**2.4 Schizophrenia and the Devil's triangle of human genetics**

The three epidemiological characteristics of schizophrenia - high prevalence, high heritability and low fitness - form a Devil's triangle; any combination of the two tends to exclude the third, and in this triangle most diseases vanish except for schizophrenia (**Fig. 1**). Diseases with high prevalence and high heritability such as type 2 diabetes and adult cancers are late-onset diseases and exhibit almost normal reproductive fitness. Diseases with high heritability and low reproductive fitness such as most harmful Mendelian diseases in childhood are rare. Diseases with low reproductive fitness and high prevalence such as poor nutrition, severe injuries and infections in childhood or early adulthood are mainly due to the environmental factors.

This may lead us to strongly suspect that schizophrenia has a unique etiological basis among the many human diseases.

Confidence Interval 0.3% - 2.7%) (Saha et al., 2005); the prevalence of schizophrenia, at the macro-level, varies within narrow limits (Jablensky, 1995), and appears to be stable across generations in several countries (Harrison et al., 1991; Osby et al., 2001). This

It has long been known that schizophrenia runs in families (McGue & Gottesman, 1991). Adoption studies demonstrate an increased risk of schizophrenia in biological relatives of adoptees with schizophrenia, suggesting that genetic components play an important role in the etiology of schizophrenia (Kendler & Dichl, 1993). Now it has been established by twin studies that heritability of schizophrenia is ~0.85 (Cannon et al., 1998; Cardno

Although the mode of transmission of schizophrenia is still unknown, several reports suggest a higher maternal transmission of schizophrenia (Shimizu et al., 1987; Goldstein et

It has been well documented that the fertility of patients with schizophrenia, particularly of males, is remarkably reduced compared to healthy individuals (Böök, 1953; Larson & Nyman, 1973; Ødegård, 1980; Nanko & Moridaira, 1993; Fãnanás & Bertranpetit, 1995; Nimgaonkar, 1998; McGrath et al., 1999; Haukka et al., 2003; Svensson et al., 2007). The latest meta-analysis (Bundy et al., 2011) shows that fertility ratio (patients/controls) is ~0.39 and that the reduction of fertility is more pronounced in males (male/female ratio

Because schizophrenia is an early onset disease (late adolescence ~ early adulthood), psychotic symptoms of the disease such as autistic way of life and abnormal behaviors may make mating unsuccessful. This tendency may be more pronounced in males because the age at onset is significantly lower in males than in females (Jablensky, 1995; Kulkarni & Fink, 2000). Thus, unsuccessful mating, coupled with an increased mortality (McGrath et al.,

The three epidemiological characteristics of schizophrenia - high prevalence, high heritability and low fitness - form a Devil's triangle; any combination of the two tends to exclude the third, and in this triangle most diseases vanish except for schizophrenia (**Fig. 1**). Diseases with high prevalence and high heritability such as type 2 diabetes and adult cancers are late-onset diseases and exhibit almost normal reproductive fitness. Diseases with high heritability and low reproductive fitness such as most harmful Mendelian diseases in childhood are rare. Diseases with low reproductive fitness and high prevalence such as poor nutrition, severe injuries and infections in childhood or early adulthood are mainly due to

This may lead us to strongly suspect that schizophrenia has a unique etiological basis

2008), may remarkably reduce the fertility of patients with schizophrenia.

**2.4 Schizophrenia and the Devil's triangle of human genetics** 

epidemiological fact suggests that schizophrenia has an ancient origin.

**2.2 Schizophrenia as a heritable disease** 

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

**2.3 Schizophrenia as a low fitness disease** 

et al., 1999).

is ~0.54).

the environmental factors.

among the many human diseases.

Fig. 1. Devil's triangle of human genetics (Doi et al., 2009)
