A large number of human disorders—autism and cancer among them—display a confusing pattern of inheritance. In some cases, they are clearly genetic, with frequent occurrences in individual families. But in others, new cases will appear in families that were otherwise unaffected.

Initially, this pattern was assumed to result from diseases that had multiple causes. But with some diseases, we've come to recognize that mutations (whether inherited or not) play a much larger role than expected. The latest disease to join this category is schizophrenia.

Schizophrenia is a behavioral disorder that follows the pattern of many others, including autism and dyslexia: in many cases, it runs in families, and these families have allowed us to identify mutations in key genes that are associated with the disorder. In many other instances, however, only a single individual in a family is affected, which suggests that environmental causes may play a key role in these cases.

In recent years, an alternative explanation has been proposed: mutations are nearly always important for these diseases, but the mutations aren't always inherited. This first became clear for cancer, where researchers realized that sporadic cases of the disease resulted from mutations that cells had picked up over the course of their history in the body (and that environmental influences act by altering the frequency of mutations). There's generally a substantial overlap between these sporadic mutations and the ones that are mutated in the cancer's heritable form.

But the cells that become cancerous often take decades of environmental insults to pick up mutations, which doesn't explain many behavioral disorders. These can have an early onset and may be associated with structural differences in the brain that arise early in development—potentially prior to birth. There doesn't seem to be the same sort of room for mutations in these cases. Plus, even if we suspected in the past that mutations were involved, we didn't have the technology to find them.

Better tools

Over the last few years, however, that last bit has changed. First, we developed the technology to screen the entire genome for what are called copy number variations (CNVs), areas where a section of a chromosome was duplicated or deleted. When we looked, we discovered that new CNVs—ones that weren't inherited from either parent—were more common in individuals with autism than in controls. These mutations seem to arise either in the production of eggs and sperm or in the first few cell divisions after fertilization, so they can cause effects as the brain develops.

Even as those results came in, technology continued to improve, and the new schizophrenia study takes advantage of a technique called whole exome sequencing. Instead of looking for large-scale changes like CNVs, exome sequencing focuses on small changes that take place in key areas: the one to two percent of the human genome that actually codes for proteins (this portion is contained in things called exons, hence the term "exome"). This can be sequenced using the same high-throughput machines that are being used to complete whole genomes and, because there's so much less DNA to sequence, it's possible to look at many more individuals.

Comparing exomes

That's precisely what the researchers behind the new study have done. They sequenced the entire exomes of 53 schizophrenia patients, along with the exomes of their parents, in families that have no wider history of the disease. Then, as controls, they sequenced similar trios in families that had no history of schizophrenia at all. (As part of this work, they actually identified some families that had new CNVs, but to keep them from confusing matters, didn't include them in the final analysis.)

With the sequencing done, the researchers looked over the results, trying to spot cases where an individual had a DNA sequence that wasn't present in either parent. In just over half the individuals with schizophrenia, the team was able to spot one or more of these differences, and most of are predicted to alter the function of the gene they reside in. In contrast, less than a third of the control cases seemed to have these new mutations, which were ten times less likely to alter any genes. At least one of the genes identified in the patient population had previously been associated with an inherited form of schizophrenia.

These results suggest that schizophrenia is generally caused by mutations, even in cases where the mutations haven't been inherited. This still leaves significant space for environmental influences, though; these could influence the occurrence of the disease by altering the mutation rate, for example. Schizophrenia is a complex disease, and environmental factors may also alter the timing of its onset and its progression afterwards.

The results clearly have significance beyond schizophrenia. Many other disorders, including ALS and dyslexia, show the same sort of pattern: a mix of inherited and sporadic cases. Autism and schizophrenia, by showing that mutations may underlie both types of case, may provide a model that helps us understand a wide variety of disorders.

Nature Genetics, 2011. DOI: 10.1038/ng.902 (About DOIs).