempts to illuminate the underlying genetic architecture, although recent genome-wide association studies have begun ...[more]

PMID: 25496659

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Project description: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.

Dataset Information

The impact of clinical heterogeneity in schizophrenia on genomic analyses.

Publications

The impact of clinical heterogeneity in schizophrenia on genomic analyses.

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