**6. Conclusion**

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.

Impact of Epidemiology on Molecular Genetics of Schizophrenia 131

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Rather, they seem to argue in favor of the mitochondrial genome model, suggesting a necessity of paradigm shift from the nuclear genome model to the mitochondrial genome model in genetic research of schizophrenia in the coming years.

#### **Note: Cross-generational reduction of females with pathogenic genes in the mitochondrial genome model**

At first we define several notations. *N*1: the number of normal females in the first generation; *N*2: number of female offspring of normal females; *S*1: the number of unaffected female siblings of patients in the first generation; *S*2: the number of female offspring of unaffected female siblings of patients; *P*1: the number of female patients; *P*2: the number of female offspring of female patients; *r* (0 < *r* < 1): the proportion of gene carriers in normal females in the first generation. Then the number of female gene carriers in the first generation is ( <sup>1</sup> *S*<sup>1</sup> *P*<sup>1</sup> *rN* ) and the frequency of female gene carriers in the first generation is given by:

$$f\_1 = \frac{rN\_1 + S\_1 + P\_1}{N\_1 + S\_1 + P\_1} = r + \frac{S\_1 + P\_1}{N\_1 + S\_1 + P\_1} \cdot (1 - r) \cdot \frac{1}{r}$$

And the frequency of female gene carriers in the second generation is given by:

$$f\_2 = \frac{rN\_2 + S\_2 + P\_2}{N\_2 + S\_2 + P\_2} = r + \frac{S\_2 + P\_2}{N\_2 + S\_2 + P\_2} \cdot (1 - r) \cdot f\_2$$

Thus we have (**Table 3**):

$$-\Delta = f\_1 - f\_2 = \left(\frac{S\_1 + P\_1}{N\_1 + S\_1 + P\_1} - \frac{S\_2 + P\_2}{N\_2 + S\_2 + P\_2}\right) \times (1 - r) < 5.06 \times 10^{-3} \text{ .} $$


Table 3. Epidemiological data by Haukka et al. (2003)

In this largest-sampled cohort study to date, Haukka et al. comprised all births in Finland during 1950-1959 (N=870,093) and followed up through the National Hospital Discharge Register for Hospitalizations between 1969 and 1992. *N*: normal females; *S*: unaffected female siblings of patients; *P*: female patients with schizophrenia

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Rather, they seem to argue in favor of the mitochondrial genome model, suggesting a necessity of paradigm shift from the nuclear genome model to the mitochondrial genome

At first we define several notations. *N*1: the number of normal females in the first generation; *N*2: number of female offspring of normal females; *S*1: the number of unaffected female siblings of patients in the first generation; *S*2: the number of female offspring of unaffected female siblings of patients; *P*1: the number of female patients; *P*2: the number of female offspring of female patients; *r* (0 < *r* < 1): the proportion of gene carriers in normal females in the first generation. Then the number of female gene carriers in the first generation is ( <sup>1</sup> *S*<sup>1</sup> *P*<sup>1</sup> *rN* ) and the frequency of female gene carriers in the first generation is given by:

111 11

222 22

111 222

*NSPNSP* 
