Is schizophrenia genetic? Genes, environment and family risk
Schizophrenia runs in families, but no single gene causes it.
Twin studies, the 287 DNA regions linked to it, and the role of the early-life environment.
Published 9 min read
Before exploring how schizophrenia or psychosis can be genetic, let me draw you a picture.
It’s the second day of Christmas and a big family comes together: tables get extended, meals are steaming, laughter fills the hot room, the first, then the second “cheers” comes round. And gradually, the faces on my dad’s side of the family tree start turning red. It’s funny how easily you can identify who’s related by blood - we’d all have red smiley faces in a photo from that day.
No surprises there: I used to be a red-cheeked child myself. Any emotion, inconvenience, or physical exercise would make my face flush.
I’m not trying to prove that genes actually work here. I’m focusing on this particular example because having rosacea highlights the reactivity of the individual’s skin, and how the skin and nervous system work together.
Another reason is that the skin (specifically the epidermis (opens in a new tab)) and the nervous system originated from one embryonic cell population - ectoderm (opens in a new tab). We can call them the closest relatives, as they were basically one tissue before week 3-4 of the embryo’s development.1,2
They still work closely together, and their reactivity is something that can be compared. The brain’s reactivity lies in its synapses.
A synapse is the junction where one nerve cell passes a signal to the next. The first cell releases a chemical messenger, and receptors on the second cell respond to it. How strongly the second cell responds depends on how much messenger is released and how many receptors it has.
In schizophrenia, some synapses appear to react more strongly than usual. In 1996, Marc Laruelle and his colleagues gave amphetamine to 15 people with schizophrenia and 15 people without it. Amphetamine makes nerve cells release dopamine (opens in a new tab). The researchers measured how much dopamine was released in the striatum (opens in a new tab), a region deep in the brain. In people with schizophrenia, the release was considerably larger. The larger the release, the more their psychotic symptoms increased.3
Genes may be part of the reason. Many of the genes linked to schizophrenia shape how synapses are built and how they work.4
I’m not implying that the brain’s reactivity is necessarily the cause of schizophrenia. But I think it helps to picture the genetics of schizophrenia as a unique inherited landscape of the nervous system, not as a single protein that was coded incorrectly.
It’s the same with rosacea: there is no single gene responsible, and so far several regions of DNA have been linked to it.5 The problem remains the skin’s reactivity, and as far as we know, it can come from multiple loci (opens in a new tab) and be either amplified or soothed by the environment.6
Genes, proteins and variants
What does it actually mean when a study links a gene to schizophrenia? Let’s follow one such gene, GRIN2A, from the DNA to the synapse.
A gene is a segment of DNA. Some genes contain the instructions for making a protein, and humans have about 19,900 of these protein-coding genes. Many genes do not code for a protein at all. Instead, they help to switch genes on and off.7
GRIN2A belongs to the first group: it holds the instructions for one protein. To build that protein, the cell reads the gene’s DNA for instructions: which amino acids to use, and in what order to link them into a chain.8 For GRIN2A, the chain is 1,464 amino acids long, so the coding part of the gene holds 1,464 codons (opens in a new tab) (instructions), followed by a stop codon.9
Once the cell has built this protein from the GRIN2A gene, the protein becomes one part of the NMDA receptor (opens in a new tab). Nerve cells place this receptor on the receiving side of many synapses, where it responds to the chemical messenger glutamate (opens in a new tab). When a synapse is used often, NMDA receptors help it to become stronger (opens in a new tab), a process that underlies learning and memory.9,10
Everyone has the GRIN2A gene, but not everyone has exactly the same version of it. Small differences in DNA between people are called variants. A variant can change how the receptor works, or how many receptors a nerve cell makes. This can affect how strongly a synapse responds to glutamate.
Large genetic studies have found that some variants of GRIN2A are more common in people with schizophrenia than in people without it.4,11 This is what it means when a study links GRIN2A to schizophrenia. GRIN2A is not a gene that only people with schizophrenia have. Everyone has it, and some versions of it make schizophrenia more likely.
Twins and heritability
Identical twins develop from one fertilised egg and share virtually all of their DNA. Non-identical twins share, on average, half of the variants in which people differ, like any brothers and sisters. Comparing the two kinds of twins shows how strongly genes influence a condition.
Danish researchers made this comparison for all twins born in Denmark between 1951 and 2000. When one identical twin had schizophrenia, the other developed it in about 33 of 100 cases. In non-identical twins, this happened in about 7 of 100 cases.12
The gap between these figures points to a strong genetic influence. Yet two in three identical twins of a person with schizophrenia did not develop it themselves, so genes cannot be the whole explanation.
From these data, the researchers estimated the heritability of schizophrenia at 79%.12 Heritability is a statistic about a population, not about a person. It estimates how much of the variation in risk between people in that population is associated with differences in their genes. A heritability of 79% does not mean that 79% of a person’s risk is genetic, or that 79 in 100 relatives will develop schizophrenia.
Risk for relatives
In the general population, about 7 in 1,000 people develop schizophrenia at some point in their lives.13
Having a parent with schizophrenia raises this risk. A Danish study of 2.7 million people calculated the risk of schizophrenia up to the age of 52. It was below 1 in 100 for people whose parents did not have schizophrenia, about 7 in 100 for people with one parent with schizophrenia, and about 27 in 100 for people with two.14 Put the other way round, 93 in 100 people with one parent with schizophrenia had not developed it by the age of 52.
The risk is also higher for brothers and sisters of a person with schizophrenia: they are about seven times as likely to develop it as people with no affected parent, brother or sister.15
Yet most people with schizophrenia have no parent, brother or sister with the diagnosis. In a Danish study of 1.75 million people, family history accounted for about 5 in 100 cases at the population level.15
What the large DNA studies found
In 2022, a large genetic study compared the DNA of 76,755 people with schizophrenia and 243,649 people without it. Among millions of common variants, it found 287 loci where variants were more frequent in people with the diagnosis.4
The study refers to loci (the plural of locus) rather than genes. A locus is a stretch of the DNA spiral, and it does not have to carry a gene to be significant.
Why stretches, and not single genes or single variants? Variants that sit close together on the DNA are usually passed from parent to child as one block. So when one variant turns out to be more common in people with schizophrenia, its neighbours in the block are more common too. The study cannot tell which of them actually changes the risk. It can only point to the stretch of DNA that holds the block, and that stretch is the locus.16
A locus may hold one gene, several genes or none. A locus without a gene can still matter, because it can contain DNA that switches a gene nearby on or off.17
To find out which genes the loci point to, the researchers ran further analyses. They linked 120 genes to some of the 287 loci. Most of these genes are active in nerve cells, and many are involved in the structure and function of synapses (opens in a new tab).4
Some variants are rare but have a much larger effect. In 2022, Tarjinder Singh and colleagues sequenced the protein-coding parts of the DNA of 24,248 people with schizophrenia and 97,322 people without. Ultra-rare variants in 10 genes raised the odds of schizophrenia between 3 and 50 times. GRIN2A, the gene followed earlier in this article, is one of them. Very few people carry such variants.11
Variants can also be larger. A few people carry deletions or duplications of whole stretches of DNA, called copy number variants. Certain ones, such as a deletion on chromosome 22 known as the 22q11.2 deletion, carry a substantial risk of psychiatric conditions. Only a small share of people with schizophrenia carry one of them. For those who do, the variant may have played a large part in their risk.18
Genetic testing
No genetic test can predict whether a person will develop schizophrenia. Polygenic risk scores, which add up the effects of many common variants, are used in research. The International Society of Psychiatric Genetics does not recommend them for clinical use. Its experts have not reached consensus on testing for copy number variants in most adults with schizophrenia.18
For people with a family history of schizophrenia, a clinical geneticist or genetic counsellor can explain what the figures mean in their own situation.
Genetic predisposition and early development
What people inherit is a predisposition, not schizophrenia itself. In 1977, the psychologists Joseph Zubin and Bonnie Spring described this as a vulnerability model. A person’s vulnerability, shaped by genes and by earlier experience, determines how much stress it takes before symptoms appear.19
Ten years later, the psychiatrist Daniel Weinberger proposed that schizophrenia begins with changes in early brain development that stay silent for years. In his model, symptoms appear only when the affected brain areas mature, much later in life.20
Weinberger’s model puts early life in focus, and several early exposures are linked to schizophrenia. Complications of pregnancy, abnormal growth of the fetus and complications of delivery are all associated with it, although most raise the odds by less than twofold.21 People with schizophrenia have experienced adversity in childhood more often than people without it, with odds about 3.6 times higher.22
Where a child grows up matters too. In Denmark, people who spent their first 15 years in the capital, Copenhagen, were 2.75 times as likely to develop schizophrenia as people who grew up in the countryside. The more years a child lived in a city, the higher the risk.23
These exposures do not affect everyone equally, and genes appear to change how sensitive a person is to them. A Finnish study followed adopted children of mothers with schizophrenia-spectrum disorders and compared them with adoptees without this family history. The functioning of the adoptive family predicted schizophrenia-spectrum disorders only in the adoptees at high genetic risk.24
In 2018, Gianluca Ursini and colleagues found a similar interaction with complications around pregnancy and birth. In people who had such complications, polygenic risk scores explained more than five times as much of the liability to schizophrenia as in people who had not.25
The Stanford neuroscientist Robert Sapolsky reviews decades of research like this in his book Behave (opens in a new tab). His advice on how to look at a gene is: “Don’t ask what a gene does; ask what it does in a particular context.” Genes, he writes, “aren’t about inevitability. Instead they’re about context-dependent tendencies, propensities, potentials, and vulnerabilities.”26
He makes a similar point about early life: “While little in childhood determines an adult behavior, virtually everything in childhood changes propensities toward some adult behavior.”26
To conclude, what people inherit is a predisposition: genes shape how the brain’s synapses are built and how strongly they respond. Pregnancy and birth, childhood, the place a child grows up and stress later in life then act on that starting point. This helps to explain why most children of a parent with schizophrenia do not develop it themselves, and why schizophrenia often appears in families with no history of it.
