German Researchers Launch Study to Identify Genomic Variants

A new study launched by scientists at Hannover Medical School (MHH) in Germany is determined to find out why patients respond differently to COVID-19. With the help of industry partners including Bionano Genomics, Genoox, Rescale, and Amazon, the investigators aim to study 1,000 patients with SARS-CoV-2 to better understand the disease.

Maximilian Schieck, an investigator at the Department of Human Genetics at Hannover Medical School, said the university began laying the groundwork for its study of COVID-19 in March, received ethical approval by the end of the month, and has already begun enrolling patients. Based on phenotypic data, they will select a starter set of 100 patients to undergo analysis on Bionano's Saphyr platform to unravel structural variants that may be influencing response to the virus.

Schieck said that he and other researchers intend to "carefully select" these 100 patients for analysis based on phenotypes to "disentangle how their genetic background might influence the severity of COVID-19 symptoms." He added that the researchers will achieve this by comparing severe cases versus mild cases. The study will also look at viral strain differences, and risk factors such as age and chronic illnesses such as heart disease, diabetes, and other conditions.

The 1,000-subject study is funded by the Lower Saxony Ministry of Research and Education with €2 million ($2.2 million) for two years. It will involve not only patients but controls, including patients with respiratory symptoms but who are SARS CoV-2 negative. Participants will undergo analysis of their transcriptomes to look at gene expression, metabolomes, and a variety of immune markers such as cytokines and T-cell response.

The goal of the study is to identify genomic variants that affect the disease, and immune or metabolic variables in the healthier participants that can protect against more severe disease, and to use this knowledge for the development of novel therapies and vaccines.

"It will be key to get phenotype data on patients," added Schieck. "To really collect a thousand patients, to go into the phenotypic data which is being digitized, and then select the right patients to go onto the Bionano."

It's unclear when MHH will reach its mark of 1,000 cases, but Schieck suggested it might have the first 100 samples by May. According to the World Health Organization, Germany has about 137,000 confirmed cases. About 4,100 people have died to date. In contrast, Spain has seen about 188,000 cases and 20,000 deaths. Italy has been among the hardest hit in Europe, with 172,000 cases and 23,000 deaths.

What that disparity means for German researchers is more time to recruit people to the study, as well as to conduct decent phenotyping. "We are still in a calm situation in that the numbers are still quite low" noted Schieck.

The department was already well prepared to take on such a study, even prior to the pandemic. As a part of RESIST, a research cluster investigating infection susceptibility, it had already invested in a Saphyr instrument, and was therefore an obvious partner for Bionano, which is supporting a similar study of coronavirus in Wuhan, China.

That study is also looking for how genetic variation influences response to disease, but the two studies "are completely separate" and are not sharing data, according to Sven Bocklandt, senior director of marketing and scientific affairs at San Diego-based Bionano. He added that MHH is well positioned to undertake a study of COVID-19 because it has already been using the Saphyr with the "exact goal of seeing how variation in the human genome affects susceptibility to infectious disease."

While other companies have acknowledged shortages on reagents due to the ongoing health crisis, Bocklandt said that centers that have systems installed make ideal partners, because the company now faces logistical challenges in installing new systems and sending people to train researchers.

"We are focusing our work in existing install sites and not on shipping instruments to universities and installing them there," said Bocklandt. "The real logistical issue is just installing new instruments," he added. "Getting consumables to our users is not a problem."

Bionano's Saphyr system enables analysis of structural variation and consists of an instrument, chip consumables, reagents, and a suite of data analysis tools. Labeled DNA samples are stretched within nanochannels in a flow cell and then are imaged. These are then assembled into a de novo genome map. According to Schieck, the researchers aim to pair this data with exome sequencing and whole-genome sequencing data. He said that the structural variation data obtained by the Saphyr will help inform the study's findings.

"It's known from our work on primary immunodeficiency and susceptibility that it's not all on sequence variants and severe cases can be influenced by structural variants," said Schieck. "Bionano is a good, streamlined approach to go and identify structural variants that might have a role in COVID-19."

An immediate target will be the X chromosome, because of generally observed worse symptoms in male patients compared to female patients. "Many people are talking about the ACE2 receptor on the X chromosome, which we will be looking at for structural variants," said Schieck. "Even though we are still in an early phase of recruitment, there seems to be a tremendous effect on male patients in terms of symptoms," he noted. Furthermore, the genome-wide data will also be used to investigate whether other genes are affected by structural variants, which could have a role in the course of COVID-19.

Bocklandt said that Bionano will donate consumables necessary for the study. A number of other companies will support the researchers. These include Rescale, which provides a computing cloud platform integrated with Saphyr, as well as Amazon Web Services, which will also provide computing time for analysis. Both are making their resources available through the Tech Against Covid initiative to offer supercomputing to researchers working on kits and vaccines for COVID-19.

Genoox, a Palo Alto, California-based genetic analysis tools company, will make its platform available for annotating and classifying genomic variants along with next-generation sequencing data. "Bionano identifies structural variants throughout the genome, but we don't produce a clinical report," commented Bocklandt. "Genoox takes data from the Illumina short-read sequencing and Bionano and combines and interprets that, putting it all into a clinical report."

Amir Trabelsi, Genoox's cofounder and CEO, said the firm's technology uses AI to prioritize the variants most relevant to a patient's clinical symptoms and find patterns in cohorts of patients.

"Specifically with Bionano, as they are specialized in complex variations, we help to make Bionano detection of those variants by adding additional layers of information we get from short-read sequencing," said Trabelsi.

"As Hannover Medical School uses different genomic sequencing technologies to learn the different markers on each patient, we combine those technologies in a unique way that help improve both technologies' detection and accuracy if they were running separately," he said. "By that we can help cover more areas, such as the immune system which is suspected to contribute to the differences between patients."

Schieck did not provide a timeline for when the researchers aim to complete or report their analyses. He noted that the study has joined the COVID-19 Host Genetics Initiative, an international effort to share data and analyses on patients with the disease involving dozens of existing studies, research centers, and biobanks across Europe, Asia, and North America.