Bipolar disorder linked to genetic traits

Two genes that influence the activity of nerve cells in the brain may play a key role in a person's risk for bipolar disorder, marked by dramatic swings from depression to manic behavior, researchers said on Sunday.

The findings are not expected to lead to a genetic test for the risk of the condition but could help unravel the mystery of how it arises and lead to better treatments, they reported in the journal Nature Genetics.

An international team of scientists examined the genomes of 10,596 people mainly from Britain and the United States, including 4,387 with bipolar disorder, also sometimes known as manic-depression.

The researchers found those with bipolar disorder more likely to have certain variants of the ANK3 and CACNA1C genes. Proteins made by the two genes help govern the flow of sodium and calcium ions into and out of neurons in the brain, influencing the activity of these nerve cells.

"The key importance of this is that it gives us a clear idea of the sorts of chemicals and mechanisms in the brain that are involved in bipolar disorder," Nick Craddock of Britain's Cardiff University, who helped lead the study, said in a telephone interview.

"Over a number of years, that will help researchers to develop better approaches to diagnosis and treatment."

Because it tends to run in families, scientists have been trying to pinpoint genes involved in bipolar disorder. This was the largest genetic analysis of its kind on the disease, which affects an estimated 1 percent to 3 percent of adults worldwide, Craddock said.

The brain disorder causes extreme shifts in mood, energy and ability to function. It is marked by high periods of elation or irritability and low periods of sadness and hopelessness that can last months.

EQUILIBRIUM

The proper function of brain neurons depends on a delicate equilibrium between sodium and calcium, the researchers said.

"The brain operates according to how quickly calcium and sodium are going in and out of cells and how much of it goes in and out," Craddock said.

The findings suggest that bipolar disorder may stem at least in part from malfunctions in the flow of these ions, which are electrically charged versions of the chemicals.

There is a need for better treatment, Craddock said. Lithium, the most common, helps only about two-thirds of those with the disorder and can cause drowsiness, weight gain and mild shakiness.

The U.S. government's National Institutes of Health helped fund the research. Dr. Thomas Insel, director of the NIH's National Institute of Mental Health, said the findings may help solve the puzzle that is bipolar disorder.

"It's not going to tell us the whole story -- it doesn't give you the whole puzzle -- but it's something to build on," Insel said in a telephone interview.

Craddock said identifying the two gene variants probably will not be helpful in determining an individual's risk for the disorder because many who do not have the disease will have the genes.

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Longterm smoking linked to gene

For most people, the first experimental drags on a cigarette bring on nausea, coughing and other signals from the brain that say, "Turn back. This is a bad idea." But for some, they bring a wave of pleasure.

Those in the second group likely bear a gene type that not only increases their addiction risk, but has been implicated in the development of lung cancer, researchers said on Friday.

"If you have this variant, you are going to like your earliest experiences with smoking," said Ovide Pomerleau of the University of Michigan Medical School, whose research appears in the journal Addiction.

Pomerleau said the finding suggests that for some, smoking even one cigarette is a bad idea. "It's a trap," he said in a telephone interview.

"What they don't realize is if they have this kind of genetic make-up, they are on their way to dependency," he said, and that raises their risk for lung cancer.

The research is part of a growing understanding of genetic factors involved in nicotine addiction and lung cancer.

Teams of scientists reported earlier this year that smokers who had certain changes in three nicotine receptor genes -- which control entry of nicotine into brain cells -- were more likely to develop lung cancer than other smokers.

This week, Canadian researchers said that, by manipulating receptors for the chemical dopamine, they were able to control which rats in a study enjoyed their first exposure to nicotine and which were repelled by it.

Pomerleau said the field may soon lead to new treatments for nicotine addiction and tests to assess addiction risks.

Smoking causes nine out of 10 cases of lung cancer, the leading cause of cancer death in men worldwide and the second-leading cause of cancer death among women.

Pomerleau and colleagues studied data from 435 people. Some had tried a cigarette but never developed a habit; others smoked at least five cigarettes a day for the past five years.

Regular smokers in the study were far more likely than those who had never smoked to have a change in the CHRNA5 nicotine receptor gene. Smokers were eight times more likely to report liking cigarettes from the start.

Pomerleau said work has begun to develop a genetic screen for the CHRNA5 variant. Two other researchers on the team, Laura Bierut and John Rice at Washington University, hold a patent on the gene variant, which has been licensed by privately held Perlegen Sciences Inc.

Pfizer Inc, maker of the smoking cessation drug Chantix owns a $50 million stake in Perlegen.

Pomerleau, who has served on Pfizer's scientific advisory board, said he favors development of diagnostic tests, as long as people understand it is not the only risk factor for nicotine addiction.

"What we don't know is far greater than what we do know," he said.

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3 new genes found for schizophrenia

International researchers have identified three new DNA variations that increase the risk of schizophrenia and said on Wednesday they were some of the strongest genetic links yet found to the disease.

The results published in two independent studies in the journal Nature also confirmed a previously known genetic variation and could lead to new treatments for the condition that affects around 1 in 100 people, the researchers said.

"This is, if you like, the beginning of a new era in the field, said David St. Clair, a psychiatrist at the University of Aberdeen in Scotland who worked on both studies.

"Once we understand what the mutations are doing, new drugs and new approaches like preventative measures can be developed. It opens up the way to new methods for classifying and diagnosing people with the illness."

Schizophrenia, characterized by hallucinations, delusions and disordered thinking, is far more common in men than in women and is usually diagnosed in late adolescence or early adulthood.

While anti-psychotic drugs such as AstraZeneca's Seroquel and Eli Lilly and Co's Zyprexa can help, such drugs do not cure the mental illness and can cause unpleasant side-effects, including sometimes dangerous weight gain.

In the studies, the researchers analyzed the genes of 6,000 to 10,000 people from around the world, half of whom had schizophrenia.

They found one mutation on chromosome 1, two on chromosome 15 and confirmed a variant associated with the condition on chromosome 22. These changes can increase the risk of developing schizophrenia by up to 15 times, the researchers said.

The findings also suggest that the variants, while rare, pack a powerful punch and occur at a far higher rate than other uncommon mutations -- around 1 in every 10,000 people rather than 1 in every 10 million, St. Clair said.

"They are more common than your average rare variant," he said in a telephone interview. "We are now looking to see if there are environmental factors that affect the rate these variations come into the population."

In each case certain genes are knocked out, or deleted, on the chromosome. They are also found in some people with autism and other psychological disorders, suggesting the conditions may be related, the researchers said.

The next step is determining how these deletions affect brain function, according to the researchers, who included scientists from deCODE genetics in Iceland and the U.S. based Broad Institute of MIT and Harvard Universities in Massachusetts.

"This work opens up an entirely new way to think about schizophrenia and eventually will suggest avenues for researching therapies for the sake of patients and families suffering from this terrible disorder," said Pamela Sklar of the Broad Institute, who led one of the studies.

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