Complex Rare Variation and Its Role in Endophenotypic Variation in Schizophrenia

Abstract

In this issue of Biological Psychiatry, Yeo et al. (1) present some tantalizing (albeit preliminary) evidence that the cumulative number of complex rare sequence variants, specifically copy number variants (CNVs) representing deletions, correlates with postulated endophenotypes for schizophrenia such as general cognitive ability and various structural magnetic resonance imaging measures. I will use the term endophenotype for such quantitative traits because they have heritable components and they show some evidence for genetic correlation with disease liability (2). This evidence for genetic correlation may be indirect as reflected by the observed differences in means between cases, their first-degree relatives, and controls or measured directly by formal quantitative genetic analysis in families. A review of such studies by Burdick et al. (3) concludes that general cognitive ability is an endophenotype for schizophrenia. Multiple studies [e.g., (4)] also support schizophrenia-related endophenotypic status for a number of neuroimaging derived measures. Thus, the focal phenotypes in this study are also likely endophenotypes for schizophrenia.