Even the most strongly hereditary mental illnesses, such as schizophrenia and bipolar disorder, are rarely passed directly from parent to child. Most cases appear to arise out of the blue – not from a single faulty gene but from thousands of genetic variants scattered across the genome. In other words, these disorders can affect anyone.
Schizophrenia and other strongly hereditary mental illnesses most often strike people whose parents are healthy. Even those with no family history of the disorders may still be at risk. This has been shown by a comprehensive register study in Denmark that challenges assumptions about who can be affected – and suggests that prevention and treatment should be considered far more broadly than before.
“The study clearly shows that we are all at risk of developing even the most highly hereditary mental illnesses such as schizophrenia, bipolar disorder and depression,” says co-author Esben Agerbo, noting that 89% of the people who develop schizophrenia have neither parents nor siblings with schizophrenia. Depression has the same pattern: 60% of the people who develop depression have no family members with depression.
“Mental illness is therefore far from being confined to families that are already affected. This underlines how important it is that we not dismiss mental illness as only affecting certain families but consider everyone to be at risk,” he says.
Idea arose from a theoretical study
The road to these results has been long and rocky. Although researchers have long suspected that this was the case, developing methods to prove it has been difficult. The suspicion arose when Esben Agerbo read an article in the European Journal of Human Genetics in 2010 that challenged the conventional view of how characteristics, competencies and diseases are passed on from generation to generation.
Until then, the genetic inheritance theory of Austrian natural scientist Gregor Mendel had been the prevailing view. Back in the 1800s, Mendel conducted experiments with pea plants that suggested that traits such as colour and shape are inherited according to fixed patterns. Mendel discovered that genes control hereditary traits. Each parent passes on one version of a gene, with some traits dominating over others.
The laws of inheritance do not explain everything
Mendel’s laws of inheritance are still used today to understand everything from eye colour to hereditary diseases such as cystic fibrosis or Huntington’s disease – and they still hold true for traits linked to single genes. However, as the article from 2010 challenged, many diseases are triggered by an unfortunate combination of thousands of small risk bits – genetic variants– scattered like tiny dots on a map across the entire genome, hence the article’s title: “Sporadic cases are the norm for complex disease”.
And this is where Mendel’s theory of inheritance falls short in describing the consequences for the carriers of such genomes and their offspring. Even if the parents were so unfortunate that their two pools of thousands of genetic variants together formed a new genome that could trigger serious mental disorders, both the mother and father would be well below the disease threshold at which the risk becomes high enough to trigger the disorder. This relationship is described in the well-known genetic Falconer’s liability threshold model – a way of explaining how a disease can be hereditary without being present in the parents.
Because these variants are scattered across the entire genome, each one on its own has almost no impact – even though each slightly increases the risk of, for example, schizophrenia. Therefore, only the child actually carries the seed of the disease. In some cases, it is able to manifest itself, whereas in others it is triggered by traumatic events such as divorce or long-term unemployment.
There is an invisible overall risk associated with each individual. This explains why mental disorders can be highly hereditary but not necessarily present in the parents – precisely because they are each below the threshold for disease development.
“Although the point seemed counterintuitive at first, it still seemed very convincing to me. But since it was based on theoretical calculations, I became curious to see whether I could prove that this is actually the case in reality using population data stored in Denmark’s unique patient registries,” says Esben Agerbo.
Large register data and church records reveal hidden traces of disease
The new register study covers 3,048,583 people of Danish origin born between 1955 and 2006. They were followed from 1970 to 2021, corresponding to a total of 80 million person-years.
The data come from the CPR Register, the Psychiatric Central Research Register, the National Patient Register and a beta version of the Multigeneration Register. The latter combines information about family relationships from the CPR Register with old church records and can therefore map family relationships back to 1920.
To convert the enormous quantities of data into an atlas of mental illness, the researchers used two mathematical models called multistate models. These can be compared with a living family tree, in which each member changes status over time – from healthy to ill or vice versa. This enables researchers to follow how diseases arise and move through the family.
Lifetime risk is low for most people
One multistate model functions as a kind of dynamic population overview that follows all individuals until they eventually develop one or more mental disorders, all of which are linked to varying degrees of genetic inheritance.
The other model calculates the risk by looking at people with no family history, thus showing how diseases arise among people with no genetic predisposition. By comparing the two models, the researchers separated the hereditary risk from the general population risk of developing a specific mental disorder.
This makes it possible, for example, to calculate the risk that the brother of a person with a mental disorder will develop the same disorder before becoming 30 years old – and over the course of his entire life. The atlas thus provides information on the lifetime risk of schizophrenia, which is stated as 1.28% and shows that 89.3% of cases have neither parents nor siblings with schizophrenia.
Similarly, the atlas shows that depression has a lifetime risk of 7.8%, and the risk of developing depression is 14.9% for people who have a parent with recurring periods of severe depression. Finally, the atlas indicates that the lifetime risk of bipolar disorder is 1.21%, and 86.4% of cases have no family history of bipolar disorder.
For the first time, you can determine your risk
The researchers themselves call the study groundbreaking because, for the first time ever, it describes the absolute risk: how many of 100 people with a sick parent will actually develop the disease themselves. This is more accurate than the relative risk(a statistical measure of how much the risk is increased), which has been the only guideline to date and says nothing about how great the risk is for an average person in the general population.
“The absolute risk is easier to understand for both patients and practitioners,” points out Esben Agerbo, referring to the literature on research communication.
So the relative risk often ends up misleading the general population, doctors, psychologists and practitioners by giving the impression that having a mother with schizophrenia poses a 10 times higher risk of developing schizophrenia compared with the average in Denmark, and the researchers hope that the new absolute figures will paint a more accurate picture of the situation.
The atlas clearly shows that we all have a risk of being affected by mental illness and that having a family history of a disorder only slightly increases one’s own risk – the absolute risk remains very low, even if it is slightly higher than average.
“We must be careful not to explain other people’s illnesses by saying that they probably come from their parents or only affect specific families that we have nothing to do with. These illnesses are not confined to families with a known history,” says Esben Agerbo.
And when you obtain a new perspective on diseases, it also calls for a different approach to prevention. Esben Agerbo advocates pursuing a dual strategy that includes both individual measures in the form of personalised medicine and therapy programmes and more population-oriented efforts focusing on, for example, stress reduction, alcohol prevention and mental health promotion.
“Prevention should not only target families we know are affected. It must be able to support new cases throughout the population,” he says. “The genetics of disease are so complex that we can never predict exactly who will be affected – and that is why the effort must be broad, ranging from improving mental health in schools and workplaces to rapid assistance when illness strikes,” he concludes.
