Elsevier

Journal of Psychiatric Research

Volume 33, Issue 6, November–December 1999, Pages 543-548
Journal of Psychiatric Research

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Genetic and non-genetic vulnerability factors in schizophrenia: the basis of the “Two hit hypothesis”

https://doi.org/10.1016/S0022-3956(99)00039-4Get rights and content

Introduction

Schizophrenia is a psychiatric disorder that afflicts 0.5–1% of the general population. It is clinically characterized by disturbed thought processes, delusions, hallucinations and/or reduced social skills (Andreasen, 1995). This severe mental disorder strikes human beings in their early adulthood, causes lifelong disability for most of the sufferers and is therefore one of the ten most expensive disorders worldwide. Its direct and indirect costs mount up to 33 billion dollars per year, while afflicting all ethic backgrounds, genders, socioeconomic classes and nationalities. The course of the illness is characterized by episodes of acute psychotic symptoms followed by phases of remission where symptoms like reduced drive and affect as well as disturbed cognitive functions prevail. Despite the severeness of the disorder its origins are unclear until now.

The neuropathological and neuroanatomical findings in patients with schizophrenia have been proposed to arise from dysfunction of structural reorganization during early brain development (Waddington, 1993, Weinberger, 1995), or postnatally from altered maturation of synaptic elimination (Feinberg, 1982). Morphometric and in vivo neuroimaging studies described enlarged ventricles, cerebral atrophy of temporal lobe and prefrontal structures, and increase in the gyrification index (Arnold and Trojanowski, 1996). One of the most consistent results is the lack of astrogliosis in schizophrenic brains, which would be a requirement for severe and chronic neurodegenerative processes (Arnold et al., 1996, Arnold et al., 1998, Falkai et al., 1999a, Roberts et al., 1986, Roberts et al., 1987).

Despite confusing and sometimes contradictory findings, a number of abnormalities have been identified and confirmed by meta-analysis, including ventricular enlargement and decreased cerebral (cortical and hippocampal) volume. There is considerable evidence for preferential involvement of the temporal lobe and moderate evidence for an alteration in normal cerebral asymmetries as extensively reviewed by Harrison recently (Harrison, 1999, Powers, 1999). Morphometric studies of gross structures generally confirm the clinical in vivo neuroimaging findings of enlarged ventricles, decreased size of ventromedial temporal lobe structures, increase in the gyrification index and decreased parahippocampal cortical thickness (Arnold and Trojamowski, 1996; Bogerts et al., 1991, Buchsbaum, 1990, Degreef et al., 1992, DeLisi et al., 1988, Frith, 1997, Harvey et al., 1993, Honer et al., 1996, Kleinschmidt et al., 1994). Morphometric microscopy studies frequently observe alterations in neuron density, shape and decreased neuron size in limbic, temporal (Arnold et al., 1995, Falkai and Bogerts, 1986, Kovelman and Scheibel, 1984, Scheibel and Kovelman, 1981, Zaidel et al., 1997a, Zaidel et al., 1997b), and frontal regions (Akbarian et al., 1993, Akbarian et al., 1996, Benes and Bird, 1987, Benes et al., 1987, Benes et al., 1991, Goldman and Selemon, 1997). Changes in the position and density of neuronal clusters within the entorhinal cortex (Arnold et al., 1991, Falkai et al., 1999b, Jakob and Beckmann, 1994), and alterations in the positioning of neurons in the frontal cortex (Akbarian et al., 1993, Akbarian et al., 1996) imply distorted neuronal migration. If schizophrenia can be traced back to molecular defects during brain development and maturation, one has to consider that first clinical signs precede the manifestation of acute symptoms by months and years. Twin studies revealed divergence between ill and non-ill twin as early as five years (Torrey et al., 1994). Hospitalization of patients with schizophrenia occurs early in adulthood, at a time point when all neurodevelopmental and maturational processes have been completed. The adoption studies of schizophrenia have been valuable in establishing the significance of both genetic and environmental factors with relatives exhibiting more frequent typical, narrowly defined schizophrenia but also non-psychotic forms of the illness (reviewed in Tienari and Wynne, 1994). However, the genetic contribution has been shown to be prevailing.

Looking at the clinical picture of schizophrenia we assume that a single event during brain development or maturation, which is suggestive from a neuroanatomical perspective is rather unlikely to cause the disease. A plethora of research activities elucidated that genetic and environmental factors seem to contribute in an equal fashion and may serve as a basis for the observed neuroanatomical findings. In the following paragraphs we are discussing the genetic and environmental factors that contribute to schizophrenia. Two competing hypothesis are formulated leading to an integrative pathophysiological concept, the “Two hit hypothesis” of schizophrenia.

Section snippets

First hypothesis: multiple susceptibility genes contribute to schizophrenia

Linkage studies have provided strong evidence for several loci on different chromosomes suggesting that multiple gene loci, each of small to moderate effect, are involved in the variability and liability of genetic screens (Bassett, 1991, Cloninger, 1997, Karayiorgou and Gogos, 1997, Kendler and Diehl, 1993, Murphy et al., 1996). The non-mendelian pattern of inheritance suggests weak penetrance of gene effects. Twin studies, however indicate genetic contribution as well. Approximately 48% of

Second hypothesis: non-genetic factors contribute to the etiology of schizophrenia

A plethora of epidemiological findings implicate that the intrauterine period is critical for development of schizophrenia. It has been suggested that maternal infections, more prevalent in the winter months might be responsible for the excess of winter-born patients with schizophrenia. Other risk factors seem to be urban birth (Torrey et al., 1997b) and upbringing (Lewis et al., 1992, Torrey et al., 1997a), maternal dietary insufficiency (Susser et al., 1996), maternal stress (Myhrman et al.,

The “Two hit hypothesis”

There is evidence for an inherited pattern for susceptibility for schizophrenia, which is likely due to mutant gene function in an affected family. Linkage studies clearly implicate a considerable contribution of several susceptibility gene loci, however no candidate gene has evolved from these studies so far. Most of the index patients, however display no obvious family history, probably due to redundancy of gene effects. Hence, environmental factors may also be able to trigger the disease

Summary and conclusions

The suggested “Two hit hypothesis” requires a genetic defect (mutant candidate gene) that leads to a deficient neuronal network (first hit). The second hit being an environmental hazard, like a viral infection, modulates the mutant candidate gene activity leading to an ongoing psychotic illness. The deficient neuronal network constitutes of subtle abnormalities like disturbed gyrification and in addition there is growing evidence for an ongoing reduction of the gray matter compartment. Gene

Acknowledgements

With kind support from the Vada and Theodore Stanley Foundation.

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