Functional Analysis of Schizophrenia Risk Genes: Complements on an Elegant Piece of Work

Schizophrenia (see here) is a debilitating disorder comprising of three symptom domains: 1. The so-called positive (psychotic) symptoms of auditory hallucinations (hearing voices), paranoia and disorganised behaviour; 2. Negative symptoms, such as a lack of motivation and the loss of pleasure in activities that were formerly pleasurable; and 3. Cognitive deficits, reflected by a lack of mental agility and a general “brain fog”. Although the positive symptoms are relatively well-controlled by first- and second-generation antipsychotic drugs, such as haloperidol, risperdol, olanzapine, paliperidone, and aripiprazole, all of which antagonise dopaminergic D2 receptors, the negative symptoms and cognitive deficits are poorly treated. Unfortunately, the search for new treatments for schizophrenia is hampered by the lack of an understanding of the underlying pathological mechanisms. However, recent genetic data has begun to shine light onto some of the mysteries of the disorder and have implicated a role for complement component 4 (C4) genes (see here).

Prior to the advent of genome-wide association (GWA) studies, candidate gene studies implicated a number of different genes in the pathogenesis of schizophrenia (such as COMT, DISC1, DTNBP1 and NRG1) yet due to a lack of statistical power, these have failed to provide meaningful insights into the pathology of the disease (see here). More recently, the use of genome-wide association (GWA) studies, which links disease risk to specific regions of the genome, has begun to identify genetic variants associated with schizophrenia. Hence, the Schizophrenia Working Group of the Psychiatric Genomics Consortium reported at least 108 different regions of the genome associated with a risk of schizophrenia (see here). These data highlighted associations between the dopamine D2 receptor and genes involved in glutamate neurotransmission, consistent with the well-described dopamine and glutamate dysfunction hypotheses of schizophrenia. Intriguingly, a number of other genes were associated with the immune system, of which the strongest were those associated with the major histocompatibility complex (MHC), a region containing 18 polymorphic human leukocyte antigen (HLA) genes. The genetic links between the immune system and schizophrenia is consistent with epidemiological data suggesting, for example, that over a third of cases could be prevented if infection in pregnant women was prevented (see here).

Fig 1Complex association

The MHC is a complicated region of Chromosome 6 and is divided into three classes (MHC I, II and III; see figure 1, taken from here). Recent work from Sekar and colleagues (see here) has focussed upon the most strongly associated markers in the Class III region and more specifically the C4 gene. The C4 gene has the added complexity of existing as C4A and a C4B isotypes, both of which vary in structure and copy number and both have a long and short form, differentiated by the present or absence, respectively, of a human endogenous retroviral (HERV) insertion, which lengthens the gene but not the protein sequence. To cut a long and complicated story short, the different C4 alleles resulted in widely varying levels of C4A and C4B expression in the brain (Figure 2 – see Sekar et al) with greater levels of C4A expression being related to a greater risk of schizophrenia.


Figure 2. Expression levels of C4A RNA


In the immune system, C4 activates C3, which in turn covalently attaches to its targets and triggers engulfment by phagocytic cells and in the developing mouse brain, C3 is important for synaptic pruning, a crucial process in neurodevelopment. Accordingly, Sekar and colleagues showed that mice deficient in the C4 gene had deficits in synaptic remodelling (reduced synaptic pruning) similar to those observed in C3-deficint mice. Hence, the increased expression of C4 protein in schizophrenia may well result in increased synaptic pruning that might in turn be related to the cortical thinning and reduction in synaptic organisation that have been reported in schizophrenia. Although such studies will not directly lead to novel therapeutics, they nevertheless demonstrate an elegant translation of genetic information into functional studies and provide the basis for hypotheses that might possibly transform the treatment of this disorder.


Blog writted by John Atack


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