Researchers find genetic links between traits are often overstated

Many estimates of how strongly traits and diseases share genetic signals may be inflated, according to a new UCLA-led study that indicates current methods for assessing genetic relationships between traits fail to account for mating patterns.

Through the use of powerful genome sequencing technology, scientists in recent years have sought to understand the genetic associations between traits and disease risk, hoping that discoveries of shared genetics could point to clues for tackling diseases. However, UCLA researchers said their new study, published Nov. 17 in Science, provides caution against relying too heavily on genetic correlation estimates. They say that such estimates are confounded by non-biological factors more than has been previously appreciated.

Genetic correlation estimates typically assume that mating is random. But in the real world, partners tend to pair up because of many shared interests and social structures. As a result, some genetic correlations in previous work that have been attributed to shared biology may instead represent incorrect statistical assumptions. For example, previous estimates of genetic overlap between body mass index (BMI) and educational attainment are likely to reflect this type of population structure, induced by "cross-trait assortative mating," or how individuals of one trait tend to partner with individuals of another trait.

The study authors said genetic correlation estimates deserve more scrutiny, since these estimates been used to predict disease risk, glean for clues for potential therapies, inform diagnostic practices, and shape arguments about human behavior and societal issues. The authors said some in the scientific community have placed too much emphasis on genetic correlation estimates based on the idea that studying genes, because they are unalterable, can overcome confounding factors.

"If you just look at two traits that are elevated in a group of people, you can't conclude that they're there for the same reason," said lead author Richard Border, a postdoctoral researcher in statistical genetics at UCLA. "But there's been a kind of assumption that if you can track this back to genes, then you would have the causal story."

Based on their analysis of two large databases of spousal traits, researchers found that cross-trait assortative mating is strongly associated with genetic correlation estimates and plausibly accounts for a "substantial" portion of genetic correlation estimates.

"Cross-trait assortative mating has affected all of our genomes and caused interesting correlations between DNA you inherit from your mother and DNA you inherit from your father across the whole genome," said study co-author Noah Zaitlen, a professor of computational medicine and neurology at UCLA Health.

The researchers also examined genetic correlation estimates of psychiatric disorders, which have sparked debate in the psychiatric community because they appear to show genetic relationships among disorders that seemingly have little similarity, such as attention-deficit hyperactivity disorder and schizophrenia. The researchers found that genetic correlations for a number of unrelated traits could be plausibly attributed to cross-trait assortative mating and imperfect diagnostic practices. On the other hand, their analysis found stronger links for some pairs of traits, like anxiety disorders and major depression, suggesting that there truly is at least some shared biology.

"But even when there is a real signal there, we're still suggesting that we're overestimating the extent of that sharing," Border said.

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Differences between brains of primates are small but significant, study shows

While the physical differences between humans and non-human primates are quite distinct, a new study reveals their brains may be remarkably similar. And yet, the smallest changes may make big differences in developmental and psychiatric disorders.

Understanding the molecular differences that make the human brain distinct can help researchers study disruptions in its development. A new study, published recently in the journal Science by a team including University of Wisconsin-Madison neuroscience professor Andre Sousa, investigates the differences and similarities of cells in the prefrontal cortex -- the frontmost region of the brain, an area that plays a central role in higher cognitive functions -- between humans and non-human primates such as chimpanzees, Rhesus macaques and marmosets.

The cellular differences between these species may illuminate steps in their evolution and how those differences can be implicated in disorders, such as autism and intellectual disabilities, seen in humans. Sousa, who studies the developmental biology of the brain at UW-Madison's Waisman Center, decided to start by studying and categorizing the cells in the prefrontal cortex in partnership with the Yale University lab where he worked as a postdoctoral researcher.

"We are profiling the dorsolateral prefrontal cortex because it is particularly interesting. This cortical area only exists in primates. It doesn't exist in other species," Sousa says. "It has been associated with several relevant functions in terms of high cognition, like working memory. It has also been implicated in several neuropsychiatric disorders. So, we decided to do this study to understand what is unique about humans in this brain region."

Sousa and his lab collected genetic information from more than 600,000 prefrontal cortex cells from tissue samples from humans, chimpanzees, macaques and marmosets. They analyzed that data to categorize the cells into types and determine the differences in similar cells across species. Unsurprisingly, the vast majority of the cells were fairly comparable.

"Most of the cells are actually very similar because these species are relatively close evolutionarily," Sousa says.

Sousa and his collaborators found five cell types in the prefrontal cortex that were not present in all four of the species. They also found differences in the abundancies of certain cell types as well as diversity among similar cell populations across species. When comparing a chimpanzee to a human the differences seem huge -- from their physical appearances down to the capabilities of their brains. But at the cellular and genetic level, at least in the prefrontal cortex, the similarities are many and the dissimilarities sparing.

"Our lab really wants to know what is unique about the human brain. Obviously from this study and our previous work, most of it is actually the same, at least among primates," Sousa says.

The slight differences the researchers found may be the beginning of determining some of those unique factors, and that information could lead to revelations about development and developmental disorders at a molecular level.

"We want to know what happened after the evolutionary split between humans and other primates," Sousa says. "The idea is you have a mutation in a gene or in several genes and those genes now have slightly different functions. But if these genes are relevant for brain development, for example, how many of a certain cell is produced, or how cells are connecting to other cells, how is it affecting the neuronal circuitry and their physiological properties? We want to understand how these differences lead to differences in the brain and then lead to differences we can observe in adults."

The study's observations were made in the brains of adults, after much of the development is complete. This means that the differences may be occurring during the brain's development. So, the researchers' next step is to study samples from developing brains and extend their area of investigation past the prefrontal cortex to potentially find where and when these differences originate. The hope is that this information will lead to a more robust foundation to lay developmental disorder research on top of.

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Neuronal plasticity in chronic pain-induced anxiety revealed

Hokkaido University researchers have shown how chronic pain leads to maladaptive anxiety in mice, with implications for treatment of chronic pain-related psychiatric disorders in humans.

Chronic pain is persistent and inescapable, and can lead to maladaptive emotional states. It is often comorbid with psychiatric disorders, such as depression and anxiety disorders. It is thought that chronic pain causes changes in neural circuits, and gives rise to depression and anxiety.

Researchers at Hokkaido University have identified the neuronal circuit involved in chronic pain-induced anxiety in mice. Their research, which was recently published in Science Advances, could lead to the development of new treatments for chronic pain and psychiatric disorders such as anxiety disorders and major depressive disorder.

"Clinicians have known for a long time that chronic pain often leads to anxiety and depression, however the brain mechanism for this was unclear," said Professor Masabumi Minami of the Faculty of Pharmaceutical Sciences at Hokkaido University, the corresponding author of the paper.

The researchers looked at how neuronal circuits were affected by chronic pain in mice. They used an electrophysiological technique to measure the activities of neurons after four weeks of chronic pain. They found that chronic pain caused the neuroplastic change which suppressed the neuronal pathway projecting from the brain region called bed nucleus of the stria terminalis (BNST) to the region called lateral hypothalamus (LH).

Using chemogenetics, an advanced technique to manipulate neuronal activity, they showed that restoration of the suppressed activity of this neuronal pathway attenuated the chronic pain-induced anxiety. These findings indicate that chronic pain-induced functional changes in the neuronal circuits within the BNST leads to maladaptive anxiety.

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A new understanding of mental illness

The causes of psychiatric disorders are poorly understood. Now, in work led by researchers at McGill University, there is evidence that a wide range of early onset psychiatric problems (from depression, anxiety and addictions to dyslexia, bulimia, and ADHD) may be largely due to the combination of just three factors. The first is biological -- in the form of individual variability in the brain's dopamine reward pathway. The second is social -- and points to the important role of early childhood neglect or abuse. And the third is psychological -- and relates to temperament, and particularly to tendencies toward impulsivity and difficulty controlling emotions. These findings have implications for understanding both the causes of a wide range of psychiatric disorders and the features worth targeting in early intervention efforts.

"Until recently, it was thought that psychiatric disorders reflected discrete disease entities, each with their own unique causes," says Marco Leyton, the senior author on a recent study published in Neuropsychopharmacologyand a professor in McGill's Department of Psychiatry and Senior Scientist at the Research Institute of the McGill University Health Centre. "The present research upends this idea, suggesting instead that most early onset disorders largely reflect differential expressions of a small number of biological, psychological and social factors."

First study to combine three key factors: temperament, trauma and dopamine

Earlier research has suggested that each of the three factors, in isolation, has at least modest effects on the development of psychiatric disorders. In comparison, the authors of this new study had the first ever opportunity to examine all three factors together. Fifty-two young people, living in the Montreal or Quebec City areas (30 women and 22 men), who have been followed since birth by Jean Séguin (Université de Montréal) and Michel Boivin (Université Laval), had brain imaging scans (PET and MRI) that measured features of their dopamine reward pathway. These brain features were then combined with information about their temperamental traits and histories of early life adversity.

High accuracy & potential predictive value of approach

Strikingly, this combination of just three factors predicted, with over 90% accuracy, which participants had mental health problems either in the past or during the study's three-year follow-up period. Indeed, since the results are so novel and potentially so important, CIHR has provided an additional two million dollars to double the sample size and follow the participants through to their mid-20s. "And the results do need to be replicated, both in larger and ethnically more diverse groups," emphasizes the paper's first author, Maisha Iqbal, a graduate student in McGill's Integrated Program in Neuroscience. "If replicated, our research could transform the way we think about mental illnesses."

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Deciphering the genetics behind eating disorders

 Anorexia nervosa, bulimia nervosa and binge-eating disorder are the three main eating disorders that 4 out of in 10 individuals living in Western Europe will experience at some point in their lives. In recent years, studies on the genetic basis of anorexia nervosa have highlighted the existence of predisposing genetic markers, which are shared with other psychiatric disorders. By analysing the genome of tens of thousands of British people, a team from the University of Geneva (UNIGE), the University Hospitals of Geneva (HUG), King's College London, the University College London, the University of North Carolina (UNC) and The Icahn School of Medicine at Mount Sinai have built on these initial results by discovering similarities between the genetic bases of these various eating disorders, and those of other psychiatric disorders. Eating disorders differ in their genetic association with anthropometric traits, like weight, waist circumference or body mass index. Thus, genetic predisposition to certain weight traits may be a distinctive feature of anorexia nervosa, bulimia nervosa or binge-eating disorder. The study is published in the International Journal of Eating Disorders.

"Previous studies, which highlighted a genetic association between a high risk of anorexia nervosa and a low risk of obesity, have begun to lift the veil on certain aspects of how eating disorders develop that had been mostly neglected until then," explains Nadia Micali, Professor at the Department of Psychiatry at UNIGE Faculty of Medicine and Head of the Division of child and adolescent psychiatry at the HUG, who directed this work. She continues, "However, the same work has not been done for the two other major eating disorders: bulimia nervosa and binge-eating disorder. The goal of our study was to understand similiarities and differences amongst all eating disorders in the role of genes governing body weight."

The genome of more than 20,000 people examined

To understand the similarities and differences between the genetic patterns of anorexia nervosa, bulimia nervosa and binge-eating disorder, the research team analysed the genomes of more than 20,000 people. These were taken from two large population-based studies conducted in the UK: the UK Biobank and the Avon Longitudinal Study of Parents and Children.

First author, Dr Christopher Hübel, from King's College London said: "We were able to access volunteer's DNA, their basic health data (weight, age, etc.) and responses to health questionnaires, including possible psychiatric disorders and their eating disorder history. We are grateful for this access as we were able to conduct multifactorial analyses and calculate more than 250 polygenic scores for each person. Each polygenic score sums the risk genes involved in a specific trait, such as depression, for example. We calculated polygenic scores for psychiatric disorders, such as schizophrenia and obsessive-compulsive disorder, and metabolic and physical traits, including insulin sensitivity, obesity and high BMI." Thus, the higher the score, the greater the genetic risk, whether it is blue eyes or the development of a given disease.

The research team then examined the associations between the polygenic scores of these volunteers (representing genetic liability to psychiatric disorders, metabolic and physical traits) and eating disorders.

A combination of psychiatric and body weight regulation genetic risk

The study shows that while there are great genetic similarities between anorexia nervosa, bulimia nervosa and binge-eating disorder, there are also notable differences.

Nadia Micali details these results: "The similarities lie in the association with psychiatric risks: anorexia nervosa, bulimia nervosa and binge-eating disorder share genetic risk with certain psychiatric disorders, in particular for schizophrenia and depression, thus confirming the strong psychiatric component of these diseases. However, the big difference concerns the associated genetics of body weight regulation, which are opposite between anorexia on the one hand, and bulimia nervosa and binge-eating disorder on the other, the latter being linked to a high genetic risk of obesity, and high BMI."

A genetic predisposition to a heavy weight versus a light weight may constitute a determining factor that pushes individuals with similar psychiatric genetic risk to different eating disorders.

"The metabolic and physical component would therefore direct the individual either towards anorexia nervosa or towards bulimia nervosa or binge-eating disorder," analyses Nadia Micali. "Moreover, this study confirms a clear genetic relationship between binge-eating disorder and attention deficit hyperactivity disorder (ADHD), that was already clinically observed, which might be linked to greater impulsivity, which is shared by these disorders." The role of genetic patterns in body weight regulation identified in this study provides a better understanding of the genetic basis of eating disorders, and of how they differ in their genetic marking despite their similarities. This work could lead to better understand the development of eating disorders.

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