The Maddening Genetics of Schizophrenia

January 22, 2014

By Aaron Krol 

January 22, 2014 | Today saw the publication of a pair of papers in Nature that together make up the largest genetic study of schizophrenia ever conducted. A team of researchers from the Icahn School of Medicine at Mount Sinai, in collaboration with partners at the Broad Institute, the Wellcome Trust Sanger Center, UNC, the University of Cardiff, and the Swedish Karolinska Institute, together collected whole exome sequences of nearly 7,000 individuals, including over 3,000 diagnosed with schizophrenia, in order to shed light on the genetic variation underlying the disease.

These studies together provide the strongest evidence yet for the involvement of certain key areas of the genome in the biology of schizophrenia. 

Schizophrenia represents a serious challenge for geneticists. Like autism spectrum disorders (ASD), schizophrenia encompasses a wide range of symptoms and presentations, and has never been clearly linked to any single gene in even a minority of cases. While the disorder is strongly heritable, its causes most likely include a complex network of very rare mutations in many regions of the genome, combined with important environmental factors. And as with ASD, it isn’t clear that all cases of schizophrenia should be considered the same condition at all: mutations in different genetic pathways may eventually be connected to distinct subtypes of schizophrenia, each with their own pathologies and potential treatments.

Nevertheless, groups interested in the disorder have pressed on with large-scale genomic studies, as a promising way to track down the cellular processes at the heart of schizophrenia. “We’ve made an enormous amount of progress studying schizophrenia lumped together,” Dr. Pamela Sklar, Chief of the Division of Psychiatric Genomics at the Icahn Medical Institute and senior author of one of the new Nature papers, told Bio-IT World. “And in fact we’re making more and more progress by not refining the differences between these disorders… so that we can get what I like to call the overall architecture of the disorder.”

The studies published today get at that architecture in two ways. One study is conducted population-wide, using discharge records from Swedish hospitals to collect patients with and without schizophrenia. With over 5,000 whole exomes, the authors looked for a polygenic burden in schizophrenia cases – the possibility that a broad swath of genes, considered together, could be connected to schizophrenia even if none of those genes could be implicated individually.

This approach reflects the complexity of the disorder. The authors did not expect to find any one gene carrying a significant burden for the disease, even with a population large enough to pick up very rare mutations. “Everything about schizophrenia that we’ve ever learned is that it’s really quite genetically complex,” says Dr. Sklar. “And so [what] we’re learning now is that the rare variants are just as complex as everything else.”

However, by narrowing their search to areas of the genome that had seemed promising in previous studies, the authors hoped to strengthen the evidence that mutations anywhere in these areas are a risk factor for schizophrenia.

With that in mind, the researchers chose around 2,500 genes – roughly 10% of the coding genome – mostly involved in neurological processes, and searched for mutations that their algorithms expected to be “disruptive,” meaning they either shut down or drastically changed the gene’s expression. The result was a small but significant effect: the shizophrenia group was 12% more likely to carry a disruptive mutation to any one of these genes than the control group.

The second study looked at exome trios – sets of children with schizophrenia, plus their unaffected parents – collected with the help of clinics in Bulgaria. Over 600 of these trios were sequenced. This approach lets researchers find de novo mutations, which are much more likely to be involved in the disorder, by searching for genetic variants that only the affected children carry. Again, the authors did not expect to find any specific gene that could be reliably pinned to schizophrenia – in fact, even with the large sample size, only a single gene, TAF13, had de novo mutations in more than one child – but did consider patterns among the genes implicated. 

Importantly, both papers analyzed individual sets of genes – much smaller than the full swath of genes considered, but still made up of 20-70 related genes each. The two papers flagged several of the same gene sets as carrying unusually high mutation rates in their schizophrenia populations, including the ARC complex, the PSD-95 complex, NMDAR genes, and genes involved in calcium ion channels. That two independent studies converged on the same spectrum of genes is highly significant for the future of schizophrenia research. “The two papers support each other nicely,” says Dr. Sklar, “and they were from very different patient populations with very different sampling parameters.”

While these gene sets are spread out widely across the genome, they have key similarities in function. All of them are expressed in neurons, and affect how synapses are formed and operate. “The synapse is involved in how cells communicate with each other, in the plasticity of the brain, the ability to learn new information and to remember things,” says Dr. Sklar. “And so the fact that we’ve identified… genes in those complexes [as] involved, I think strongly substantiates some earlier biological observations about synapses, and suggests that those really are an important place to look for schizophrenia pathology.”

Understanding the contribution of these genes to schizophrenia is still a daunting task. Even the ARC complex, the most significant gene set in the large population study, was involved in only nine out of more than 2,500 schizophrenia cases – and the ARC complex consists of 28 different genes. Nonetheless, large studies like this are zeroing in on the cellular processes behind schizophrenia, and provide valuable leads for developing treatments that may be effective in at least a few genetic subtypes of the disease.

“What makes me hopeful is that I’ve been doing this now for fifteen years,” says Dr. Sklar. “In the beginning of doing this, nobody thought that genetics would lead to anything, that you would ever get genetic data that was meaningful… It’s clear that we are making progress in understanding the genetics. I think of it as building the foundation.”