**5.2 The results of association studies to date accord with the mitochondrial genome model but not with the nuclear genome model**

Since a resistance gene in the nuclear genome model cannot be associated with the disease unless it is linked with a susceptibility gene, resistance genes in the nuclear model should be located in the vicinity of susceptibility genes, which disagrees with the results of association studies to date.

For example, on the chromosome 1, all of the schizophrenia-associated genes that could meet the criterion (*RGS4*, *PLXNA2*, *DISC1*) are located on 1q, while four resistance genes (*MHTFR*, *GRIK3*, *PDE4B*, *GSTM1*) are on 1p (**Table 2**). Fifteen resistance genes are located on 2q, 5q, 7q, 10q, 11p, 12p, 12q, 13p, 13q, 16p, 17p, and 19q, where no schizophreniaassociated variants that could meet the criterion are located (data: not shown). Therefore, the results of association studies to date argue against the nuclear genome model.

A possible interpretation which accords with the nuclear genome model might be that many nuclear susceptibility genes of less than the highest mutation rates have not been detected by association studies to date due to lack of power. In this case, however, an enormous sample size (more than 3.7~370 million case-control pairs) would be required to identify them as was mentioned above. In other words, such an enormous sample size is required to prove the nuclear genome model.

On the other hand, every resistance gene on *any* chromosome can be associated with schizophrenia in the mitochondrial genome model; since mtDNA is transmitted only via females and there is no link between the nuclear genome and the mitochondrial genome, every nuclear genome which interacts with a pathogenic mitochondrial genome to alter severity and risk of the disease is subject to natural selections in the predisposed maternal lineage that succeeds to a same pathogenic mitochondrial genome. Therefore, every resistance gene for schizophrenia in the mitochondrial genome model is to be subject to a positive selection in the predisposed maternal lineage, thereby associating with schizophrenia.

Thus, the mitochondrial genome model is compatible with the results of the association studies to date.

It should be noted that in the mitochondrial genome model every facilitating gene (a gene that increases the severity and morbid risk in the predisposed population) on any chromosome may diminish in the predisposed matrilineal pedigrees by negative selection, thereby negatively associating with the disease.

Schizophrenia-associated variants listed in the top 45 in the SZGene Database (the version of 10th December, 2010) were selected. Based on the genotype distributions in meta-analyses, allele frequencies and the case-control differences were calculated. 4 variants at the 3 loci (*RGS4*, *PLXNA2*, *DISC1*) could meet the criterion under the assumption that the mutation

Impact of Epidemiology on Molecular Genetics of Schizophrenia 125

mitochondrial genome, the mtDNA hypothesis predicts: (2) a higher maternal transmission of schizophrenia, and (3) positive associations between resistance genes and schizophrenia as well as negative associations between facilitating genes and schizophrenia (see 5.2). These predictions seem to be consistent with other major epidemiological findings and the results

**5.3.1 Mitochondrial dysfunction and enhanced oxidative stress in affected individuals**  The hypothesis predicts that patients with schizophrenia show mitochondrial dysfunction

Indeed, in the past decade, mitochondrial dysfunction and oxidative stress in schizophrenia has been suggested by several independent lines of evidence (for review, see Marchbanks et al., 1995; Ben-Shaffer, 2002; Wood et al., 2009); those include mitochondrial hypoplasia, disturbed oxidative phosphorylation, and altered mitochondrial-related gene expression in

The pioneering works in this field may be noteworthy (Utena & Niwa, 1992). As early as 1950, Hayashi, in a longitudinal study on glucose metabolites in blood sampled from the superior bulb of the internal jugular vein of schizophrenics, observed a decreased carbonic dioxide production in the brain and a higher level of lactate and glutathione, the brain's dominant free radical scavenger, in patients in an acute exacerbation of the illness. Utena and Ezoe (1951) reported a decreased glucose consumption *in vitro* in cortical brain tissues sampled from patients with schizophrenia who underwent prefrontal leukotomy. Takahashi (1953) confirmed this finding and emphasized the necessity of further investigations on oxidative phosphorylation in the brain tissue of schizophrenics. In line with those findings was the report by Stabenau et al. (1969), who observed, in a biochemical study of discordant monozygotic twin pairs, that lactate production and the lactate-pyruvate ratio were higher in the affected twins than the unaffected cotwins. More recently, Prabakaran et al. (2004), in a large-scale functional genomics study, suggested a state of intermittent or chronic hypoxic stress and mitochondrial dysfunction in the brain

The hypothesis predicts a higher maternal transmission of schizophrenia. Although there has been no convincing evidence for maternal transmission of schizophrenia, several reports suggest a higher maternal transmission of schizophrenia (Shimizu et al., 1987; Goldstein et

Some researchers have proposed the hypothesis that schizophrenia is associated with *de novo* mutations arising in paternal germ cells (Malaspina et al., 2001; Zammit et al., 2003; Byrne et al., 2003; El-Saadi et al., 2004; Sipos et al., 2004). It is based on the observation ('paternal age effect') that the risk of schizophrenia in the offspring seems to increase as the

However, the difference in the mean ages of fathers between affected and unaffected individuals are not very large (< 1.7 years) (Malaspina et al., 2001; El-Saadi et al., 2004). Furthermore, the risk of schizophrenia was also increased in the offspring of younger men

of the genetic and the pathophysiological studies to date.

and enhanced oxidative stress.

of patients with schizophrenia.

**5.3.2 The mode of transmission** 

al., 1990; Valero et al., 1998; Li et al., 2007).

paternal age advances from 20 years to over 50 years.

several cell lines.


rates at those loci are near the upper limit in the autosomes. All of them are located on 1q, while 4 resistance genes (*MHTFR*, *GRIK3*, *PDE4B*, *GSTM1*) are on 1p. \* schizophreniaassociated alleles; variants that could meet the criterion are shown in bold characters

Table 2. Schizophrenia-associated genes on the chromosome 1 that could meet the criterion
