Supposedly distinct psychiatric conditions may have same root causes

An analysis of genetic variants in more than a million people diagnosed with neurodivergences and mental health conditions — by far the largest study of its kind to date — found that 14 conditions typically thought of as distinct actually fall into five underlying genetic groups.

This finding is encouraging for people diagnosed with multiple psychiatric disorders, says Andrew Grotzinger of the University of Colorado Boulder, a member of the research team behind the analysis. People may think that means there are a lot of problems at home, he says, but there may be only one root cause.

“For the millions of people who are diagnosed with multiple psychiatric disorders, this indicates that there are not several separate things going on,” says Grotzinger. “I think it makes a big difference for a patient to hear that.”

When biologists began looking for genetic variants associated with a higher risk of developing a range of psychiatric disorders, they expected to find different variants for each. Instead, it has become clear that there is a lot of overlap. Some researchers have even suggested that all of these conditions have a single underlying cause, called p-factor.

This latest study suggests that the reality lies somewhere between these two extremes. That doesn’t provide much support for the idea of ​​a p-factor: Even if some genetic variants were linked to all 14 conditions, they were involved in fundamental processes that cause many different problems, beyond mental illness, when they go wrong, Grotzinger says.

On the other hand, the team also found relatively few variants linked to higher risk of a single disease. Instead, the variants tended to fall into five clusters, with particularly high overlap between schizophrenia and bipolar disorder, and between major depression, PTSD and anxiety.

Many variants linked to schizophrenia and bipolar disorder were in genes active in excitatory neurons – which make other neurons more likely to fire – while many variants linked to depression, PTSD and anxiety were in genes active in oligodendrocytes, the cells that produce the myelin sheaths around nerves.

The other three groups identified by Grotzinger and colleagues were: ADHD and autism; OCD, anorexia nervosa and Tourette syndrome; and substance use disorders and nicotine dependence.

The findings could help explain why two-thirds of people diagnosed with a psychiatric problem receive more than one during their lifetime. It could also be seen as evidence that the diagnostic criteria used by psychiatrists are wrong, says Grotzinger.

“If you went to the doctor and had a runny nose, cough and sore throat, you wouldn’t want to be diagnosed with a runny nose, cough or sore throat. You would want to be diagnosed with a cold,” he says.

“We assign distinct labels to things that are not very biologically separable,” says Grotzinger. “But other clinicians might argue that even if the genetic differences are minor, these things require different treatments.”

Clinicians also tend to think that there is a “correct” diagnosis for every person, Grotzinger says. “People may treat these diagnostic manuals as religious texts. » However, the degree of genetic overlap discovered in the new study suggests that there is often no single correct diagnosis.

“This is an impressive paper,” says Avshalom Caspi of Duke University in North Carolina. “Many mental disorders are not distinct disorders, but share common pathways that affect neurodevelopment, cognition and emotion. This is increasingly appreciated today.”

Researchers should no longer study conditions in isolation, says Terrie Moffitt, also at Duke. “Funders should be much more careful in awarding grants to researchers who study one disorder at a time, lest a large portion of research resources be wasted. »

However, Moffitt believes the study relies on mental health data collected using outdated models. People should be followed for longer periods to get better data for genetic analysis, she says.

As Grotzinger and colleagues acknowledge, the study was also largely limited to people of European ancestry because there was insufficient data available on other groups.

Grotzinger also says that we still know too little about the effects of these genetic variants to begin to apply this knowledge – for example, to screening embryos during IVF, a process that raises ethical questions.

“We’re starting to get there, but we don’t know exactly what these genes do,” he says. “It’s not that I think embryo screening is wrong; it’s bad science.”