Rare structural variants in schizophrenia: one disorder, multiple mutations; one mutation, multiple disorders

Abstract

Recent studies have established an important role for rare genomic deletions and duplications in the etiology of schizophrenia. This research suggests that the genetic architecture of neuropsychiatric disorders includes a constellation of rare mutations in many different genes. Mutations that confer substantial risk for schizophrenia have been identified at several loci, most of which have also been implicated in other neurodevelopmental disorders, including autism. Genetic heterogeneity is a characteristic of schizophrenia; conversely, phenotypic heterogeneity is a characteristic of all schizophrenia-associated mutations. Both kinds of heterogeneity probably reflect the complexity of neurodevelopment. Research strategies must account for both genetic and clinical heterogeneity to identify the genes and pathways crucial for the development of neuropsychiatric disorders.

Figure 1. Detecting the association of rare structural variants (SVs) with disease

Three different approaches to detecting the association of rare SVs with disease are shown. The association of rare structural variants with disease can be determined by comparing cases and controls with respect to the frequency of an individual mutation (single marker association, Panel a), the aggregate frequency of multiple mutations within a single gene or region (gene-wise mutational burden, Panel b), or the aggregate frequency of all rare structural variants (genome-wide mutational burden, Panel c). Panels A and B depict a typical genome browser view displaying tracks for SVs and annotated genes, c depicts an ideogram displaying the distribution of SVs genome-wide.