The previous post in this series described the symptoms of schizophrenia. Here we turn to the causes of schizophrenia. There has been major progress in this area over the last twenty years. A number of factors have been identified which carry a risk for schizophrenia. Some of these factors are genetic, others impact during the course of life.

Usually schizophrenia emerges in late adolescence or early adulthood, as the intellect, personality and neural networks are being sculpted. The population risk is slightly less than 1%, with a slight excess of male sufferers (1.4:1). Males also tend to show a more severe pattern of illness, with more impoverishment of the personality and psychological decline.

Risk Factor Categories

The risk factors for schizophrenia can be grouped into several categories (Figure 1). The perinatal category includes hypoxic and nutritional insults to the developing brain in-utero. The second category includes being brought up in city environment, particularly for immigrants. The third category includes drugs of abuse, specifically strong cannabinoid CB₁ receptor agonists. Finally, there is the genetic category, which can be subdivided into single nucleotide polymorphisms (SNPs) and copy number variants (CNVs).

Figure 1. Risk factors for schizophrenia.

Genetic risk factors

It has long been recognized that schizophrenia runs in families (Figure 2), but until the last decade attempts to identify specific genes floundered. Technological advances have revolutionized the field. It is now feasible to screen an individual’s DNA at every base pair (A, T, C, G) in every chromosome. Variants (say the substitution of an A for a T) are called single nucleotide polymorphisms (SNPs) when they occur in at least 5% of the overall population.

In the technique known as GWAS (genome wide association study) tens of thousands of patients are compared against tens of thousands of controls. So far, 145 SNPs have been shown to confer risk for schizophrenia (Figure 3). Each SNP on its own carries a very small risk, but they are common in the population, and their effects are additive. Two SNPs of considerable interest are the gene for a calcium channel (CaV1.2) and the gene for a protein called complement C4a.

Figure 3. Single nucleotide polymorphisms which confer a risk for schizophrenia.

The second major breakthrough in schizophrenia genetics are copy number variants (CNVs). Copy number variants are deletions or duplications of a long stretch of DNA, typically incorporating half a dozen genes or so. So far eight CNVs which confer a risk for schizophrenia have been identified. Each of these CNVs carry a very high risk. A CNV of considerable interest is NRXN1 (Figure 4).The NRXN1 protein forms a physical bridge which stabilses synaptic connections in the brain. The NRXN1 story provides strong evidence for a long-held theory that the pathology of schizophrenia stems from abnormal connectivity within neural networks.

Figure 4. Copy number variants which carry a risk for schizophrenia.

We can recap. A number of factors confer risk for the development of schizophrenia. These can be categorized into several categories – perinatal, environmental, cannabinoid CB₁ drugs, and genes. The gene category includes SNPs (such as, complement C4a, the calcium channel CaV1.2) and CNVs (such as NRXN1). In the next post in this series we will look at the neurobiology of these components and cannabinoid CB₁ drugs.

Further posts in this series:

What exactly is schizophrenia?

 Future posts in this series:

What happens to the nervous system in schizophrenia?

The prognosis of schizophrenia.

How is schizophrenia treated?