ViewpointGenetic and non-genetic vulnerability factors in schizophrenia: the basis of the “Two hit hypothesis”
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.
References (92)
Symptoms, signs, and diagnosis of schizophrenia
Lancet
(1995)- et al.
Evidence for activation of microglia in patients with psychiatric illnesses
Neurosci. Lett.
(1999) Integrated viral genes as potential pathogens in the functional psychoses
J. Psychiatr. Res.
(1987)- et al.
Relationship of birth season to clinical features, family history, and obstetric complication in schizophrenia
Psychiatry Res.
(1996) - et al.
Increased prevalence of the cavum septum pellucidum in magnetic resonance scans and post-mortem brains of schizophrenic patients
Psychiatry Res.
(1992) Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence?
J. Psychiatr. Res.
(1982)- et al.
In vivo morphometry of planum temporale asymmetry in first-episode schizophrenia
Schizophr. Res.
(1994) Microglia: a sensor for pathological events in the CNS
Trends. Neurosci.
(1996)- et al.
Schizophrenia and city life
Lancet
(1992) - et al.
Borna disease virus: implications for human neuropsychiatric illness
Trends. Microbiol.
(1995)
Do ‘clumsy’ fetuses cause labor and delivery complications?: A study of offspring at risk for psychosis [letter]
Schizophr. Res.
Psychoneuroimmunology and the cytokine action in the CNS: implications for psychiatric disorders
Prog. Neuropsychopharmacol. Biol. Psychiatry
Genes, viruses and neurodevelopmental schizophrenia
J. Psychiatr. Res.
Is there gliosis in schizophrenia? Investigation of the temporal lobe
Biol. Psychiatry
Gliosis in schizophrenia: a survey
Biol. Psychiatry
Urban birth and residence as risk factors for psychoses: an analysis of 1880 data
Schizophr. Res.
Seasonality of births in schizophrenia and bipolar disorder: a review of the literature
Schizophr. Res.
The neurodevelopmental basis of schizophrenia: clinical clues from cerebro-craniofacial dysmorphogenesis, and the roots of a lifetime trajectory of disease
Biol. Psychiatry
Schizophrenia: from neuropathology to neurodevelopment
Lancet
Altered distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase cells in frontal lobe of schizophrenics implies disturbances of cortical development
Arch. Gen. Psychiatry
Maldistribution of interstitial neurons in prefrontal white matter of the brains of schizophrenic patients
Arch. Gen. Psychiatry
Schizophrenia susceptibility and chromosome 6p24-22
Nat. Genet.
Recent advances in defining the neuropathology of schizophrenia
Acta. Neuropathol. (Berl.)
Some cytoarchitectural abnormalities of the entorhinal cortex in schizophrenia
Arch. Gen. Psychiatry
Smaller neuron size in schizophrenia in hippocampal subfields that mediate cortical-hippocampal interactions
Am. J. Psychiatry
Glial fibrillary acidic protein-immunoreactive astrocytosis in elderly patients with schizophrenia and dementia
Acta. Neuropathol. (Berl.)
Absence of neurodegeneration and neural injury in the cerebral cortex in a sample of elderly patients with schizophrenia
Arch. Gen. Psychiatry
Linkage analysis of schizophrenia: challenges and promise
Soc. Biol.
Schizophrenia a subtle defect in neurotrophic gene function?
Neurol Psychiatry Brain Res.
An analysis of the arrangement of neurons in the cingulate cortex of schizophrenic patients
Arch. Gen. Psychiatry
Increased vertical axon numbers in cingulate cortex of schizophrenics
Arch. Gen. Psychiatry
Deficits in small interneurons in prefrontal and cingulate cortices of schizophrenic and schizoaffective patients
Arch. Gen. Psychiatry
Evidence of reduced temporolimbic structure volumes in schizophrenia
Arch. Gen. Psychiatry
Frontal lobes, basal ganglia, temporal lobe — three sites for schizophrenia?
Schizophr. Bull.
Multilocus genetics of schizophrenia
Curr. Opin. Psych.
Analysis of chromosome 22 markers in nine schizophrenia pedigrees
Am. J. Med. Genet.
Perinatal complications and reduced size of brain limbic structures in familial schizophrenia
Schizophr. Bull.
Failure to find a chromosome 18 pericentric linkage in families with schizophrenia
Am. J. Med. Genet.
Cell loss in the hippocampus of schizophrenics
Eur. Arch. Psychiatry Neurol. Sci.
No evidence for astrogliosis in brains of schizophrenic patients. A post-mortem study
Neuropathol. Appl. Neurobiol.
Defective corticogenesis and reduction in Reelin immunoreactivity in cortex and hippocampus of prenatally infected neonatal mice
Mol. Psychiatry
Functional brain imaging and the neuropathology of schizophrenia
Schizophr. Bull.
Obstetric complications and schizophrenia: a meta-analysis
Br. J. Psychiatry
Functional and anatomical aspects of prefrontal pathology in schizophrenia
Schizophr. Bull.
Schizophrenia genesis
Cited by (251)
Prenatal infection and adolescent social adversity affect microglia, synaptic density, and behavior in male rats
2023, Neurobiology of StressModeling psychotic disorders: Environment x environment interaction
2023, Neuroscience and Biobehavioral ReviewsMaternal infection during pregnancy aggravates the behavioral response to an immune challenge during adolescence in female rats
2023, Behavioural Brain ResearchAcute IL-6 exposure triggers canonical IL6Ra signaling in hiPSC microglia, but not neural progenitor cells
2023, Brain, Behavior, and Immunity