Missing heritability paradox in schizophrenia: hypothesis and plausible clues

Abstract

Genetic research on schizophrenia, a common psychiatric disease with complex etiology and high (56-80%) heritability, has failed to identify causal genes, variants or causative mechanisms. Given the extensive effort and limited success to date, it is imperative to review potential reasons for this missing heritability. We argue that a successful elucidation of hereditary mechanisms in schizophrenia will likely involve; the identification of discrete endophenotypes; attention to the role of neurodevelopment and cell differentiation; consideration of the genome structure including temporal and spatial patterns, accommodation of environmental effects at the level of gene expression including any sex differences and pattern of mutations including de novo events and the use of analytic techniques that go beyond genome wide association studies. Identification of the heritable component of schizophrenia and sources of “missing heritability” is needed to understand the cause/s of the disorder and to facilitate the development of effective corrective and possibly preventive measures.