Advancing the Field of Polygenic Risk Score Testing Applications from the Lab to Your Smartphone

Polygenic risk scores (PRS)—which quantify inherited risk by integrating multiple sites of DNA variation—promise a more personalized approach to medicine. For many years, academic groups have been grappling with the mechanics of creating PRS, relying on large-scale GWAS analyses from large patient cohorts like the UK Biobank and others to identify varying gene loci linked with an increased risk of disease. Commercial companies have joined in the pursuit of credible PRS applications, each with their own analytical and reporting approaches. As yet, the field is still in flux, and will likely remain so for the next few years as companies sort through their target markets: from users of ancestry research sites, corporate wellness programs, and the typical healthcare consumers interested in learning more about their own health risks.

Expanding beyond monogenic variants
For many years, the field of genetic testing has largely been in search of the rare, single disease-causing gene, or monogenic, variant. These are diseases linked to a single faulty gene, as in cystic fibrosis, hemophilia, Huntington disease, sickle cell anemia, Duchenne muscular dystrophy, and several others.

But single variants do not explain most of the risk for most diseases. Instead, searching among hundreds of thousands of DNA variants, usually single nucleotide polymorphisms (SNPs) involved in a polygenic disorder, requires a much larger analysis. The result, a polygenic risk score that informs individuals with a higher risk for a particular condition compared with the overall population.

Lasse Folkersen
Lasse Folkersen, PhD, Impute.me

Moving toward the next act in genetic testing
“When consumer genetic testing really got started back in 2013 or so, analysis tools, such as those from Promethease and 23andMe, tended to focus on one variant at a time using a microarray platform,” says Lasse Folkersen, PhD of Impute.me, a non-profit genetics analysis site. “But the real progress is made when you look through GWAS studies, looking for common variants, and adding them together to make a predictive risk score.” As a big believer in the freedom of genetic information for individuals, Folkersen started Impute.me in 2015 as a third-party bridge to provide analysis of what is currently known and possible in genetics research. “It is important to provide that information broadly because I believe that otherwise it would be a fight between hesitant clinical geneticists that probably would only ever find the rarest of the rarest strong variant and ‘happy go lucky cowboy’ commercial organizations,” he says.

Consumer genetics companies widen their menu
On the commercial front, well-known ancestry sites like Ancestry and MyHeritage have branched out beyond using DNA to track ancestral lineage. Many have established partnerships with other companies to allow users to download their genetic information and look for associations and risks for diseases. (Several of these companies are described further. While both Ancestry and MyHeritage briefly offered their own health report products they have discontinued these services.

Bertram Koelsch
Bertram Koelsch, PhD
Health Product R&D, 23andMe

Other consumer genetics companies focus more on providing users with health-based information. “Our mission statement has always been to help people access understand and benefit from the human genome and ask our customers to be part of research driving science forward,” says Bertram Koelsch, PhD, Health Product R&D at 23andMe, perhaps the best-known direct to consumer genetic testing company. “Polygenic risk scores are a great tool to understand the genetics of complex disease so that’s where we’re leveraging these polygenic scores.”

23andMe’s PRS approach involves combining genetic information from their customers with phenotypic information. Users subscribe to the service with scores provided for about 35 conditions ranging from including risk of coronary artery disease, diverticulitis, skin cancers, and Type 2 diabetes (gestational or type 2). “We make a big point to our customer that genetics is only part of the equation; lifestyle has an important role, too,” Koelsch says. “We’re driving across to customers that though they may have susceptibility to develop a condition, they can make decisions about lifestyle factors to hopefully reduce the risk.”

Thomas Slavin
Dr. Thomas Slavin, MD
Chief Medical Officer, Myriad Genetics

Myriad Genetics offers many genetic tests, but breast cancer is the primary therapeutic area the company is focusing on with PRS. In 2017, Myriad Genetics launched its RiskScore PRS for women without monogenic variants in breast cancer genes. Historical barriers and lack of diverse ancestries in genome-wide association studies, which have been conducted primarily in individuals of European descent, have prevented polygenic risk scores for breast cancer from being available for women of all ancestries. Additionally, genetic markers that are linked to breast cancer do not confer the same risk across different ancestries. To address this, the company expanded access to genetic testing with the launch of its PRS validated for women of all ancestries in 2021.

“RiskScore delivers a personalized five-year and remaining lifetime risk assessment for breast cancer,” says Thomas Slavin, MD, Chief Medical Officer at Myriad. “It incorporates a woman’s own clinical risk factors, family history, and unique genetic, ancestry-informed breast cancer risk markers.”

Alicia Zhou
Alicia Zhou, PhD
Chief Scientific Officer at Color

Servicing corporate wellness programs
Developing a PRS product for breast cancer also ranks high as a target for Color Health, which has been working on the WISDOM study comparing the use of a polygenic score for breast cancer in a randomized controlled setting predicting which individuals are likely to progress to breast cancer. “The work we are doing here is not about necessarily diagnosing someone with breast cancer but using it as a screening tool to potentially change the way orfrequency of other, potentially more invasive screening,” says Alicia Zhou, PhD, Chief Scientific Officer at Color. “I think that’s actually probably the next phase for polygenic scores.

In contrast with 23andMe, most of Color’s customers and clients are governments, public health institutions, employers, and national health initiatives, and research studies for the purposes of sort of prevention rather than diagnosis. The company is part of the All of Us genetic research program funded by the NIH dedicated to gathering high-quality genomes from more than one million individuals. “Gaining as much genetic data from a large variety of people – and including information on the clinical phenotype side – are what are going to strengthen these PRS algorithms,” says Zhou.

Focused only on PRS

George Busby
George Busby, PhD
CSO and co-founder, Allelica

Self-described as “The Polygenic Risk Score Company,” Allelica’s mission is to provide health care systems and clinical laboratories with a PRS platform. “We’ve developed software specifically for reporting and developing new polygenic risk scores,” says George Busby, DPhil, Chief Scientific Officer, and co-founder at Allelica. “We have built polygenic risk scores by incorporating approaches that use fine-mapping – an additional piece of information that you can pull into the polygenic risk that takes some prior information about the potential functional significance of various parts of the genome. What we have done is to build multiple different PRS panels on a validation dataset using a variety of different methods.” The company’s PRS performance metrics are aligned to subscribe to polygenic risk score reporting standards, as documented in a 2021 Nature paper.

Allelica sees itself as an enabler for any organization that wants to either report clinical grade PRS, or develop their own. “We have developed an end to end PRS solution that is a Laboratory Developed Test that enables any physician to order and report PRS for coronary artery disease, breast and prostate cancer.” says Busby. Allelica also integrate their PRS into clinical risk models to provide an overall assessment of common disease risk. In terms of target market, Allelica does not sell direct to consumer. “We really believe in the clinical utility of our report, so we want it to be physican-led”.

Phone-based apps
Ali Torkamani at the Scripps Research Translational Institute embraces the concept of individuals gaining access to their genetic information. In 2017, his team developed MyGeneRank, a smart-phone app targeted to people interested in learning more about their risk of coronary artery disease (CAD). Users download their genetic data from genetic testing sites like23andMe, My Heritage, and others looking for 168 genetic variants associated with CAD.

Ali Torkamani
Ali Torkamani
Scripps Research Translational Institute

“After we get the genetic data, we do genotype imputation to flesh out the information,” says Torkamani, referring to a population genetics approach inferring most of the common genetic variants in a person’s genome. “We use correlations between whole genome sequence data and other data sets from genome-wide association studies to infer an individual’s genotype across the genome,” he says. “From there you can calculate pretty much any polygenic risk score.”

To date, about 3,800 individuals have downloaded the app to determine their CAD risk; about 1,500 of them indicate on follow-up they received their score and understand the information provided. The company is moving towards a new system of collecting information from a consented electronic health record. “We hope to see if getting this information has and longer-term health outcomes prevention of heart attack,” says Torkamani, who adds the team plans to spin out a company to deliver additional PRS information in employee health programs for other diseases, including breast, prostate, and colorectal cancers, and glaucoma.

As a self-described “Marketplace for Genomic Reports” GenePlaza has gone even farther fully embracing app-based PRS products directly to consumers. Like MyGeneRank, GenePlaza’s users input their genetic data from other providers like 23andMe, Ancestry, or MyHeritage, or they can buy a DNA collection test from GenePlaza. For a fee as little as $10, users can then purchase one of about 20 risk evaluation tools ranging from how quickly one metabolizes coffee to the risks of developing addiction or several particular diseases.

Alain Coletta
Alain Coletta, GenePlaza

“We are not selling a diagnostic, just a score associated with a risk for a condition,” says GenePlaza’s founder Alain Coletta. Based in Brussels, GenePlaza collaborates directly with vendors to create the models. “The data comes in, our algorithms impute the data, and results are displayed to the users,” he explains. “The imputation process allows us to identify a group of new variants which might not be present in the usual DNA testing chips – from Illumina, Affymetrix, and others which sample DNAat about 700,000 locations in the genome. Coletta emphasizes that companies like GenePlaza are trying to bring forward information that was already funded by taxpayers in large cohort GWAS studies and is freely available. “We make it easier by providing the model and users pay for the computational time,” Coletta explains.

A similar app-based company that uses uploaded data from testing sites, Genomelink.io also provides direct-to-consumer trait analysis via smartphone, with a vision of creating an infrastructure in consumer genomics. Currently, the company offers hundreds of traits analyses, including how one’s DNA may inform several physical and mental health traits.

Some important limitations
A common concern among developers and users of academic and commercial companies involved in PRS development is that a PRS score is only as reliable as the genome-wide variation detected in a population. Most large GWAS cohorts skew towards analysis of individuals with European ancestry, meaning that PRS scores for people not included in that group may not be as reliable.

Aside from a few key medical conditions, like coronary artery disease, deciphering the clinical management of a ‘risky’ PRS evaluation is unsettled. Should an individual with a higher PRS adjust their lifestyle or medical treatment to potentially ward off disease?

Another consideration is that PRS evaluation mostly provides results in terms of being at an increased risk for a condition. But no PRS technology can provide an absolute probability of developing a disease. It is likely that will remain unchanged for the foreseeable future.

Until then, as individuals become more familiar with their accessing their own genetic information, the use of PRS evaluation grows. It can be as easy as opening another app on the phone and clicking on a results tab.

 

Alice McCarthy is a science writer based in Massachusetts. As a scientific storyteller with a business background, she enjoys translating research and medical discoveries into stories for a wide range of readers—from patients to physician scientists to business executives. For the past decade she has particularly focused on telling the stories of the genomic revolution in terms of new treatments and research strategies.

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