Many of the genetic variations that increase risk for schizophrenia are rare, making it difficult to study their role in the disease. To overcome this, the Psychiatric Genomics Consortium, an international team led by Jonathan Sebat, PhD, at University of California San Diego School of Medicine, analysed the genomes of more than 41,000 people in the largest genome-wide study of its kind to date. Their study reveals several regions of the genome where mutations increase schizophrenia risk between four- and 60-fold.

These mutations, known as copy number variants, are deletions or duplications of the DNA sequence. A copy number variant may affect dozens of genes, or it can disrupt or duplicate a single gene. This type of variation can cause significant alterations to the genome and lead to psychiatric disorders, said Sebat, who is a professor and chief of the Beyster Center for Genomics of Neuropsychiatric Diseases at UC San Diego School of Medicine. Sebat and other researchers previously discovered that relatively large copy number variants occur more frequently in schizophrenia than in the general population.

In this latest study, Sebat teamed up with more than 260 researchers from around the world, part of the Psychiatric Genomics Consortium, to analyse the genomes of 21,094 people with schizophrenia and 20,227 people without schizophrenia. They found eight locations in the genome with copy number variants associated with schizophrenia risk. Only a small fraction of cases (1.4 percent) carried these variants. The researchers also found that these copy number variants occurred more frequently in genes involved in the function of synapses, the connections between brain cells that transmit chemical messages.
With its large sample size, this study had the power to find copy number variants with large effects that occur in more than 0.1 percent of schizophrenia cases. However, the researchers said they are still missing many variants. More analyses will be needed to detect risk variants with smaller effects, or ultra-rare variants.

“This study represents a milestone that demonstrates what large collaborations in psychiatric genetics can accomplish,” Sebat said. “We’re confident that applying this same approach to a lot of new data will help us discover additional genomic variations and identify specific genes that play a role in schizophrenia and other psychiatric conditions.”

University of California San Diego Health health.ucsd.edu/news/releases/Pages/2016-11-22-study-finds-rare-genetic-variations-linked-to-schizophrenia.aspx

A single chemical receptor in the brain is responsible for a range of symptoms in mice that are reminiscent of obsessive-compulsive disorder (OCD), according to a Duke University study.

The findings provide a new mechanistic understanding of OCD and other psychiatric disorders and suggest that they are highly amenable to treatment using a class of drugs that has already been investigated in clinical trials.

“These new findings are enormously hopeful for considering how to approach neurodevelopmental diseases and behavioural and thought disorders,” said the study’s senior investigator Nicole Calakos, M.D., Ph.D., an associate professor of neurology and neurobiology at the Duke University Medical Center.

OCD, which affects 3.3 million people in the United States, is an anxiety disorder that is characterized by intrusive, obsessive thoughts and repeated compulsive behaviours that collectively interfere with a person’s ability to function in daily life.

In 2007, Duke researchers (led by Guoping Feng, who is now at the Massachusetts Institute of Technology) created a new mouse model of OCD by deleting a gene that codes for Sapap3, a protein that helps organize the connections between neurons so that the cells can communicate.

Similar to the way some people with OCD wash their hands excessively, the Sapap3-lacking mouse grooms itself excessively and shows signs of anxiety. Although researchers praised the new model for its remarkable similarity to a human psychiatric disorder, and have begun using it to study OCD, questions remain about how the loss of the Sapap3 gene leads to the grooming behaviours.

In the new study, Calakos’s team found that over-activity of a single type of receptor for neurotransmitters — mGluR5, found in a brain region involved in compulsive behaviours — was the major driver for the abnormal behaviours. When researchers gave Sapap3-lacking mice a chemical that blocks mGluR5, the grooming and anxiety behaviours abated.

“The reversibility of the symptoms was immediate — on a minute time frame,” Calakos said. In contrast, the original study describing Sapap3-lacking mice found that antidepressants could help treat symptoms but on the time scale of weeks, as is typical with these drugs in patients.

The immediate effects seen in the new study were also surprising, given that the brains of these mice appear developmentally immature and neurodevelopmental diseases are not typically thought of as being easily reversible, Calakos said.

Intriguingly, by taking normal laboratory mice and giving them a drug that boosted mGluR5 activity, Calakos’s team could instantaneously recreate the same excessive grooming and anxiety behaviours they saw in the Sapap3-lacking mice.

The researchers found that without a functioning Sapap3 protein, the mGluR5 receptor is always on. That, in turn, makes the brain regions involved in compulsion overactive. In particular, a group of neurons that give the “green light” for an action, like face-washing, is working overtime.

Calakos said that mGluR5 should be considered for the treatment of compulsive behaviours. “But which people and which compulsive behaviours? We don’t know yet,” she added.

Duke University today.duke.edu/2016/07/ocdreceptor

The leading cause of death in the world remains cardiovascular diseases, which are responsible for more than one third of overall mortality, according to the World Health Organization. Obesity and diet are obvious culprits behind heart disease but, over the past decade, research has also pointed to genetic factors, specifically mutations in cell adhesion components—the forces that bind cells together.

In a new study, scientists from the Florida campus of The Scripps Research Institute offer new molecular insights into how the interaction between specific genetic mutations and a cytoskeletal protein critical for the proper development and maintenance of heart tissue can lead to conditions such as dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM)—and ultimately heart failure.

The new study, which was led by Associate Professor T. Izard of the Florida campus of TSRI. The new insights could aid in the development of drug therapies to strengthen the hearts of patients suffering from age-related heart failure.

The study focuses on the protein vinculin and a variant form known as metavinculin, which is found only in muscle tissue. Vinculin has been shown to reinforce the myocardial cell cytoskeleton, improving heart muscle contractility and prolonging life, while metavinculin plays an essential role in the development and function of the heart.

Both vinculin and metavinculin regulate cell adhesion and migration by linking the cell’s cytoskeleton to adhesion receptor complexes via a process known as dimerization—the joining of two similar subunits. Control of the dimerization process is crucial for normal protein function in cell adhesion sites.

But mutations in the variant metavinculin, either inherited or spontaneous, corrupt this process, altering dimerization and, the study suggests, producing a decreased ability to stabilize critical cell adhesions, weakening the heart muscle over time.

The researchers found that these mutations—specifically, a mutation known as R975W in metavinculin—dictate the type of interaction during dimerization and can actually block the process. That, in turn, results in heart muscles that are far more susceptible to stress-induced heart disease.

The Scripps Research Institute www.scripps.edu/news/press/2016/20160811izard.html

A new non-invasive method of predicting the risk of developing a severe form of liver disease could ensure patients receive early and potentially life-saving medical intervention before irreversible damage is done.

Using information collected in a liver biopsy study, researchers at Cardiff University have developed a method of determining the onset of non-alcoholic steatohepatitis (NASH) through the analysis of lipids, metabolites and clinical markers in blood.

NASH is the most extreme form of non-alcoholic fatty liver disease (NAFLD) – a range of conditions caused by a build-up of fat in the liver. With NASH, inflammation of the liver damages the cells, potentially causing scarring and cirrhosis.

Currently, the diagnosis of NASH can only be done with a liver biopsy – an invasive and costly procedure. The new research could lead to a simple blood test that could catch the onset of NASH before inflammation damages the liver.

Dr You Zhou from Cardiff University’s Systems Immunity Research Institute said: “Many people with non-alcoholic steatohepatitis do not have symptoms and are not aware they are developing a serious liver problem. As such, diagnosis often comes after irreversible damage is done. Our quicker and less invasive method of diagnosis could mean that more people with non-alcoholic fatty liver disease could be easily tested to determine whether they are progressing to non-alcoholic steatohepatitis, the more severe form of the disease.”

A healthy liver should contain little or no fat. It’s estimated that around 20% of people in the UK have early stages of NAFLD where there are small amounts of fat in their liver. NASH is estimated to affect up to 5% of the UK population and is now considered to be one of the main causes of cirrhosis – a condition where irregular bumps replace the smooth liver tissue, making it harder and decreasing the amount of healthy cells to support normal functions. This can lead to complete liver failure.

Common risk factors for both NAFLD and NASH are obesity, lack of physical exercise and insulin resistance. But if detected and managed at an early stage, it’s possible to stop both NAFLD and NASH from getting worse.

The new method of NASH diagnosis will undergo further investigation with a view to developing a simple blood test that can be used by clinicians to provide effective medical care for patients at high risk of the disease.

Cardiff University www.cardiff.ac.uk/news/view/482735-non-invasive-diagnosis

Newcastle scientists and medics have developed a new type of genetic blood test that diagnoses scarring in the liver – even before someone may feel ill. It is the first time an epigenetic signature in blood has been discovered which is diagnostic of the severity of fibrosis for people with Non-alcoholic Fatty Liver Disease (NAFLD).

NAFLD, caused by being overweight or having diabetes, affects one in three people in the UK and may progress to cirrhosis and liver failure, requiring a transplant.

The Newcastle team describe the proof of principle research in which they measure specific epigenetic markers to stratify NAFLD patients into mild or severe liver scarring, known as fibrosis.

Dr Quentin Anstee, Clinical Senior Lecturer at Newcastle University, Consultant Hepatologist within the Newcastle Hospitals and joint senior author explained what it could mean for patients: “This scientific breakthrough has great promise because the majority of patients show no symptoms.

“Routine blood tests can’t detect scarring of the liver and even more advanced non-invasive tests can really only detect scarring at a late stage when it is nearing cirrhosis. We currently have to rely on liver biopsy to measure fibrosis at its early stages – by examining a piece of the liver under the microscope.

“We know that the presence of even mild fibrosis of the liver predicts a worse long-term outcome for patients with NAFLD and so it’s important to be able to detect liver scarring at an early stage.”

In this first stage of research the team developed the blood analysis in 26 patients with NAFLD. The test detects chemical changes on tiny amounts of “cell-free” DNA that are released into the blood when liver cells are injured. Changes in DNA methylation at genes like PPARγthat controls scar formation are then used to stratify patients by fibrosis severity.

Senior author Dr Jelena Mann of Newcastle University’s Institute for Cellular Medicine added: “This is the first time that a DNA methylation ‘signature’ from the blood has been shown to match the severity of a liver disease.

“It opens up the possibility of an improved blood test for liver fibrosis in the future.” Newcastle University