Persistence problem in schizophrenia and mitochondrial DNA

Abstract

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. © 2006 Wiley‐Liss, Inc.

Clinical and sociodemographic comparison of people at high‐risk for psychosis and with first‐episode psychosis

“…Immigration, ethnicity, employment, marital status and living arrangements did not seem to differ between both groups. Moreover, the proportion of first‐degree relatives with psychotic illness was very similar, which may support hypotheses on different degrees of genetic penetrance or different gene‐environment interactions (48, 49).…”

Mitochondrial DNA (mtDNA) and schizophrenia

“…However, the inheritance of maternal mtDNA mutations or variants could explain the aetiological heterogeneity of schizophrenia. Inheritance of maternal mtDNA mutations may also explain the persistence of the disease at a high prevalence despite a strong negative selection pressure due to patients’ diminished reproductive fitness [38]. Likewise, epidemiological data support the existence of pathogenic genes located in mtDNA that may persist through sex-related mechanisms [39].…”

“…This is due to lack of valid phenotypic definition and absence of good theories of pathophysiology [97]. The mitochondrial dysfunction in schizophrenia has been hypothesised as an explanation for the heterogeneity of clinical and pathological manifestations [15] and the mtDNA has been indicated as an underlying etiologic genetic factor [38,66].…”

Mitochondrial involvement in psychiatric disorders

“…Interestingly, there is some evidence for high maternal transmission of SZ (16)(17)(18)(19), as well as BPD (20), which supports the hypothesis that increased risk for these disorders is related to mitochondrial dysfunction. However, it is also possible that this relationship may be due to environmental factors (21). Failure to find a pattern of maternal inheritance as well as evidence of paternal inheritance have also been reported in SZ and BPD (22,23).…”