Largest psychiatric genetic study in history shows a common genetic basis that underlies 5 types of mental disorders

Structure of the CACNA1C gene product, a calcium channel named Cav1.2, which is one of 4 genes that has now been found to be genetically held in common amongst schizophrenia, bipolar disorder, autism, major depression and attention deficit hyperactivity disoder. Groundbreaking work on the role of this protein on anxiety and other forms of behavior related to mental illness has previously been established in the Rajadhyaksha laboratory at Weill Cornell Medical Center.

From the New York Times:
The psychiatric illnesses seem very different — schizophrenia, bipolar disorder, autism, major depression and attention deficit hyperactivity disorder. Yet they share several genetic glitches that can nudge the brain along a path to mental illness, researchers report. Which disease, if any, develops is thought to depend on other genetic or environmental factors.

Their study, published online Wednesday in the Lancet, was based on an examination of genetic data from more than 60,000 people worldwide. Its authors say it is the largest genetic study yet of psychiatric disorders. The findings strengthen an emerging view of mental illness that aims to make diagnoses based on the genetic aberrations underlying diseases instead of on the disease symptoms.

Two of the aberrations discovered in the new study were in genes used in a major signaling system in the brain, giving clues to processes that might go awry and suggestions of how to treat the diseases.

“What we identified here is probably just the tip of an iceberg,” said Dr. Jordan Smoller, lead author of the paper and a professor of psychiatry at Harvard Medical School and Massachusetts General Hospital. “As these studies grow we expect to find additional genes that might overlap.”

The new study does not mean that the genetics of psychiatric disorders are simple. Researchers say there seem to be hundreds of genes involved and the gene variations discovered in the new study confer only a small risk of psychiatric disease.

Steven McCarroll, director of genetics for the Stanley Center for Psychiatric Research at the Broad Institute of Harvard and M.I.T., said it was significant that the researchers had found common genetic factors that pointed to a specific signaling system.

“It is very important that these were not just random hits on the dartboard of the genome,” said Dr. McCarroll, who was not involved in the new study.

The work began in 2007 when a large group of researchers began investigating genetic data generated by studies in 19 countries and including 33,332 people with psychiatric illnesses and 27,888 people free of the illnesses for comparison. The researchers studied scans of people’s DNA, looking for variations in any of several million places along the long stretch of genetic material containing three billion DNA letters. The question: Did people with psychiatric illnesses tend to have a distinctive DNA pattern in any of those locations?

Researchers had already seen some clues of overlapping genetic effects in identical twins. One twin might have schizophrenia while the other had bipolar disorder. About six years ago, around the time the new study began, researchers had examined the genes of a few rare families in which psychiatric disorders seemed especially prevalent. They found a few unusual disruptions of chromosomes that were linked to psychiatric illnesses. But what surprised them was that while one person with the aberration might get one disorder, a relative with the same mutation got a different one.

Jonathan Sebat, chief of the Beyster Center for Molecular Genomics of Neuropsychiatric Diseases at the University of California, San Diego, and one of the discoverers of this effect, said that work on these rare genetic aberrations had opened his eyes. “Two different diagnoses can have the same genetic risk factor,” he said.

In fact, the new paper reports, distinguishing psychiatric diseases by their symptoms has long been difficult. Autism, for example, was once called childhood schizophrenia. It was not until the 1970s that autism was distinguished as a separate disorder.

But Dr. Sebat, who did not work on the new study, said that until now it was not clear whether the rare families he and others had studied were an exception or whether they were pointing to a rule about multiple disorders arising from a single genetic glitch.

“No one had systematically looked at the common variations,” in DNA, he said. “We didn’t know if this was particularly true for rare mutations or if it would be true for all genetic risk.” The new study, he said, “shows all genetic risk is of this nature.”

The new study found four DNA regions that conferred a small risk of psychiatric disorders. For two of them, it is not clear what genes are involved or what they do, Dr. Smoller said. The other two, though, involve genes that are part of calcium channels, which are used when neurons send signals in the brain.

“The calcium channel findings suggest that perhaps — and this is a big if — treatments to affect calcium channel functioning might have effects across a range of disorders,” Dr. Smoller said.

There are drugs on the market that block calcium channels — they are used to treat high blood pressure — and researchers had already postulated that they might be useful for bipolar disorder even before the current findings.

One investigator, Dr. Roy Perlis of Massachusetts General Hospital, just completed a small study of a calcium channel blocker in 10 people with bipolar disorder and is about to expand it to a large randomized clinical trial. He also wants to study the drug in people with schizophrenia, in light of the new findings. He cautions, though, that people should not rush out to take a calcium channel blocker on their own.

“We need to be sure it is safe and we need to be sure it works,” Dr. Perlis said.

Pee marks the spot


Human beings tend to avoid places that smell of urine. But to mice, there is something positively addictive about the scent; they like to go back to a spot where they found the excretions again and again. Now, researchers have discovered that this behavior is triggered by a single protein in the urine of male mice.

Mice use scent to mark their territory, advertise their social dominance, and convey information about their health and reproductive status. But these are usually volatile pheromones that disperse quickly, and it has remained unclear what exactly stimulates a female to be attracted to a specific male.

Previous research had shown that female laboratory mice often return to a place where they have come across cage bedding soiled by males. Now, researchers at the University of Liverpool in the United Kingdom have confirmed this. Female mice spent five times as much time in a place where they had encountered a dish with male urine than at a place where they encountered water. Just 10 minutes of exposure to the urine was enough for the mice to show this place preference even after 14 days.

However, if the mice were prevented from by a mesh screen touching the urine with their nose, the place seemed to lose its attractiveness. “That suggested that the story was not as simple as everybody assumed and volatile pheromones were not responsible,” says behavioral ecologist Jane Hurst, one of the authors of the study. By separating the urine into different fractions, the scientists showed that a protein called darcin that they had identified in 2005—and which mice can only detect if their noses touch the urine—is responsible for the frequent visits. Pure darcin, produced in cell culture in the lab, elicited the same reaction, the authors report online today in Science.

“This is a really compelling story,” says Lisa Stowers, a neuroscientist at the Scripps Research Institute in San Diego, California. “Mammals were thought to be much more complex, but this study shows that a single chemical can lead [them to act] in a certain way.” The study is “very simple and elegant,” she adds. But it also raises new questions. For instance: There are many other ways a mouse could learn to return to a certain place. “So what is the benefit of evolving this [special] mechanism?”

Hurst says that what fascinates her is that the pheromones induce learning in the mice. And the animals do not only learn to be attracted to the place where they encountered the darcin. “They learn the odor cues of that specific male and are then attracted to it,” Hurst says. “Being familiar with a scent really seems to be important for whether a female is interested in a male.” The reason, Hurst suggests, is that dominant males, who make attractive mates, tend to leave the most marks in a certain territory.

The researchers showed that male mice, too, are attracted to a place if they have encountered darcin there, probably to foster a behavior called countermarking. “If males come across another male’s scent mark, they put their own, fresher urine there,” Hurst explains. This could also be the reason why some laboratory strains seem to have lost the ability to produce darcin: Because laboratory mice are usually group-housed, they have been selected to be less aggressive, and not producing darcin could help reduce tensions.

Thanks to Dr. Rajadhyaksha for bringing this to the attention of the It’s Interesting community.