Copy number variations in schizophrenia: critical review and new perspectives on concepts of genetics and disease

Abstract

Objective: Structural variations of DNA, such as copy number variations (CNVs), are recognized to contribute both to normal genomic variability and to risk for human diseases. For example, schizophrenia has an established connection with 22q11.2 deletions. Recent genome-wide studies have provided initial evidence that CNVs at other loci may also be associated with schizophrenia. In this article, the authors provide a brief overview of CNVs, review recent findings related to schizophrenia, outline implications for clinical practice and diagnostic subtyping, and make recommendations for future reports on CNVs to improve interpretation of results.

Method: The review included genome-wide surveys of CNVs in schizophrenia that included one or more comparison groups, were published before 2009, and used newer methods. Six studies were identified.

Results: Despite some limitations, these initial genome-wide studies of CNVs provide replicated associations of schizophrenia with rare 1q21.1 and 15q13.3 deletions. Collectively, the results point to a more general mutational mechanism involving rare CNVs that elevate risk for schizophrenia, especially more developmental forms of the disease. Including 22q11.2 deletions, rare risk-associated CNVs appear to account for up to 2% of schizophrenia.

Conclusions: The more penetrant CNVs have direct implications for clinical practice and diagnostic subtyping. CNVs with lower penetrance promise to contribute to our genetic understanding of pathogenesis. The findings provide insight into a broader neuropsychiatric spectrum for schizophrenia than previously conceived and indicate new directions for genetic studies.

FIGURE 1. Examples of Chromosome Regions With Normal Diploid Status and With Copy Number Variations (CNVs)^a

^a Flanking segmental duplications increase the risk for structural genomic changes, such as CNVs. Normal diploid status is shown in the example at the top. Examples of CNVs (a to d, below) show the change in copy number in various configurations. A simple loss (example a) is often called a microdeletion and a simple gain (example b) a microduplication. While CNVs associated with genomic disorders are more prone to higher mutation rates because of the highly identical sequences in segmental duplications, most CNVs in the genome do not arise from events mediated by segmental duplication. CNVs may involve no, one, or multiple genes (genomic extent including exons and introns shown in magenta).

FIGURE 2. Neuropsychiatric Phenotypes Associated With Copy Number Variations (CNVs)^a

^a The top diagram illustrates the discovery of rare CNVs, which may be discovered in studies of both adult-onset and developmental diseases; studying individual CNVs can delineate the spectra of their respective phenotypic expressions. The charts below represent three CNVs having elevated prevalences in schizophrenia. These indicate the most common core phenotype of ascertainment based on current knowledge; the expression spectrum may change as more data accumulate. Proportions would differ if combined phenotypes of ascertainment (e.g., schizophrenia and mental retardation) were considered.