Novel Insights Into the Causes of Schizophrenia: Part 2

March 15, 2016

The identification of a genetic risk factor has shed light on the underlying neurobiology of the disorder.

Schizophrenia and the C4 gene

Although the work of Sekar and colleagues advances our understanding of schizophrenia, much work remains to be done. Schizophrenia is a syndrome, which likely encompasses numerous diseases with a shared phenotype-namely psychosis. For example, a recent study identified 3 neurobiologically distinct psychosis phenotypes-termed biotypes-independent of clinical symptoms.7

Despite longstanding evidence that schizophrenia is associated with immune system dysfunction, there is significant heterogeneity in findings in this research area, including negative studies. One potential explanation for the observed heterogeneity is that immune dysfunction is present only in a subset of patients with schizophrenia. Thus, it would be important, for example, to understand whether there are differences in the C4 gene (and its expression) between patients with schizophrenia with and without evidence of immune dysfunction. Are there specific demographic and clinical characteristics that distinguish patients with schizophrenia based on different C4 gene variants?

Many genes associated with a modest, but significant, increased risk of schizophrenia have been identified.5 In the Sekar study, the C4AL-C4AL haplotype was associated with 1.27-fold increased odds of schizophrenia, or a 27% increased risk. By comparison, other replicated risk factors for schizophrenia, such as prenatal maternal infections or advanced paternal age, are associated with a 2- to 3-fold increased odds of schizophrenia.8,9

There is evidence, for example, that familial liability may interact with prenatal exposure to infection to synergistically increase schizophrenia risk.10 Thus, future studies are needed to explore interactions between the C4 gene and other genes involved in cortical maturation, synaptic pruning, and neurotransmission, as well as other environmental risk factors, on schizophrenia risk and, more generally, on brain development.

What it all means to your practice

The work by the Harvard team represents a bold step in our journey toward understanding the etiopathophysiology of schizophrenia. Namely, the identification of a genetic risk factor has shed light on the underlying neurobiology of the disorder.

An obvious question emerges-for psychiatrists, for patients, and for family members: what are the immediate, direct implications of this study for my clinical practice, myself, and/or my loved one? Should we pursue C4 genetic testing for existing patients with schizophrenia? For persons at clinical high risk for psychosis? For unaffected family members? A second, follow-up question is: for persons with the highest risk C4 haplotype (ie, C4AL-C4AL), how might this affect treatment-do patients with schizophrenia need some kind of (adjunctive) immune-based therapy? For high-risk patients, are there readily available treatments that might impact on synaptic pruning?

Regarding the first question: the modest increased risk of schizophrenia associated with the C4 gene is not currently sufficient to justify widespread testing as a biomarker of schizophrenia risk. Since the prevalence of schizophrenia is approximately 1%, this means that among persons with the highest risk C4 haplotype (C4AL-C4AL, associated with 1.27-fold increased odds of schizophrenia, or a 27% increased risk), over 98% will not develop schizophrenia. Regarding the follow-up question, unfortunately, there are no readily available or emerging associated treatments that target this aspect of immune function.

Nevertheless, patients identified as being at increased risk for schizophrenia (because of a family history of schizophrenia in a first-degree relative and/or evidence of prodromal or attenuated psychotic symptoms) represent an important population for further study. For example, C4 gene variants-in combination with other measures-might help identify persons already at increased risk for schizophrenia who are more likely to go on to develop the disorder.

In parallel, it is also important to ascertain whether unaffected first-degree relatives of patients with schizophrenia have a similar pattern of C4 gene variants and expression, as a potential endophenotype of the disorder. Furthermore, given the efficacy of adjunctive treatment with anti-inflammatory agents in some patients with schizophrenia, C4 gene variants might also help identify patients who are more likely to benefit from this treatment approach.11 It will be informative to explore relationships between C4 gene variants and specific symptom domains in patients with schizophrenia. These new findings will, no doubt, mark the start of a journey towards the development of novel treatment approaches.


Dr Miller is Associate Professor in the Department of Psychiatry at Georgia Regents University in Augusta, GA, and Schizophrenia Section Editor for Psychiatric Times. He reports no conflicts of interest concerning the subject matter of this article.


1. National Institute of Mental Health Strategic Plan. Online. strategic-plan-2008.pdf. [corrected final:]

2. Sekar A, Bialas AR, de Rivera H, et al. Schizophrenia risk from complex variation of complement component 4. Nature. 2016;530:177-183.

3. Cannon TD, Chung Y, He G, et al. Progressive reduction in cortical thickness as psychosis develops: a multisite longitudinal neuroimaging study of youth at elevated clinical risk. Biol Psychiatry. 2015;77:147-157.

4. Glausier JR, Lewis DA. Dendritic spine pathology in schizophrenia. Neuroscience. 2013;251:90-107.

5. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421-427.

6. Shi J, Levinson DF, Duan J, et al. Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature. 2009;460:753-757.

7. Clementz BA, Sweeney JA, Hamm JP, et al. Identification of distinct psychosis biotypes using brain-based biomarkers. Am J Psychiatry. December 7, 2015; Epub ahead of print.

8. Brown AS, Derkits EJ. Prenatal infection and schizophrenia: a review of epidemiologic and translational studies.Am J Psychiatry. 2010;167:261-280.

9. Miller B, Messias E, Miettunen J, et al. Meta-analysis of paternal age and schizophrenia risk in male versus female offspring. Schizophrenia Bull. 2011; 37:1039-1047.

10. Clarke MC, Tanskanen A, Huttunen M, et al. Evidence for an interaction between familial liability and prenatal expsure to infection in the causation of schizophrenia. Am J Psychiatry. 2009;166:1025-1030.

11. Sommer IE, van Westrhenen R, Begemann MJ, et al. Efficacy of anti-inflammatory agents to improve symptoms in patients with schizophrenia: an update. Schizophr Bull. 2014;40:181-191.