Schizophrenia Has a High Heritability, but Where Are the Genes?

Abstract

Schizophrenia is a debilitating psychiatric disorder affecting 1% of the world’s population. The diagnostic criteria (DSM IV) are broad and characterized by positive and negative symptoms which vary from patient to patient and over the course of the illness. The disease is known to have a genetic component, a reported heritability estimate of 80% and a concordance rate of ~50% in monozygotic twins. Most research on the disease has concentrated on the search for genes using traditional approaches. This includes cytogenetics, linkage, association, gene expression and whole genome scans. Although this extensive research has identified a number of genomic regions of interest and some candidate genes, it has not produced any confirmed causations. Yet, identification of the cause(s) of this disease will be required in order to develop effective preventive management and corrective strategies. Considering the decades of research in the field, one obvious question arises: where are the genes that cause schizophrenia? This forms the focus of the chapter. During the course of this discussion, we will argue that there are two main reasons as to why traditional genetic approaches have met with little success in schizophrenia. First is the diagnosis of the clinical phenotype. There are no biological markers of this disease and the diagnosis is based on interviews and self-reporting of the patient. Also, the DSM-IV diagnostic criteria are broad enough that two individuals with schizophrenia may have very few symptoms in common. This leads to a highly heterogeneous sample, which is not optimal in traditional genetic research, or research on complex disorders. The second issue deals with the genetic hypothesis being tested. Here the assumption is that a number of genetic variants of small to moderate effect interact with environmental factors leading to a predisposition for schizophrenia. What is not fully appreciated is the actual number of potential gene variants involved, the heterogeneous mechanism and timing of their occurrence and recurrence and any understanding of their interaction with the environment. These issues recognize that there is a long pathophysiological chain that extends from genes, through proteins, neurons, cognition, behaviour, symptoms, and finally to the DSM-IV construct of schizophrenia.