**5.3.2 The mode of transmission**

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

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 paternal age advances from 20 years to over 50 years.

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

Impact of Epidemiology on Molecular Genetics of Schizophrenia 127

A role of oxidative stress in the pathogenesis of rheumatoid arthritis has been suggested by several lines of evidence (for review, see Hitchon et al, 2004). In addition, it has been shown that chronic oxidative stress in the synovial T lymphocytes is not secondary to exposure to environmental free radicals but originates from intracellularly produced reactive oxygen species (Remans et al, 2005). Therefore, a presumptive susceptibility gene for rheumatoid arthritis, which may cause intracellular oxidative stress in several cell lines, could be a facilitating gene for schizophrenia in this model and is likely to be subject to a negative

Indeed, robust evidence shows a negative association between schizophrenia and rheumatoid arthritis while the exact mechanism is still unknown (Vinogradov et al., 1991; Jablensky, 1995; Rubinstein, 1997; Oken 1999). According to the nuclear genome model, several hypotheses have been proposed such that pathogenic genes for schizophrenia may

Thus the mitochondrial genome model may offer a new explanation for the low comorbidity between schizophrenia and rheumatoid arthritis and the additional prediction: most of patients with both of the diseases would be females because the survival rate of males in early life stage must be remarkably reduced due to lack of the antioxidant defense by estrogen, and show more negative symptoms, poorer response to neuroleptic medication,

The hypothesis predicts that early-life exposure to environments which induce strong oxidative stress can increase the risk of later development of schizophrenia in the

Indeed, prenatal environmental factors such as severe nutritional deficiency (Susser, et al., 1996), exposure to increased homocysteine (Brown et al., 2007) or lead (Opler & Susser, 2005), and infection of influenza virus (Limosin et al., 2003; Brown et al., 2004; Opler & Susser, 2005) and Toxoplasma gondii (Brown et al., 2005) have been suggested to increase the risk for schizophrenia. More recently, it has been suggested that central nervous system infections of cytomegalovirus or mumps virus in childhood may also increase the risk for schizophrenia (Dalman et al., 2008). All of these factors have been shown to affect mitochondria, inducing strong intracellular oxidative stress and/or apoptosis (Akaike et al., 1990; Edlund et al., 1994; Speir et al., 1998; He et al., 2003; Berger et al., 2004; Zaki et al., 2005; Gupta et al., 2004; Kruman et al., 2006; Wang et al., 2006; Poncet et al., 2006; Chang et al.,

**5.3.6 Increased obstetric complications in the birth of patients with schizophrenia** 

It has been suggested that mitochondrial dysfunction may be involved in the etiology of preeclampsia (Shanklin et al., 1990; Barton et al., 1991; Furui et al., 1994). In addition, a high incidence of preeclampsia, eclampsia, and stillborn infants has been observed in a family with a known mitochondrial disorder (Torbergsen et al. 1989). Folgero et al. (1996) demonstrated two separate mtDNA point mutations in two families having a high incidence

selection in the predisposed matrilineal pedigrees.

and/or more morphological changes in the brain.

**5.3.5 Prenatal risk factors for schizophrenia** 

predisposed population.

2007; Nishikawa et al., 2007).

of preeclampsia and eclampsia.

be protective genes for rheumatoid arthritis and vice versa.

(< 21 years) (Malaspina et al., 2001; El-Saadi et al., 2004; Sipos et al., 2004) as well as in the offspring of younger women (< 20 years) (El-Saadi et al., 2004). Therefore, major roles of paternally derived mutations in schizophrenia seem to remain unsubstantiated.

Indeed, no available data can exclude the possibility that the 'paternal age effect' has a 'maternal origin'; while women in many countries today may be usually supposed to bear children after the age of 20 years and not to marry much older men or too young men unless the men have special socio-economic benefits, a certain proportion of predisposed women might behave differently.

It should be noted that in the famous twin study by Gottesman and Bertelsen (1989) which included almost equal number of male and female monozygotic twins, most schizophrenic twins whose offspring are affected are females (12 out of 14), implying that the transmission was mainly via females ( <sup>14</sup> <sup>14</sup> <sup>14</sup> 14 12 14 13 14 14 *pC C C* 0.5 0.5 0.5 0.007 ). While this gender effect might be due to non-genetic factors such as stronger psychological interactions between mother and child, we must also consider the possibility that it is due to the closer genetic relationship between mother and child, i.e. the mtDNA.
