between bedside and bench Schizophrenia
Few risk loci Environmental insults Exposures Development Chance
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Many risk loci
Schizophrenia
Figure 1 Schematic of schizophrenia as a pathway disease. Genetic variants at many loci encode the components of a pathway or pathways. Many risk loci can be affected, resulting in a disease pathway greatly modified owing to polygenetic variation. When a few risk loci are affected, there may be limited impact on the disease pathway. This pathway itself—in conjunction with environmental risk factors or other factors—mediates risk of schizophrenia.
maturation13,14, this yields a testable hypothesis about a definable pathway that might mediate some component of risk. Finally, schizophrenia is highly polygenic. We now know that polygenicity is a cardinal feature of many human diseases and anthropometric traits characterized by complex inheritance of dozens to hundreds of loci (for example, Crohn’s disease, type 2 diabetes, height and body mass)15. The genetic variants involved are common with subtle effects, and some of these gene sets may have singular clinical utility. For schizophrenia, there is strong and replicated evidence that the number of loci is in the thousands8. Indeed, this polygenic component (that must include common variation rather than being a reflection of multiple rare variants) accounts for 23–33% of variance in liability to schizophrenia on the order of a third of the heritability8,16. This also suggests that so-called ‘missing heritability’ is merely hidden and imperfectly assessed by current genotyping technologies. A recent paper about nonsyndromic autism provided a tantalizing glimpse of how genetic variation might relate to altered biological pathways17. Typical patterns of gene expression in frontal and temporal cortex were attenuated in autism. An empirically derived gene expression module that was underexpressed in autism was enriched for known autism susceptibility genes and genetic association signals. Although not completely elucidated, these data support the notion that polygenetic variation
for autism alters the expression and regulation of a transcriptional network that mediates risk for autism. A similar model could hold for schizophrenia. For schizophrenia, the hypothesis is that polygenetic variation alters a biological pathway. Removal of any single node through protein-killing mutation either may have no effect, owing to the emergent network property of robustness, or, for network hubs, may yield a phenotype other than schizophrenia, such as mental retardation or autism. There are many ways in which such a pathway could mediate liability to schizophrenia—by being insufficiently robust or overly rigid in response to environmental insult, for example, or by coding an inappropriate developmental program. The conceptualization of schizophrenia as a pathway disease has an immediate implication.
A priority for the field18 must be to complete genomic screens of a sufficient number of cases to define the pathway components with precision (for instance, 50,000 cases and 50,000 controls would afford power19 similar to the GIANT height meta-analysis20). If this can be accomplished, it should be possible to develop assays to monitor pathway function in living cells. Knowledge derived from this work could lead to the fulfillment of the ultimate promise of genomics—primary prevention of the development of schizophrenia in those at risk and the development of more effective therapeutics in an era where big pharma has turned sharply away from psychiatric drug development. Critically, it is possible that any such pathway is intrinsically modifiable and that people with schizophrenia are not ‘doomed from the womb’ but rather could anticipate return to relatively normal long-term function. COMPETING FINANCIAL INTERESTS The author declares no competing financial interests. 1. van Os, J. & Kapur, S. Lancet 374, 635–645 (2009). 2. Collins, P.Y. et al. Nature 475, 27–30 (2011). 3. World Health Organization. The global burden of disease: 2004 update. (2008). 4. Friedhoff, A.J. & Van Winkle, E. Nature 194, 897–898 (1962). 5. Sherrington, R. et al. Nature 336, 164–167 (1988). 6. Ripke, S. et al. Nat. Genet. 43, 969–976 (2011). 7. Levinson, D.F. et al. Am. J. Psychiatry 168, 302–316 (2011). 8. International Schizophrenia Consortium et al. Nature 460, 748–752 (2009). 9. Barabási, A.L., Gulbahce, N. & Loscalzo, J. Nat. Rev. Genet. 12, 56–68 (2011). 10. Lichtenstein, P. et al. Lancet 373, 234–239 (2009). 11. Stefansson, H. et al. Nature 460, 744–747 (2009). 12. Kwon, E., Wang, W. & Tsai, L.H. Mol. Psychiatry advance online publication, doi:10.1038/mp.2011.170 (20 December 2011). 13. Szulwach, K.E. et al. J. Cell Biol. 189, 127–141 (2010). 14. Smrt, R.D. et al. Stem Cells 28, 1060–1070 (2010). 15. Visscher, P.M. et al. Am. J. Hum. Genet. 90, 7–24 (2012). 16. Lee, S. et al. Nat. Genet. (in the press). 17. Voineagu, I. et al. Nature 474, 380–384 (2011). 18. Sullivan, P. Mol. Psychiatry 17, 2–3 (2011). 19. Yang, J., Wray, N.R. & Visscher, P.M. Genet. Epidemiol. 34, 254–257 (2010). 20. Lango Allen, H. et al. Nature 467, 832–838 (2010).
■ bedside to bench
Schizophrenia, social environment and the brain Heike Tost & Andreas Meyer-Lindenberg More than a century after the initial description of schizophrenia as a clinical entity, the need for effective treatments is as pressing as ever. Though schizophrenia is widely recognized as
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a major cause of the global burden of disease1, affected individuals and clinicians continue to face an often chronic and debilitating condition with a mortality gap of more than 15 years. 211
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Although available medications such as dopamine D2 receptor antagonists relieve symptoms of acute psychosis, they have substantial side effects and provide limited relief of cognitive impairments and negative symptoms2, which are critical for quality of life and long-term patient disability. This unsatisfactory state of affairs is partly a consequence of the lack of pathophysiological knowledge—an issue that is largely rooted in the biological complexity of the disorder2,3, but arguably also in some conceptual limitations of the way translation is pursued in psychiatry today, where research tends to be focused on single facets of biology such as receptor class or single genetic variants. It is clear that schizophrenia has a prominent neurodevelopmental component, and signs of the disease can in retrospect be found long before the first psychotic episode. An important translational strategy has therefore been to look at the way causal factors operate in the brain. Over the years, a variety of genetic, neural and environmental causes of schizophrenia have been proposed, including progressive brain pathology, defective ego, nutritional deficit, dopamine dysfunction, chromosomal abnormality and childhood trauma2,3. In the past decade, the identification and investigation of genetic risk variants and their neural systems correlates have been a productive focus of investigation3. This line of research has been facilitated by the formation of large multinational research consortiums capable of detecting signals of small effects size and the broad availability of high-throughput genetic and neuroimaging techniques. Although emphasizing genes is crucial given the high heritability of schizophrenia, it might be time to extend the strong molecular genetics focus of the 2000s to include the environment. This strategy is in accordance with modern pathophysiological models, which underscore the crucial relevance of gene-environment interactions for normal and irregular brain development2–4. For almost a century, epidemiological studies have provided strong evidence for environmental risk factors of psychosis5. Even though, over a population, exposures such as obstetric complications, cannabis abuse and traumatic experiences explain less of the total risk variance compared to genes, the relative risk of individual environmental stressors exceeds the effects of common genetic variants in exposed individuals by far3,5. This is demonstrated by Heike Tost and Andreas Meyer-Lindenberg are at the Central Institute of Mental Health, University of Heidelberg, Medical Faculty Mannheim, Mannheim, Germany. e-mail:
[email protected]
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Social-emotional processing network Genetic risk factors for schizophrenia CACNA1C ZNF804A
PFC
ACC
vmPFC
VS AMY
Social-environmental risk factors for schizophrenia Urban upbringing Social status processing
Katie Vicari
© 2012 Nature America, Inc. All rights reserved.
between bedside and bench
Figure 1 Effects of social environmental risk factors for schizophrenia on regulatory circuits of human social-emotional processing. In this circuitry, the anterior cingulate cortex (ACC) is a key node that is influenced by higher-order cognitive processing areas such as the prefrontal cortex (PFC), and it provides top-down control of subcortical neural areas modulating stress response, salience and negative emotion, such as the amygdala (AMY) and the ventral striatum (VS). Effects of urban upbringing and social status processing can challenge ACC function and limbic structures such as ventral striatum and amygdala. Similarly, established genetic risk variants for schizophrenia can affect ACC-amygdala coupling (for example, ZNF804A) and activation (for example, CACN1AC). This highlights a neural circuit where social environmental and genetic risk factors for schizophrenia converge. vmPFC, ventral medial prefrontal cortex.
MI: PLEASE ADD A FIGURE CREDIT FOR
Katie Vicari
risk increases of about 250% for some social environmental risk factors compared to at most 35% for common genome-wide–supported psychosis risk variants5. Many of these environmental factors raise the risk for a variety of mental disorders in a nonspecific manner, similar to the effects of most genes studied in psychiatry. However, two environmental stressors stand out for having an impact predominantly on schizophrenia: urban upbringing and migration. Meta-analyses show that the incidence of psychosis is doubled in individuals raised in urban environments6, with evidence of a dose-risk relationship7 that probably reflects causation6. In agreement with the notion of a neurodevelopmental disorder4, the adverse effects of urbanization are moderated by genetic risk (such as being a relative of an affected individual)5,6 and are timelocked to childhood and early adolescence7. Correspondingly, there is a twofold increase in risk for schizophrenia in first- and secondgeneration immigrants independent of ethnicity or host country8. Although the evidence for a causal link between social environment and schizophrenia is therefore strong, the difficult task remains to sort out which of the many
potential physical (for example, noise, green space or pollution), biological (for example, infection or vitamin D deficiency) and psychological factors contribute to these epidemiological observations. Both urbanization and migration involve societal transitions that confront individuals with a distinctive set of social challenges, such as disintegration of family networks, increased competition and growing class differences. A recent multilevel longitudinal study examining incidence of psychosis in an extensive population sample9 brings these social factors into sharper focus—it indicates that the risk for psychosis is shaped by the interaction of subjectspecific characteristics, including minority status, social fragmentation and deprivation, and incongruous characteristics of the social context in which these individuals are raised9. These data suggest that social marginalization, and in particular the accumulation of facets that define individuals as being different from their social surroundings, are potential risk factors for schizophrenia. This is especially true for genetically vulnerable subjects, in which previous studies have shown that the risk after urban birth is even higher5,6. The timing of
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both genetic and urban effects further suggests an impact on the developing brain that impairs the ability of subjects to deal with social stressors at the time of illness manifestation. These exciting epidemiological observations should prompt new benchwork defining the neural mechanisms that could mediate the synergistic risk of genes and social environment. Some biological substrates have been hypothesized5, in particular stress-induced dysregulation of the hypothalamus-pituitaryadrenal axis and sensitization of mesolimbic dopamine pathways3,5. This research needs to be brought to the next level by examining brain effects of specific aspects of social life linked to schizophrenia risk. The first steps in this direction are being taken. Recent functional neuroimaging work in healthy humans during social evaluative stress processing shows an association of a key region for regulation of limbic activity and negative emotion, the anterior cingulate cortex, with urban upbringing10 (Fig. 1). Consistent with this, structural and functional deficits in the anterior cingulate are prominent in schizophrenia and precede the onset of the disorder11. Further research is needed to identify component features of the urban social environment that prompt disturbed processing in this region and the downstream limbic structures it regulates. For instance, an earlier study has examined the neural processing of social status12, a strong predictor of mental and physical health in humans that has been hypothesized to play a part in urban risk for schizophrenia. Individuals exposed to unstable social hierarchies show a specific activation of
neural circuits involved in emotion and salience processing. This included, again, the anterior cingulate cortex, but also structures such as the amygdala and ventral striatum12 (Fig. 1). Supporting the epidemiological observations of interacting genetic and environmental susceptibility, genetic risk for schizophrenia affects the same brain circuits, as shown by the association of variants in CACNA1C with reduced cingulate function13 and the increased reactivity of the ventral striatum to stress in healthy first-grade relatives of individuals with schizophrenia14. Although these initial data suggest a specific neural system where genetic and social environmental risk factors for schizophrenia converge3, more detailed bench work has to follow. Specifically, to provide evidence for geneenvironment interaction in brain, subcomponents of social risk exposure such as unstable status, out-group position and discrimination should be analyzed for their neural effects in genetically stratified individuals. Further, cellular mechanisms such as epigenetic programming should be linked to these circuit abnormalities in individuals with relevant epidemiologic and genetic risk factors by using, for example, induced pluripotent stem cell technologies. A prominent theory15 of the natural history of scientific progress postulates a sequence of periodic paradigm shifts rather than gradual integrative moves. We hope that the partial neglect of social environmental risk factors in psychiatric neuroscience is coming to an end, yet active integration of genetic and environmental research will be crucial. Understanding the brain effects of gene-environment interac-
tions promises opportunities for new insights into the risk architecture of schizophrenia and, thus, for more effective treatment. Unlike the genome, the environment can be directly influenced, opening up the possibility of an evidence-based policy toward primary prevention of mental illness. Realizing this ambitious goal will require genuine multidisciplinary efforts that will join forces from fields as diverse as molecular genetics, neuroscience, epidemiology, social psychology, psychiatry, pharmacology, biostatistics and social policy. Despite the challenges involved, such integrative approaches will be necessary to provide adequate answers to the complexity of mental illness, including schizophrenia. COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests. Collins, P.Y. et al. Nature 475, 27–30 (2011). Insel, T.R. Nature 468, 187–193 (2010). Meyer-Lindenberg, A. Nature 468, 194–202 (2010). Weinberger, D.R. Arch. Gen. Psychiatry 44, 660–669 (1987). 5. van Os, J., Rutten, B.P. & Poulton, R. Schizophr. Bull. 34, 1066–1082 (2008). 6. Krabbendam, L. & van Os, J. Schizophr. Bull. 31, 795–799 (2005). 7. Pedersen, C.B. & Mortensen, P.B. Arch. Gen. Psychiatry 58, 1039–1046 (2001). 8. Bourque, F., van der Ven, E. & Malla, A. Psychol. Med. 41, 897–910 (2011). 9. Zammit, S. et al. Arch. Gen. Psychiatry 67, 914–922 (2010). 10. Lederbogen, F. et al. Nature 474, 498–501 (2011). 11. Borgwardt, S.J., McGuire, P., Fusar-Poli, P., Radue, E.W. & Riecher-Rossler, A. Neuroimage 39, 553–554 (2008). 12. Zink, C.F. et al. Neuron 58, 273–283 (2008). 13. Erk, S. et al. Arch. Gen. Psychiatry 67, 803–811 (2010). 14. Brunelin, J. et al. Psychiatry Res. 181, 130–135 (2010). 15. Kuhn, T.S. The Structure of Scientific Revolutions (University of Chicago Press, Chicago, 1962).
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