Looking for genes behind psychiatric disorders

An international conference on psycho-genetics brought experts from 40 countries to Jerusalem.

By JUDY SIEGEL-ITZKOVICH
PROF. ROBERT (HAIM) BELMAKER (photo credit: JUDY SIEGEL-ITZKOVICH)
PROF. ROBERT (HAIM) BELMAKER
(photo credit: JUDY SIEGEL-ITZKOVICH)
First-degree relatives of people who contract psychiatric diseases have to cope not only with the horrendous behaviors of their loved ones but also with the lifelong worry that they or their children might eventually suffer from the disorders as well. Fortunately, while all psychiatric disorders have a genetic basis and a family history raises the risk, almost all of them involve many defective genes that reduce the likelihood that a sufferer will have passed them on directly to their offspring. Having one or even two parents with psychiatric disorders does not mean that their children will have one.
While heritability for these major psychiatric disorders is much higher than those of physical disorders such as Parkinson’s and breast cancer, analysis of genetic links and genomes have resulted in few reproducible risk factors. Because genes are important in psychiatric disease, however, in the last decades, a subfield of behavioral neurogenetics and behavioral genetics has developed in psychiatry. Called psychiatric genetics, it examines the role of genetics in psychiatric conditions such as schizophrenia, alcoholism, bipolar disorder (manic depression) and autism.
Schizophrenia is a severe and chronic psychiatric disorder that affects how a person thinks, feels, and behaves. Fortunately, while it is very disabling, it is not the most common mental disorder. Sufferers may seem as if they have lost touch with reality. Symptoms – including hallucinations, delusions, unusual ways of thinking, reduced enjoyment and speech and difficulty starting and continuing activities – usually appear for the first time between the ages of 16 and 30, but in rare cases, they can appear in children as well.
There are theories that brain development was disrupted in the womb and that hormonal changes at the beginning of adolescence could be involved in vulnerable individuals.
Bipolar disorder is a brain disorder that causes unusual shifts in mood, energy, activity levels and the ability to carry out day-today tasks. These moods range from periods of extremely “up,” elated and energized behavior to debilitating melancholy.
The brain also undergoes major changes during the developmental disease called autism spectrum disorder. Sufferers, who vary widely in abilities and problems, usually have chronic social problems that include difficulty communicating and interacting with others, repetitive behaviors as well as limited interests or activities. The symptoms are usually diagnosed before the child’s second birthday. About one in 68 children has been identified with some form of it, and it is more common in boys than in girls.
Major depressive disorder or clinical depression is a common but serious mood disorder affecting how one feels, thinks and copes with routine activities from eating and sleeping to working. It is believed to be caused by a combination of biological, genetic, environmental and psychological factors. It can be temporary, such as postnatal depression and seasonal depression caused by inadequate light. It can be more severe in the form of psychotic depression, which includes not only low moods but also a form of psychosis.
Francis Galton, a 19th-century English Victorian statistician, anthropologist, psychologist, inventor, sociologist and founder of the eugenics movement who believed in the evolutionary ideas of Charles Darwin is credited with founding psychiatric genetics, which today is interested in developing ways to diagnose early and even prevent psychiatric diseases. The subfield really took off 30 to 40 years ago when twin studies of psychiatric diseases were launched.
Many specialists in psychiatric genetics participate in the Psychiatric Genomics Consortium (PGC), which is aimed at encouraging researchers around the world to conduct meta- and mega-analyses of genomewide genomic data for psychiatric disorders.
Launched nine years ago, the PGC has quickly rapidly become a collaborative confederation of most psychiatric genetics investigators and includes some 800 investigators from 38 countries. Genome samples have been collected from more than 900,000 people undergoing psychotherapy around the world, thus the PGC is the biggest consortium and the largest biological experiment in the history of psychiatry.
During its first five years, the PGC targeted autism, attention-deficit hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia. To this work, it has added major studies of eating disorders, substance use disorders, post-traumatic stress disorder, obsessive-compulsive disorder and Tourette’s Syndrome. The establishment and genotyping of the PGC’s primary studies was financed by a variety of national, international and commercial funders. While the idea of studying the connection between genes and pathophysiology is very simple in principle, actually carrying it out is very difficult.
THE 24TH World Congress of Psychiatric Genetics was held earlier this month in the Jerusalem International Conventional Center.
Attended by 360 experts – most of them foreign from 40 countries – it was organized by the International Society of Psychiatric Genetics and entailed a multidisciplinary approach to mental disorders.
“Those who came for the conference included researchers in basic science, psychiatrists who treat mental disorders and experts in genetic tests and analysis,” said Dr.
Yoav Kohn, chairman of psychiatry at the Hebrew University-Hadassah Medical Faculty and director of the child and adolescent psychiatry department at the Jerusalem Mental Health Center/Eitanim Psychiatric Hospital who was an organizer of the conference.
“It wasn’t easy to bring such a conference to Israel because it was scheduled four years ago during a wave of terrorism in the capital; it is far from the places where meeting are usually held and expensive for some foreigners to come. But we did it,” he told The Jerusalem Post at the convention center.
“The prevalence of psychiatric disorders, including clinical depression, is the same in all countries and peoples – in Africa and America, the north and the south. There is no community in the world without psychiatric disorders,” said Kohn. They appear in Jews as well as non-Jews, in secular, religious and ultra-Orthodox (haredi) communities. In the haredi sector today, “there is more openness.
Because it can hurt chances for making arranged marriages, some still hide the facts.
But they know that they are at least obligated to tell a potential marriage partner the truth.
As everyone in the community is supposed to get married, the fact of psychiatric disorders is more complicated, especially when it’s hard to raise a family if one or both parents suffer from mental disorders,” he explained.
“There are only rare cases of direct genetic causes,” he continued. “These usually involve mutations in the production of sperm or ova and are rare kinds that come directly from parents. They occur more often when the parent – especially the father – is older, but it can also occur in an older mother. In females, the eggs exist in the ovaries already when they are born. In males, they can produce sperm anytime.”
Researchers believe that there are more than 100 genes connected to schizophrenia, he said. Oddly, genes for autism are connected to higher intelligence in many sufferers. “If we can develop good genetic tests for psychiatric disorders, it will be easier to cope with them,” Kohn added.
As the psychiatrist responsible for the treatment of children and teens in Eitanim, Kohn said that he has seen disturbed patients as young as four years old.
“These disorders can come from genes as well as from their environment in the family.
It’s very rare to see signs of schizophrenia before the age of six or seven, but it has happened.
We can help them with medications, especially if we diagnose the problems early.”
Kohn pointed out that certain genes could cause more sensitivity to the environment, which could be bad, or it could be good. You can be happier if genes give you a positive reaction to the environment. Gene sensitivity can work both ways, he said. One step in future psychiatric care will probably be personalized medicine.
“We don’t know how effective it will be to suit treatment to the patient, and at present it is very expensive to conduct such tests. But if costs are reduced, it could be worth trying.”
ANOTHER LEADING Israeli figure at the conference was emeritus Prof. Robert (Haim) Belmaker, who spent all of his professional life as a psychiatrist in genetics research and treatment of patients. He now serves as chairman of the Israel Psychiatric Association.
He graduated with a bachelor’s degree from Harvard College in 1967 and received his MD degree from Duke University Medical School in 1971. Three years later, he made aliya with his family to Israel, holding positions in academic psychiatry, first at the Jerusalem Mental Health Center for a decade and then at Ben-Gurion University of the Negev until the president.
His research interests include affective disorders, especially mania, and the use of electroconvulsive therapy and received many prizes. He has not lost touch with clinical medicine and in addition to being an inpatient unit head until 1994, he opened a public bipolar disorders clinic 40 years ago and continues now to see patients weekly at the bipolar clinic at Hadassah-University Medical Center in Jerusalem’s Ein Kerem.
Research papers are important, he said, and he has produced his share of them, including some whose findings turned out not to have been true.
“I wrote a paper that was published in the prestigious journal Nature about a link I found between bipolar disorder and color blindness.
But it turned out not to be true. In the test of time, many hypotheses and data we found just collapse. Progress in medicine, said Belmaker, “is not linear. That we discover errors should not lead to cynicism, but we have to be sober about it.”
There are so many things that have to be investigated about psychiatric diseases.
“Our gut has microbes that have more DNA among them than does the human body. It has even been suggested that we use fecal transplants to treat mental disorders.
An Australian professor spoke at our conference about data that future antidepressants will work on the gut. To prove something, one needs five replications of the research outcomes and approval by boards and committees.
“Physicians have different ideas than researchers. Physicians know the cost of abandoning old treatments to start a new treatment. They don’t part with them easily.
If a researcher investigated only old ideas, he would not be a good researcher. One has to maintain excitement in new ideas without accepting them as a religious truth,” said Belmaker.
One new idea presented at the Jerusalem conference was on the sequencing of the whole genome of children who developed serious psychiatric problems as early as age one or two years. A child was found to have lacked a gene that causes cells to absorb vitamin B2 (riboflavin). He was treated with the vitamin and is now normal, Belmaker related.
As for the possibility that gene therapy could be used to cure psychiatric disorders, he said that “we don’t know how to repair most genes. There are so many cells in the body and so many genes. We know how to do pre-implantation genetic diagnosis to detect serious physical diseases caused by defective genes, but not how to do it for psychiatric disorders, which are almost always the result of many genes. When you get down to the molecular level, the influence of each single-nucleotide polymorphism is so tiny. Psychogenetics has taken a lot of criticism in recent years because a single gene that causes mental disorders has not been found, but this year the feeling is very upbeat, because now we can do whole genome scans and start to determine the tiny contribution that each gene makes. Defective genes,” said Belmaker, “can cause the synapse between nerve cells to produce a too-large amount of neurotransmitters that can result in psychiatric diseases.”
In another decade, he predicts, many genes that contribute to psychiatric disorders will become known and organized into groups according to what particular biological or behavioral functions they carry out. But genes, he concludes, “are not everything. You have to accept who you are and take responsibility; see what problems you have caused rather than blaming your parents, spouse, teachers and employers.”