Genetics sheds light on mental illnesses

For decades, scientists seeking genes involved in mental illness reaped mainly frustration. But in recent months, painstaking analysis of the DNA of thousands of patients has yielded important, and surprising, insights into the roots of schizophrenia, bipolar disorder, and autism.

Though the findings do not translate into better ways to diagnose or treat patients, researchers say that for the first time they are making real progress.

Dr. Thomas Insel, director of the National Institute of Mental Health, compares psychiatric genetics to a 1,000-piece jigsaw puzzle, in which researchers have just started to fit together a few edge pieces.

But "this is unprecedented progress," he said. "This is a time of real excitement in a field that up until now hasn't given us much to cheer about."

The findings, including major work published by Boston-area scientists, suggest that although mental illness is known to run in families, it may sometimes stem not from inherited defects but from spontaneous mutations that occur during earliest development in the womb.

Researchers are also finding some apparent genetic links between dramatically different disorders. For example, a genetic glitch previously shown to raise the risk of schizophrenia is also linked to autism and mental retardation, a study in the New England Journal of Medicine reported last month.

Dr. Edward Scolnick, director of the Broad Institute's Stanley Center for Psychiatric Resarch in Cambridge, has found himself telling people of late that the field of psychiatric genetics has "crossed the Mississippi."

"To explore the West, it will take a lot of work, and a lot of money," he said, arguing that the field needs an additional $200 million or more to quickly unravel the basic "genetic architecture" of severe mental illness. "There is a lot left to do. But we know how to go about it now."

The potential payoffs are great, Scolnick and other researchers say. Psychiatry is all but unique in medicine in its utter lack of chemical or biological tests to determine what a patient has. Genetic research could lead to diagnostic assays to help determine whether, say, a troubled child suffers from bipolar disorder, impending schizophrenia, or garden-variety growing pains.

Newly discovered mutations could also lead to insights into what goes wrong in the brain, and so point the way to better drugs. They could also help clinicians better decide which treatments a given patient should try.

The recent findings represent only a beginning, and a confused one at that. Hopes were high that a few common, small mutations could explain a lot of mental illness, but it may turn out that, instead, rare mutations are often to blame. And the different types of mutations may interact, combining to produce various diseases or no disease at all.

"This is just so much more complicated than anyone wanted it to be," Insel said.

But at least, researchers say, they seem to have moved on from the bad old days, when a promising gene would seem to be linked to mental illness in one study, only to be refuted in the next. The keys, they say, are pools of patients big enough to give studies real statistical power, and advances in genome sequencing technology.

Like the federal government's War on Cancer, launched in 1971 by President Richard M. Nixon, the work will take time but is sure to produce greater understanding and improved treatment, Scolnick said.

The strongest new findings include several papers that suggest that some mutations that convey added risk of mental illness are relatively rare deletions or duplications of strikingly large chunks of DNA on genetic "hot spots."

The hot spots are areas especially prone to big errors, in which multiple genes can be deleted or duplicated. They have been compared to spots in a text where whole paragraphs are missing, or sentences duplicated. The hot spot findings came as a surprise to many, Insel said. When they first began to emerge a couple of years ago, "People said, 'No, I just don't think so, because I never saw this before,' " he said, but it turned out "we didn't see it because we weren't looking."

Scientists are now racing to figure out which of the genes that are deleted or duplicated in a hot spot are critical to the development of mental illness, and what their functions are, said Jonathan Sebat of Cold Spring Harbor Laboratory in New York, another leading researcher on the hot spots.

Four different research groups have linked hot-spot mutations to schizophrenia. And in January, researchers from the Broad Institute, a joint Harvard and MIT genomics research center, and elsewhere reported that a hot-spot mutation was found in 1 percent of people with autism, and appeared to increase a child's chances of autism one-hundred-fold. The mutations were mainly spontaneous, not handed down from parents.

Ultimately, such structural mutations - including major anomalies such as the whole extra chromosome in Down syndrome - may explain more than 20 percent of the heritable risk for mental retardation and other disorders that affect mental ability, said Evan Eichler of the University of Washington, senior author of the New England Journal paper and a leading hot-spot researcher.

"The genome is much more malleable . . . than anyone anticipated," Eichler said.

The hot-spot mutations detected so far tend to be large, but the recent wave of research has also turned up links between mental illness and tiny changes in DNA known as single nucleotide polymorphisms, or SNPs. If the hot-spot mutations are like missing or repeated paragraphs in a text, the SNPs are like a single-letter change, a typo.

Broad researchers and an international consortium reported in the journal Nature that genetic analysis of more than 10,000 people had turned up SNP variants in two genes that appeared to raise the risk of bipolar disorder, a disease of severe mood swings.

But the hot-spot findings dominate so far, Sebat said. The fact that they tend to involve relatively rare mutations has some people discouraged, he said; they are asking, "If every family is defective in its own way, how are you going to be able to treat a disorder that has hundreds of different causes?"

There is hope, however, that all those mutations can be grouped into a few critical "pathways," or sequence of events, that shed light on what goes wrong, he said. And the more clues, the better.

"If you want to connect the dots in a disorder," he said, "you need more than two or three dots."

Carey Goldberg can be reached at goldberg@globe.com.