Large Study Shows PTSD Has Strong Genetic Component

In the largest and most diverse genetic study to date of post-traumatic stress disorder (PTSD), scientists reveal that PTSD has a strong genetic component similar to other psychiatric disorders.

The findings are published in the journal Nature Communications.

Despite much research, it has remained unclear why some people go on to develop PTSD after a traumatic event while others do not. Some researchers suggest that the disorder is only a social construct, but other studies point to the fact that genetics may be involved.

In the new study, researchers from the University of California (UC) San Diego School of Medicine and more than 130 additional institutions participating in the Psychiatric Genomics Consortium suggest that genetics may account for between five and 20 percent of the variability in PTSD risk following exposure to a traumatic event.

“Our long-term goal is to develop tools that might help clinicians predict who is at greatest risk for PTSD and personalize their treatment approaches,” said the study’s first and corresponding author Caroline Nievergelt, Ph.D., associate professor of psychiatry at UC San Diego School of Medicine and associate director of neuroscience in the Center of Excellence for Stress and Mental Health at the Veterans Affairs San Diego Healthcare System.

“We can’t always protect people from trauma. But we can treat them in the best ways possible, at the best time.”

The findings show that, like other psychiatric disorders and many other human traits, PTSD is highly polygenic, meaning it is associated with thousands of genetic variants throughout the genome, each making a small contribution to the disorder.

According to the findings, six genomic regions called “loci” contain variants strongly associated with disease risk, providing some clues about the biological pathways involved in PTSD.

“Based on these findings, we can say with certainty that there is just as much of a genetic component to PTSD risk as major depression and other mental illnesses,” said senior author Dr. Karestan Koenen, associate member of the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard.

“Our limited ability to study the living human brain and uncover the biological roots of PTSD has contributed to the lack of treatments and the stigma around this debilitating condition. Genetics helps us make new discoveries, find opportunities for new therapies, and counter that stigma,” she said.

Since many behavioral traits and psychiatric disorders have some shared genetic factors, the researchers also looked for genetic correlations between PTSD and 235 other disorders, behaviors and physical traits. They discovered significant overlap with 21, including depression, schizophrenia, neuroticism, insomnia, asthma and coronary artery disease.

“Similar to other mental disorders, the genetic contribution to PTSD correlates with that for many other traits,” said Koenen, who is also professor of psychiatric epidemiology in the Harvard T.H. Chan School of Public Health. “Further research is needed to determine what this means — whether some of the same genes that influence risk for PTSD also influence risk for other diseases like, for example, depression.”

To conduct the study, the team collaborated with the Psychiatric Genomics Consortium’s PTSD working group and Cohen Veterans Bioscience, a non-profit organization dedicated to accelerating PTSD and traumatic brain injury research.

The team built an international network of more than 200 researchers, assembling data and DNA samples from more than 60 groups of people with PTSD and control subjects, including the UK Biobank.

The data included more than 200,000 people, which is 10 times larger than the first Psychiatric Genomics Consortium PTSD study, published in 2017. The study group is also the most ancestrally diverse for any psychiatric genetics study to date, with more than 23,000 people with PTSD of European ancestry and more than 4,000 of African ancestry. It also included both civilians and members of the military.

“Our study is distinguished by the fact that it’s international and is highly diverse,” Nievergelt said. “There’s greater representation here than in most studies to date.”

The team used the data to conduct a genome-wide association study (GWAS), using statistical tests to measure the effect of common genetic variants at millions of points across the genome on someone’s likelihood of developing PTSD.

The study uncovered DNA variants at six loci that were significantly tied to PTSD risk. Three of the six loci were specific to certain ancestral backgrounds — two European and one African — and three were only detected in men.

The six loci hint that inflammatory and immune mechanisms may be at play in the disorder, which is consistent with findings from previous research.

Overall, the researchers conclude that PTSD’s heritability — the level of influence genetics has on the variability of PTSD risk in the population — is between five and 20 percent, with some variability by gender. These findings were similar across different ancestral groups.

The research team also developed a polygenic score that could potentially predict one’s risk of developing PTSD following a traumatic event. Polygenic scores take into account the effects of millions of genetic variations and create a measure that can predict a person’s risk of developing a certain trait or disorder.

The team tested their scores on data from men in the UK Biobank dataset, finding that those with the highest scores had 0.4-fold greater odds of developing than those with the lowest scores.

Similarly, when applied to data from the Million Veterans Program — a study of how genes, lifestyle and military exposures impact health and illness — individuals with the highest scores had a significant increase in re-experiencing traumatic memories — a key PTSD symptom.

The researchers assert that polygenic scores are not ready for clinical use. Even larger studies with more diverse datasets are needed to improve the accuracy of PTSD prediction and confirm the genetic findings.

Source: University of California- San Diego

 

Gene May Play Role in Needing Less Sleep

Although many genetic studies have focused on the circadian rhythm, few have targeted the specific genes that regulate how much sleep our bodies require.

Now, by studying a family with several members who require significantly less sleep than the average person, researchers from the University of California, San Francisco (UCSF) have identified a new gene they believe has a direct impact on how much someone sleeps. Then they tested their findings on mice.

“It’s remarkable that we know so little about sleep, given that the average person spends a third of their lives doing it,” said Dr. Louis Ptáček, a neurologist at UCSF, and one of the paper’s two senior authors.

“This research is an exciting new frontier that allows us to dissect the complexity of circuits in the brain and the different types of neurons that contribute to sleep and wakefulness.”

The family whose DNA led to the identification of this gene is one of several that Ptáček and UCSF geneticist Dr. Ying-Hui Fu, the paper’s other senior author, are studying and includes several members who function normally on only six hours of sleep. The gene, ADRB1, was identified using genetic linkage studies and whole-exome sequencing, which revealed a novel and very rare variant.

First, the researchers investigated the role of the gene variant by studying its protein in the test tube. They discovered that the gene codes for a certain type of adrenergic receptor and that the mutant version of the protein is much less stable, altering the receptor’s function.

The researchers then conducted a number of experiments in mice carrying a mutated version of the gene. They found that these mice slept on average 55 minutes less than regular mice. (Humans with the gene sleep two hours less than average.)

Ptáček acknowledges some limitations of using mice to study sleep. One of these is that mice exhibit different sleep patterns than humans, including, for example, sleeping in shorter bouts, rather than in a single continuous period.

“But it’s challenging to study sleep in humans, too, because sleep is a behavior as well as a function of biology,” he says. “We drink coffee and stay up late and do other things that go against our natural biological tendencies.”

The investigators plan to study the function of the ADRB1 protein in other parts of the brain. They also are looking at other families for additional genes that are likely to be important.

“Sleep is complicated,” Ptáček says. “We don’t think there’s one gene or one region of the brain that’s telling our bodies to sleep or wake. This is only one of many parts.”

Fu adds that the work may eventually have applications for developing new types of drugs to control sleep and wakefulness.

“Sleep is one of the most important things we do,” she says. “Not getting enough sleep is linked to an increase in the incidence of many conditions, including cancer, autoimmune disorders, cardiovascular disease and Alzheimer’s.”

Their findings are published in the journal Neuron.

Source: Cell Press

 

Some Thrive on Very-Early-to-Bed and Very-Early-to-Rise Routine

New research suggests many extreme early birds share a genetic trait with family members that appears to help them prosper in the early routine. The UC San Francisco study finds that the behavior – called an advanced sleep phase — is more common than previously believed and may affect at least one in 300 adults.

Investigators believe a genetic link helps to lure some people to sleep at 8 p.m., and enables them to greet the new day as early as 4 a.m. The study appears in the journal SLEEP.

Advanced sleep phase means that the body’s clock, or circadian rhythm, operates on a schedule hours earlier than most people’s, with a premature release of the sleep hormone melatonin and shift in body temperature.

The condition is distinct from the early rising that develops with normal aging, as well as the waking in the wee hours experienced by people with depression.

“While most people struggle with getting out of bed at 4 or 5 a.m., people with advanced sleep phase wake up naturally at this time, rested and ready to take on the day,” said the study’s senior author, Louis Ptacek, MD, at the UCSF School of Medicine.

“These extreme early birds tend to function well in the daytime but may have trouble staying awake for social commitments in the evening.”

Additionally, “advanced sleepers” rouse more easily than others, he said, and are satisfied with an average of an extra five-to-10 minutes of sleep on non-work days, versus the 30-to-38 minutes’ more sleep of their non-advanced sleeper family members.

Ptacek and his colleagues at the University of Utah and the University of Wisconsin calculated the estimated prevalence of advanced sleepers by evaluating data from patients at a sleep disorder clinic over a nine-year period.

In total, 2,422 patients were followed, of which 1,748 presented with symptoms of obstructive sleep apnea, a condition that the authors found was not related to sleep-cycle hours.

Among this group, 12 people met initial screening criteria for advanced sleep phase. Four of the 12 declined enrollment in the study and the remaining eight comprised the 0.03 percent of the total number of patients — or one out of 300 — that was extrapolated for the general population.

Researchers note that this is a conservative figure since it excluded the four patients who did not want to participate in the study and may have met the criteria for advanced sleep phase, as well as those advanced sleepers who had no need to visit a sleep clinic.

“Generally, we find that it’s the people with delayed sleep phase — those night owls that can’t sleep until as late as 7 a.m. — who are more likely to visit a sleep clinic. They have trouble getting up for work and frequently deal with chronic sleep deprivation,” said Ptacek.

Criteria for advanced sleep phase include the ability to fall asleep before 8:30 p.m. and wake before 5:30 a.m. regardless of any occupational or social obligations, and having only one sleep period per day.

Other criteria include the establishment of this sleep-wake pattern by the age of 30, no use of stimulants or sedatives, no bright lights to aid early rising and no medical conditions that may impact sleep.

All study participants were asked about their medical histories and both past and present sleep habits on work days and work-free days. Researchers also looked at sleep logs and level of melatonin in the participants’ saliva, as well as sleep studies, or polysomnography, that record brainwaves, oxygen levels in the blood, heart rate and breathing.

Of note, all eight of the advanced sleepers claimed that they had at least one first-degree relative with the same sleep-wake schedule, indicating so-called familial advanced sleep phase.

Of the eight relatives tested, three did not meet the full criteria for advanced sleep phase and the authors calculated that the remaining five represented 0.21 percent of the general population.

The authors believe that the percentage of advanced sleepers who have the familial variant may approach 100 percent. However, some participants may have de novo mutations that may be found in their children, but not in parents or siblings, and some may have family members with “nonpenetrant” carrier mutations.

Two of the remaining five were found to have genetic mutations that have been identified with familial advanced sleep phase. Conditions associated with these genes include migraine and seasonal affective disorder.

“We hope the results of this study will not only raise awareness of advanced sleep phase and familial advanced sleep phase,” said Ptacek, “but also help identify the circadian clock genes and any medical conditions that they may influence.”

Source: University of California – San Francisco

Genetic and Behavioral Factors Increase Risk of Anorexia

New international research suggests factors that increase the risk of anorexia are likely to be metabolic as well as psychological. The new findings give hope to patients and their families as discovery of the linkage will provide new direction to clinicians and scientists looking for better treatments for the disease.

University of Otago, Christchurch researchers in New Zealand discovered some people are born with a biological predisposition to developing anorexia and that the disease affects the function of the brain as well as the metabolic system.

Investigators believe considering both genetic and biological factors will help clinicians and scientists develop better treatments for the disease with the highest mortality rate of any psychiatric disorder.

The findings, which appear in Nature Genetics, suggest people are born with a biological predisposition to developing the disease that affects function of the brain as well as the metabolic system.

Anorexia Nervosa Genetics Initiative (ANGI) researchers sampled the DNA of almost 17,000 patients and compared this with over 55,000 control cases (without anorexia nervosa) recruited from 17 countries across North America, Europe and Australia.

The lead researcher was Professor Cynthia Bulik, from the University of North Carolina and the Karolinska Institute (Sweden), who worked with more than 100 other scientists. Lead researchers from New Zealand included Dr. Jenny Jordan and genetics Professor Martin Kennedy.

The ANGI team found eight genetic variants significantly associated with anorexia nervosa, showing the origins of this serious disorder appear to be both metabolic and psychological. The researchers also found:

    • The genetic basis of anorexia nervosa overlaps with traits associated with people’s ability to metabolize fats and sugars, and body mass index.
    • Genetic factors associated with anorexia nervosa influence physical activity, which could explain the tendency for people with anorexia nervosa to be highly active despite their low-calorie intake.
    • The genetic basis of anorexia nervosa overlaps with other psychiatric disorders such as obsessive-compulsive disorder, depression, anxiety, and schizophrenia.

Dr. Jordan says current treatments for anorexia nervosa are primarily psychological therapies that help patients with the critical but difficult task of regaining weight and re-establishing normal eating. There are no specific medications for anorexia nervosa.

“The ANGI findings give us a new way of looking at this disease. For example, many people diet but only a few develop anorexia nervosa with very low levels of weight and sometimes extreme levels of exercise.

The findings that there are genetic differences relating to metabolism in people with anorexia in our study helps make sense of that. It may also help explain in part why recovery is such a struggle. These findings, that it is not just a psychiatric condition, will be hugely validating for many with anorexia nervosa and their families” explains Jordan.

University of Otago, Christchurch’s Professor Martin Kennedy says the findings indicate that people are born with a genetic predisposition for developing the disease. What this means is that they are more prone to developing the disorder, although not everyone with those patterns of DNA will do so.

“Our hope is these fundamental genetic insights will point to better ways of preventing the disorder, and better medications that target the underlying biology. Nobody chooses to succumb to this awful disease, and we need these kinds of new insights to help people survive and move on with their lives.”

Source: University of Otago

High Dopamine Levels in Women May Be Tied to Procrastination

A new German study finds that women with a genetic predisposition for higher dopamine levels in the brain may be more likely to engage in procrastinating behaviors. No such link was found in men.

“The neurotransmitter dopamine has repeatedly been associated with increased cognitive flexibility in the past,” says Dr. Erhan Genç from the Ruhr-University Bochum Department of Biopsychology. “This is not fundamentally bad but is often accompanied by increased distractibility.”

The findings are published in the journal Social Cognitive and Affective Neuroscience.

The researchers studied the genotype of 278 men and women. They were particularly interested in what is known as the tyrosine hydroxylase gene (TH gene). Depending on the expression of the gene, people’s brains contain differing amounts of neurotransmitters from the catecholamine family, to which the neurotransmitter dopamine belongs, along with epinephrine (adrenaline) and norepinephrine (noradrenaline).

The team also used a questionnaire to record how well the participants were able to control their actions. They discovered that women with poorer action control had a genetic predisposition towards higher dopamine levels.

Whether an individual tends to postpone tasks or tackle them right away depends on his or her ability to maintain a specific intention to act without being distracted by interfering factors. Dopamine could be crucial here. In previous studies, dopamine has not only been associated with increased cognitive flexibility, but it also seems to make it easier for information to enter the working memory.

“We assume that this makes it more difficult to maintain a distinct intention to act,” says doctoral candidate Caroline Schlüter. “Women with a higher dopamine level as a result of their genotype may tend to postpone actions because they are more distracted by environmental and other factors.”

Previous research has also shown gender-specific differences between the expression of the TH gene and behavior.

“The relationship is not yet understood fully, but the female sex hormone oestrogen seems to play a role,” says Genç. Estrogen indirectly influences dopamine production in the brain and increases the number of certain neurons that respond to signals from the dopamine system.

“Women may therefore be more susceptible to genetic differences in dopamine levels due to oestrogen, which, in turn, is reflected in behaviour,” says the biopsychologist.

Next, the team intends to study to what extent estrogen levels actually influence the relationship between the TH gene and action control. “This would require taking a closer look at the menstrual cycle and the associated fluctuations in the participants’ oestrogen levels,” says Schlüter.

In addition to dopamine, the TH gene also influences norepinephrine, another important neurotransmitter from the catecholamine family. The researchers aim to examine the role that these two neurotransmitters play in action control in further studies.

Source: Ruhr-University Bochum

 

Study IDs Gene Sets Tied to 5 Mental Disorders

An international study has revealed specific sets of genes associated with the development of ADHD, autism spectrum disorder, bipolar disorder, major depression and schizophrenia.

Researchers analyzed more than 400,000 individuals to determine the genes behind these five mental health disorders.

Researchers from The University of Queensland and Vrije Universiteit in Amsterdam discovered several sets of genes marked all five disorders.

“Before this analysis, we knew a lot of psychiatric disorders were related to each other due to their hereditary nature,” said UQ psychiatrist Professor Christel Middeldorp.

“We often see multiple family members with mental illness in one family, but not necessarily with the same disorder.

“We investigated if specific sets of genes were involved in the development of multiple disorders, which genes are not only related to say, ADHD, but also to the other four psychiatric disorders.

“These are genes that play a role in the same biological pathway or are active in the same tissue type.

“Genes that are highly expressed in the brain were shown to affect the different disorders, and some genes were related to all the illnesses we studied.

“It shows that there is a common set of genes that increase your risk for all five disorders.”

Study leader Dr. Anke Hammerschlag believes this occurs because of biological pathways shared by the genes in the brain. Research findings appear in the journal Psychological Medicine.

“We found that there are shared biological mechanisms acting across disorders that all point to functions in brain cells,”  Hammerschlag said.

“We also found that genes especially active in the brain are important, while genes active in other tissues do not play a role.”

The finding is important as new pharmaceutical drugs could potentially target the shared pathways.

“Our findings are an important first step towards the development of new drugs which may be effective for a wide range of patients, regardless of their exact diagnosis,” she said.

“This knowledge will bring us closer to the development of more effective personalized medicine.”

Source: University of Queensland