Psychiatry Comes of Age

In a recent post the CLAHRC WM Director opined that psychiatry was taking its first reductive steps – we are starting to understand the neurochemical mechanisms behind diseases that appear in the mind. Well our toddler has started to run and the new era has been ushered in with a brilliant recent publication in Nature.[1] The story starts, as it increasingly does in modern science, with a large collaborative effort – in this case the international Psychiatric Genomics Consortium, which carries out genetic association studies. Their Biobank harbours 39,000 cases of schizophrenia and 45,000 controls. There are many genetic polymorphisms across the genome that are associated with schizophrenia – about 100 in fact, as mentioned in a previous post. But one constellation of polymorphisms stands out in terms of the strength of its association with schizophrenia. This constellation resides in the HLA gene cluster. Genes in this cluster encode proteins that help the immune system identify foreign antigens, such as those found on the cell surface of microbes or transplanted tissue. Polymorphisms in the HLA cluster are associated with autoimmune disease, meaning that the immune system has mistakenly identified an antigen on a normal host cell for attack. Does this mean that schizophrenia might be an autoimmune disease? Well, sometimes perhaps (see below), but there is another mechanism by which HLA variants may predispose to this devastating disease. It turns out that the part of the HLA complex most closely associated with schizophrenia is the gene responsible for one of the complement proteins known as complement component 4. And this molecule is not just active in eliminating pathogens and cellular debris – it also affects nerve cells by directly accelerating the pruning of synapses. Synaptic pruning is a normal part of adolescent brain remoulding, but excessive pruning, associated with over-active complement 4, features as part of the pathogenesis in many cases of schizophrenia.[1] Enter NIHR CLAHRC East of England Director Peter Jones. Jones hypothesises that around 10% of cases of acute onset schizophrenia result from an acute autoimmune brain syndrome. He is testing this hypothesis by means of a RCT involving immunosuppression. Presumably it is no co-incidence that some cases of schizophrenia result from a form of autoimmune disease, and that genes in the HLA constellation are so frequently associated with schizophrenia. If so, much of the damage may have been done when the acute brain syndrome appears – we may need to look for an earlier, more tightly targeted therapy, and we suspect that preventing complement-mediated damage will play a role. Incidentally, this is a further example of massive scientific achievement emanating from an international collaborative effort, rather than the genius of just one individual. The future prominent scientist will increasingly be the one with the social skills to engineer a prominent place for herself on the committees that shape protocols and scientific papers, such as the Global Burden of Disease project discussed in a recent post.

— Richard Lilford, CLAHRC WM Director


  1. Sekar A, Bialas AR, de Rivera H, et al. Schizophrenia risk from complex variation of complement component 4. Nature. 2016; 530: 177-83.

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