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Nordic Project Aims to Investigate Link Between Mental Disorders and Cardiovascular Disease

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NEW YORK – A team of researchers from countries around Northern Europe will soon commence a study to better understand the genetic link between mental disorders and cardiovascular disease.

Led by investigators at the University of Oslo, the four-year CoMorMent project is slated to commence next month with a total budget of €6 million ($6.7 million). The European Commission awarded the funding through its Horizon 2020 program. The full title of the project is, "Predicting comorbid cardiovascular disease in individuals with mental disorder by decoding disease mechanisms."

According to Ole Andreassen, a professor at the Institute of Clinical Medicine at the University of Oslo, the effort developed out of discussions within the Nordic Society of Human Genetics and Precision Medicine, a recent effort to pool genomic resources between Denmark, Estonia, Finland, Iceland, Norway, and Sweden.

In particular, he credited Reykjavik, Iceland-based DeCode Genetics with the concept for CoMorMent. In 2008, the company published work in Nature showing how a genetic variant confers risk of nicotine dependence and lung cancer. DeCode CEO Kári Stefánsson is the current president of NSHG-PM. Stefánsson did not respond to a request for comment.

"DeCode discovered a genetic risk for smoking that turns out to be a risk factor for lung cancer," noted Andreassen. "Yet the gene has nothing to do with lung function or DNA repair. It has to do with smoking, which is a behavior," he said. In the case of mental disorders, he noted, there is a high occurrence or comorbidity of cardiovascular disease. The idea of CoMorMent is therefore to uncover similar genetic risks.

"We would like to find out what are the underlying mechanisms of this high morbidity and determine what is driven by lifestyle and what is inheritable susceptibility," noted Andreassen. "The hypothesis is that our lifestyle, diet, exercise, smoking habits, are in many ways driven by the brain," he continued. "If you eat unhealthy, is it the personality or lifestyle habits that are causing it? No. This is behavior which is driven by the brain."

CoMorMent has an official start date of Jan. 1, 2020, and will run through Dec. 31, 2023. In addition to the University of Oslo and DeCode, the University of Iceland, the University of Tartu in Estonia, and Karolinska Institutet in Sweden are taking part. Other participants are the Capital Region of Denmark and the University of Edinburgh in the UK. There are also two commercial medical imaging companies involved in CoMorMent: Amra Medical, a company based in Linköping, Sweden that specializes in medical imaging and precision medicine, and Multimodal Imaging Services, a San Diego-based imaging firm.

Amra's tool, called Amra Researcher, enables the classification and quantification of global and regional fat volumes, fat fractions, and lean tissue volumes in comparison to normal ranges. It relies on MRI scanning and automated analysis to report back values. The tool has been used in cardiovascular research before. A company spokesperson declined to comment on its participation in CoMorMent.

"We would like to use their technology to see how we can combine imaging and genetics to personalize treatment," Andreassen said of the project's commercial partners.

The stated aims of the project are arguably ambitious. Investigators aim to identify the molecular mechanisms common to mental disorders and unhealthy lifestyles that increase the risk of cardiovascular disease. A core resource will be access to biobanks across the region.

By the first quarter of 2020, researchers will have access to more than a million primary genotyped samples, with contributions of 330,000 samples from the University of Oslo, 300,000 from the Karolinska, 170,000 at DeCode, 150,000 at the Estonian Genome Center, and 130,000 in Denmark, as well as validation sample sets from the University of Edinburgh and the UK Biobank.

By pooling these resources, together with national health registry data, they will be able to investigate disease trajectories and comorbidity in about 1.7 million people.

Based on this data, they will use statistical tools to find variants conferring risk of both mental disorders and cardiovascular diseases, and to see how they might be mediated by lifestyle or behavior. The researchers will also characterize the mechanisms by observing structural brain changes and body fat composition from MRI data in combination with gene expression and functional studies. Resulting stratification and prediction tools will then be tested and validated in clinical samples.

"This work has been made possible because of efforts during the past few years to improve work across the Nordic countries," said Andreassen. "We are leveraging the Nordic biobanks and registries to form the core discovery platform," he said. "By combining data sets, we will disentangle the intersection of lifestyle, the brain, and cardiovascular disease," he said.

He also noted they will develop stratification tools to see if they can predict who will develop cardiovascular comorbidity and when. "This is what we would like to obtain," said Andreassen. "Because if you know your genetic risk, you can also alter your behavior and environment."

CoMorMent will also develop prediction tools to see how they can prevent cardiovascular disease in cases, or to determine if one patient has a higher risk for developing obesity or side effects for drugs, all findings that will in turn impact the clinical care of patients.

"The joint project will allow us to develop a precision medicine approach, identifying people at high risk based on genetics," said Lili Milani, head of the Estonian Genome Center. "We will focus on prediction models and try to find ways to stratify patients into different groups for better treatment of these diseases," she said. "Also, we'll look at tools for stratification of treatment to avoid side effects based on current knowledge, and making new discoveries in these different subgroups of patients."

Milani reiterated that the shared biobank resources will form the basis for the work. "Basically it's based on building on all of these Nordic biobanks and longterm longitudinal data," she said. "The sample sizes are really impressive when you sum them up, and we will use resources in Scotland and in the UK Biobank for validation as well," she said.

This is the first project to emerge from NSHG-PM, Milani underscored, though there will certainly be more.

"We are all part of different large international genomics consortiums, and we have worked together before, but this is the first time we have come together and proposed such a big study and got funding from the EC to carry it out," Milani said.

While the Estonian Biobank currently contains aout 150,000 samples, it continues to grow. The country's government allocated €2.3 million last year to genotype 50,000 people using Illumina's Global Screening Array. Milani said the Estonian Genome Center hopes to complete the genotyping of the additional 50,000 samples by June 2020. The 50,000-sample data set will then be used to validate findings in CoMorMent.

Other genotyping efforts continue at participating institutions, as well. By the first quarter of 2023, CoMorMent participants aim to have access to an additional 275,000 samples — including the 50,000 Estonian contribution — which they can use to validate their findings.

"There is so much data available now in these international, large cohorts," noted Andreassen. "We are using that to build our models and testing our findings in the Nordic countries."

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