Persistence problem in schizophrenia and mitochondrial DNA.

Schizophrenia, a major psychosis with a strong genetic component, persists over generations despite a clearly reduced reproductive fitness of the patients. This 'persistence' problem has puzzled scientists for long years. A hypothesis of 'balanced polymorphism' proposed by Huxley et al. that the incidence could be sustained by a higher fertility in the siblings of the patients has not been supported by most epidemiological studies. Multiple-genes model, which most geneticists today accept, explains that the loss of susceptibility alleles resulting from the lower fertility of the patients would have a negligible effect on the overall gene pool in the population. We carefully examined the multiple-genes model and proved it cannot account for the persistence problem without unrealistic assumptions and hence the contribution of multiple genes in the nuclear DNA to the heredity of schizophrenia should be considerably limited. We demonstrated a pathogenic gene with a low penetrance, if located in the mitochondrial DNA, could be sustained given a higher fertility of the 'female' siblings and/or a decreased male-female ratio in the offspring of the susceptible females. This hypothesis, coupled with the report which suggests mitochondrial dysfunction in schizophrenia, may encourage a new direction in genetic study of this puzzling disorder. (c) 2006 Wiley-Liss, Inc.