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Twins Discordant for Schizophrenia

Etiology of Major Psychiatric Disorders

Little is known about the etiology of major psychiatric disorders, and a diagnostic differentiation based on biological markers or objective laboratory methods is currently not available. Accordingly, it is hardly surprising that only incomplete treatments for these disorders are in use and that there is no cure in the majority of cases. Pharmacological treatment, though effective, is unsatisfactory in the sense that (1) a large proportion of patients (35% - 45%) exhibit a refractory clinical picture, and (2) the question of predicting treatment response in the individual patient is not answerable for any of the currently available antipsychotics and antidepressants.

Genetic Predisposition: Vulnerability and Resilience

Evidence from twin, family and adoption studies suggests that, ultimately, genetic markers may represent the most important trait-like characteristics in the etiology of major psychiatric disorders. However, genetic predisposition appears to vary across patients and to "explain" no more than 25% to 60% of the observed phenotypic variance, depending on the onset of illness, severity of illness, and long-term course of clinical syndromes. Therefore, genetic predisposition has been conceptualized as acting nonspecifically, by elevating a subject's "vulnerability" (or "sensitivity") to environmental or endogenous challenges. An inherited vulnerability is neither necessary nor sufficient for the development of psychiatric disorders.

The Twin Approach to Studying Genetic versus Non-Genetic Factors

Like all complex traits and illnesses, psychiatric disorders are influenced by multiple genes as well as multiple non-genetic factors. The genetic component's magnitude correlates with the severity of underlying syndromes and may vary from 10-70%. There is no single "biogenic imbalance" that causes psychiatric disorders. Rather, the complex interplay between several self-regulating, intrinsic/endogenous subsystems, upon which the organism can "normally" rely, becomes distorted, for whatever reasons. This situation is evident in monozygotic twins who share identical genomes but remain discordant over a lifetime for severe psychiatric disorders, such as schizophrenia. No more than 55% of monozygotic (mz) and 15% of dizygotic (dz) co-twins are concordant for schizophrenia. This raises the intriguing question why mz co-twins who shared the same environment have a 3.7-fold higher risk to both suffer from schizophrenic disorders, compared to dz co-twins raised together.

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Fig. 1: Within-pair concordances in mz and dz twins for the quantitative traits "finger ridge count", "body height", "shoe size", "body weight", and "brain-wave patterns". The distributions are approximately normal with means ranging between 0.99 (finger ridge count) and 0.65 (body weight). Mean values and variances are strongly correlated (the higher the mean value the smaller the variance. All means values display a mz:dz ratio of 2:1 independent of magnitude [Lykken and Stassen: data of 1,300 dizygotic and 1,434 monozygotic twin pairs].

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