Persistence criteria for susceptibility genes for schizophrenia: a discussion from an evolutionary viewpoint.

Background: The central paradox of schizophrenia genetics is that susceptibility genes are preserved in the human gene-pool against a strong negative selection pressure. Substantial evidence of epidemiology suggests that nuclear susceptibility genes, if present, should be sustained by mutation-selection balance without heterozygote advantage. Therefore, putative nuclear susceptibility genes for schizophrenia should meet special conditions for the persistence of the disease as well as the condition of bearing a positive association with the disease.

Methodology/principal Findings: We deduced two criteria that every nuclear susceptibility gene for schizophrenia should fulfill for the persistence of the disease under general assumptions of the multifactorial threshold model. The first criterion demands an upper limit of the case-control difference of the allele frequencies, which is determined by the mutation rate at the locus, and the prevalence and the selection coefficient of the disease. The second criterion demands an upper limit of odds ratio for a given allele frequency in the unaffected population. When we examined the top 30 genes at SZGene and the recently reported common variants on chromosome 6p with the criteria using the epidemiological data in a large-sampled Finnish cohort study, it was suggested that most of these are unlikely to confer susceptibility to schizophrenia. The criteria predict that the common disease/common variant hypothesis is unlikely to fit schizophrenia and that nuclear susceptibility genes of moderate effects for schizophrenia, if present, are limited to 'rare variants', 'very common variants', or variants with exceptionally high mutation rates.

Conclusions/significance: If we assume the nuclear DNA model for schizophrenia, it should have many susceptibility genes of exceptionally high mutation rates; alternatively, it should have many disease-associated resistance genes of standard mutation rates on different chromosomes. On the other hand, the epidemiological data show that pathogenic genes, if located in the mitochondrial DNA, could persist through sex-related mechanisms.