**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 of preeclampsia and eclampsia.

Impact of Epidemiology on Molecular Genetics of Schizophrenia 129

predisposed population. In addition, genomic instability may be more pronounced in males

There have been numerous reports of associations between schizophrenia and chromosomal abnormalities including fragile sites, reciprocal translocations, inversions, insertions, deletions, disomy and trisomy in many autosomes, and sex chromosome aneuploidies (Macintyre et al, 2003). However, with an exception of 22q11 deletion, none of these have been consistently replicated, and with another exception of (1,11) (q42;q14.3) balanced translocation, none provides convincing evidence for the location of a 'susceptibility' gene

A popular explanation in the nuclear genome model may be that most of these structural variants are coincidental findings of no clinical significance. Alternatively, those alterations may indicate genomic instability in schizophrenia. An increased risk of schizophrenia in individuals with 22q11 deletion (Pulver et al., 1994; Murphy et al., 1999) might be due to haplodeficiency of presumptive resistance genes of gain-offunction type and/or presumptive facilitating genes of loss-of-function type aggregated on

More recently, it has been reported that rare structural variants such as microdeletions or microduplications of sizes ranging from 100kb to 15MB throughout the genome are more frequent among individuals with schizophrenia than unaffected individuals (Walsh et al., 2008). While many of those structural variants duplicate or delete genes in neurodevelopmental pathways, one third of those do not disrupt genes, leaving their role in causation of the disease unwarranted. Another recent report (Xu et al., 2008) has shown that *de novo* copy number mutations are increased in sporadic schizophrenia. However, the cytobands of those copy number mutations are diverse among the affected individuals and their roles in the pathogenesis still remain unclear. Therefore, no available data can refute the possibility that those structural variants and copy number mutations are not the causes of schizophrenia but the results of the genomic instability in schizophrenia predicted by our

Indeed, direct measure of the de novo mutation rates shows an increased mutation rate in schizophrenia (Awadalla et al., 2010), and genomic and epigenomic instability has been suggested in schizophrenia (Smith et al., 2010). Furthermore, it has been shown that blood cells from patients with schizophrenia present a higher rate of folate-sensitive fragile sites, and that male patients exhibit twice as many fragile sites as females while there are no age effects (Demirhan et al., 2006). This sex difference may indicate that increased fragile sites expression (genomic instability) is the results of enhanced oxidative stress in patients with

Genetic research of schizophrenia based on the nuclear genome model has been one of the most active areas in psychiatry for the past two decades. Although this effort is ongoing, results of association studies have been inconsistent and the situation of molecular genetics of schizophrenia today has become much confused just contrary to our expectation. The consistent major epidemiological findings of schizophrenia, coupled with the results of association studies to date, argue against the nuclear genome model for schizophrenia.

due to lack of antioxidant protection by estrogen.

(Kirov et al., 2005).

22q11.

hypothesis.

schizophrenia.

**6. Conclusion** 

Therefore, the hypothesis predicts that the risk of preeclampsia, eclampsia, or stillbirth may be increased in the birth of patients with schizophrenia as well as in the pregnancies of women with schizophrenia. Indeed, an excess of stillbirths and neonatal deaths among women with schizophrenia has been reported by several investigators (Sobel, 1961; Rieder et al., 1975; Modrzewska, 1980; Webb et al., 2005).

Furthermore, there has been a body of evidence for an increased risk of obstetric complications in the birth of patients with schizophrenia (Dalman et al., 1999; Cannon et al., 2002). A meta-analysis of population-based data (Cannon et al., 2002) found significant estimates for three main categories of obstetric complications: (1) complications of pregnancies, (2) abnormal fetal growth and development, and (3) complications in delivery. Among all, preeclampsia was the strongest individual risk factor detected in the largest single population-based cohort study to date (Dalman et al., 1999).

Although obstetrical events in schizophrenia are often considered as having a direct causative effect, none of the available data can refute the hypothesis that they are merely markers of some other causal process (Rapoport et al., 2005), such as mitochondrial dysfunction which is implicated in this hypothesis.
