Supposedly distinct psychiatric conditions may have same root causes

An analysis of gene variants in more than a million people diagnosed with neurodivergencies and mental health conditions – by far the largest study of its kind so far – has found that 14 conditions typically regarded as distinct actually fall into five underlying genetic groups.

The finding is encouraging for those diagnosed with multiple psychiatric conditions, says Andrew Grotzinger at the University of Colorado Boulder, a member of the research team behind the analysis. People can feel this means there is a lot wrong with them, he says, but there may be just one root cause.

“For the millions of people out there who are being diagnosed with multiple psychiatric conditions, this indicates that they don’t have multiple distinct things going on,” says Grotzinger. “I think it makes a big difference for a patient to hear that.”

When biologists started looking for genetic variants that are associated with a higher chance of developing a range of psychiatric conditions, they expected to find different variants for each. Instead, it became clear that there is a lot of overlap. A few researchers have even suggested that all such conditions have a single underlying cause, dubbed the p-factor.

This latest study suggests the reality is somewhere in between these two extremes. It doesn’t provide much support for the idea of a p-factor – while some gene variants were linked to all 14 conditions, they were involved in basic processes that cause many different problems beyond mental illnesses when they go wrong, says Grotzinger.

On the flip side, the team also found relatively few variants linked to a higher risk of just a single condition. Instead, the variants tended to fall into five groups, with an especially high overlap between schizophrenia and bipolar disorder, and between major depression, PTSD and anxiety.

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

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

The findings could help explain why two-thirds of people diagnosed with a psychiatric condition get diagnosed with more than one in 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 you had a runny nose, a cough and a sore throat, you wouldn’t want to be diagnosed with runny nose disorder, coughing disorder and sore throat disorder. You’d want to be diagnosed with a cold,” he says.

“We’re giving separate labels to things that biologically are not very separable,” says Grotzinger. “But other clinicians might argue that even though the genetic differences are minor, these things require different treatments.”

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

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

Researchers should no longer study conditions in isolation, says Terrie Moffitt, also at Duke. “Funders should be much more careful about giving grants to researchers who study one disorder at a time, lest a good deal of research resources be wasted.”

However, Moffitt thinks the study relies on data about mental health that was collected using outdated designs. People should be followed over longer periods to get better data for genetic analysis, she says.

As Grotzinger and his colleagues acknowledge, the study was also largely restricted to people with European ancestry, as not enough data was available from other groups.

Grotzinger also says we still know too little about the effects of these gene variants to start applying this knowledge – for instance, for 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 scientifically.”