Sonja W. Scholz, MD, PhD, on Advancing Genomics Against Complex, Polygenic Neurodegenerative Disorders

February 18, 2021
Kenneth Bender, PharmD, MA

NeurologyLive, February 2021, Volume 4, Issue 1

Scholz was recognized for her application of advanced genetic techniques to the study of neurodegenerative disorders, including dementia with Lewy bodies, multiple system atrophy, frontotemporal dementia, progressive supranuclear palsy, and corticobasal degeneration.

Sonja W. Scholz, MD, PhD, an investigator in the Neurodegenerative Diseases Research Unit in the Division of Intramural Research at the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH), was the recipient of the annual Soriano Lectureship Award at the 2020 American Neurological Association (ANA) virtual meeting. The award acknowledges, according to the ANA, a “brilliant lecture delivered by an outstanding scientist.”

Scholz was recognized for her application of advanced genetic techniques to the study of neurodegenerative disorders, including dementia with Lewy bodies, multiple system atrophy, frontotemporal dementia, progressive supranuclear palsy, and corticobasal degeneration. She welcomed the opportunity, utilizing the occasion to describe how advances in genetics are likely to impact daily clinical practice with patients afflicted with these types of disorders.

While much of the recent excitement in this field has resulted from the identification of single-gene defects or deficiencies underlying rare monogenic disorders such as Batten disease and Rett syndrome, and from the emerging technologies to deliver gene replacement, Scholz emphasized the importance of also pursuing the genetic components of more common and more complex polygenic, age-related neurodegenerative disorders.

“A lot of the work in genetics has traditionally been done in the pediatric population, where you have the single-gene disorders. But increasingly in our adult population, we are recognizing that genetics also play a role,” Scholz told NeurologyLive®. “It shouldn’t really surprise us; our genes don‘t stop working just because we’re growing up. But it becomes more complicated. There are more risk factors rather than causative genetic factors, and it’s usually a combination of many.”

“While I think that most of the immediate translations are going to happen in the Mendelian diseases, the monogenic diseases, I think there’s also a lot of hope that this knowledge can be leveraged for the more complex genetic disorders,” Scholz commented.

After presenting her Soriano Award lecture, “Genomic Approaches Paving the Way for Precision Neurology,” Scholz spoke with NeurologyLive® regarding her work and the opportunity to pursue it in collaboration with scientists both in and outside of the NIH. That discussion has been edited and abridged, and the lecture excerpted for this profile.

Pursuing Research to Improve Clinical Outcomes

Scholz obtained her medical degree from the Medical University of Innsbruck, Austria, in 2004, after which she completed a fellowship at the Laboratory of Neurogenetics in the NIH National Institute of Aging. In 2010, she earned her PhD in neurogenomics from University College London in the United Kingdom. Before returning to the NIH, Scholz added to the clinician component of her physician-scientist background by completing her neurology residency at Johns Hopkins University School of Medicine in Baltimore, Maryland.

In 2015, Scholz received the McFarland Transition to Independence Award for Neurologist-Scientists and rejoined the NIH to lead a team of researchers in applying advanced genetic techniques to the study of neurodegenerative disorders. She established the Atypical Parkinsonism Clinic at the NIH Clinical Center to study the natural history and molecular characteristics of patients suffering from these conditions.

Scholz described the decision to complete her neurology residency even as she had established her path in research directly from medical school.

“I think the ideal scenario is to combine the clinical work with research. They’re 2 worlds that sometimes live by themselves, and I think I see myself as kind of a bridge-builder between those worlds,” she recounted.

“I really enjoy the basic sciences side, asking questions and learning more about very complicated diseases, but also kind of crystallizing out the important, translatable parts of the knowledge that we’re generating, and communicating that to the clinicians who are working with these patients. And, hopefully, contributing to the new therapies that we’re hoping to develop for patients with very complex, neurodegenerative conditions,” Scholz said.

After completing her neurology residency and receiving the McFarland Award, Scholz proposed that the NINDS establish a genetics research unit dedicated to neurodegenerative diseases. Scholz found the leadership at NINDS to be “very open to the idea” and to have already recognized the need for additional physician-scientists to work in that area.

“With the population aged more than 65 years growing quite rapidly, we’re seeing an increase in patients with neurodegenerative diseases, and that puts a huge socioeconomic burden on the society. There is a need to come up with better insights into what is actually causing these very challenging diseases, and [into] treatments,” Scholz pointed out.

Scholz integrated the Neurodegenerative Diseases Research Unit into the Laboratory of Neurogenetics, and established genetics research laboratory within the Intramural Research Program. The stated primary mission of the laboratory is to unravel the molecular genetic mechanisms that underlie these devastating diseases and identify targets for drug development.

Scholz’s efforts to focus the direction of genetic research and accelerate the attainment of meaningful findings were aided by the emphasis on collaboration in the Laboratory of Neurogenetics and at the Intramural Research Program, and her research has proceeded with national and international partners.

“Everything that we do is part of team science and team research. Nobody can do any of this by themselves,” Scholz declared. “It has to be an effort that involves the entire research community: patients, caregivers, researchers, and clinicians.”

Scholz encourages clinicians to tell patients of diverse backgrounds and ethnicity about openings in clinical trials, as well as opportunities to provide biosamples for genomic studies.

“We have great opportunities to use genomics, [and] not just for identifying underlying genetic defects that may help with the diagnosis,” Scholz explained. “By enrolling many individuals from varied backgrounds into the research studies, we can learn more about them and build a health care system that becomes more open and more equitable, as well as more precise and more personalized.”

Lecture (excerpted): What I want to docus on today is [discussing] how we can use modern genomic advances for gaining insights into the molecular characteristics underlying neurodegeneration. But I also want to highlight how we can leverage this type of knowledge to gain insight into how we can use genetic markers for predictive diagnostic, prognostic, and therapeutic approaches in the near future.

Previous speakers have mainly focused on specific Mendelian forms of disease, and I want to highlight how we can leverage genetic knowledge for the broader disease population that is suffering from more complex genetic syndromes.

Specifically, we have learned from genome-wide association studies and other genetic approaches that most diseases are, from a genetic point of view, complex. There are multiple genetic factors that are playing a role, not all of which might be disease-causing, but many of them are playing a major role in the pathogenesis.

For example, Alzheimer disease, Lewy body dementia, [and] Parkinson’s disease are common, age-related neurodegenerative diseases that in most instances occur apparently sporadically in the community. Yet all of these conditions have high heritable contributions to their etiopathogenesis.

There are an increasing number of risk genes that we’re able to decipher. GWAS (genome-wide association studies) have identified about 30 risk loci for Alzheimer disease, about 5 loci for Lewy body dementia, and approximately 90 for Parkinson disease [FIGURE 1].

So, we have to move away from our traditional thinking where we look for 1 specific molecular defect that results in 1 clear phenotype—the Mendelian diseases. But in the complex disease context, we’re mainly talking about polygenic disease factors, where multiple lower risk variants are playing a role, and in aggregate, probably together with aging and environmental factors, are enough to push your patient into disease.

Tallying the Polygenic Risk Score

Scholz emphasized the utility of the polygenic risk score (PRS) to distill genome-wide association study (GWAS) locations of loci with possible links to pathogenesis into a cumulative risk metric. In her area of research, the PRS is used to sum up the identified loci from the GWAS and weigh them by their relative effect sizes to estimate an individual’s risk for complex, polygenic degenerative neurologic disorders.

Clinical correlations of PRS for some disorders have included estimated age at onset and the rapidity of the degenerative course. In Alzheimer disease (AD), for example, Scholz has noted that individuals in the highest decile of PRS have onset more than a decade earlier than those in the lowest decile. In the genetic assessment of age-associated AD risk cited in her lecture, the investigators demonstrate that polygenic factors beyond APOE contribute to modifying AD risk.1

Scholz pointed to similar associations established for patients with Parkinson disease (PD), with patients in the highest polygenic risk category presenting with earlier disease onset. Those investigators underscore the evidence that early-onset forms of PD cannot be exclusively attributed to highly penetrant Mendelian mutation, but to an accumulation of common polygenic alleles with relatively low effect size.2

Scholz is also interested in applying PRS to better differentiate patient groups from controls to increase the precision of clinical trials. She pointed to a successful example of case-control status prediction in PD that was accomplished by combining PRS with smell test data and demographics.3 She said she anticipates that the approach can help not only to distinguish participants with PD from controls, but that it will also progress to aid early diagnosis in individuals with prodromal features.

“There’s a lot of variability in the symptoms and signs that the patients present because they’re all individuals, and that can make the diagnosis very challenging,” Scholz commented. “I think anything that can help with identifying the underlying disease mechanism will also help with instituting appropriate treatments.”

Lecture (excerpted): We can use that [PRS] to predict various outcome measures, such as phenotypes. You can stratify patients based on their severity. We can study the underlying genetic architecture and draw conclusions about how related one disease is to another on a genetic basis. But we can also be smarter about predicting which treatment responses might be useful for a given patient population [FIGURE 2].

Finding Interrelationship of Complex Neurodegenerative Disorders

Scholz is a principal investigator of new research that applied genetic risk scores established for AD and PD to a large cohort of patients with Lewy body dementia.4 She and her colleagues showed that patients with Lewy body dementia have a higher risk for both AD and PD. She pointed out that the interrelationship was present even after analysis corrected for the most common high-risk alleles (APOE, GBA, SNCA, and LRRK2).

Scholz and colleagues used GWAS analysis to identify 5 independent risk loci, with genome-wide gene-aggregation tests implicating mutations in the gene GBA. Scholz suggested that the shared risk profiles and pathways of these conditions, previously considered disparate, provide a deeper molecular understanding of the complex genetic architecture of the age-related neurodegenerative conditions.

Scholz also considered these findings as immediately clinically relevant, since a therapeutic agent that targets mechanisms for PD or AD could be a candidate for Lewy body dementia as well. Trials that provide evidence for “repurposing” a therapeutic agent could hasten the possibility of effective intervention, she suggested.

“Imagine, for example, that there is a drug that targets this specific pathway, and it shows a promising result in AD. The very obvious next thought should be, ‘Well, we’ve shown that pathway also has a defect in Lewy body dementia, so we should really try that disease population next,’” Scholz explained. “So, in a way, that can also help to accelerate the field, because we already know that these molecular overlaps exist.” Scholz also anticipated that her team’s work in demonstrating overlapping pathways in the conditions, previously considered distinct, will help prioritize the pathway targets for intervention. For example, Scholz and colleagues suspected from their mapping that SNCA-AS1 may prove to be “a more amenable therapeutic target” than SNCA itself due to its neuronal specificity.4

Lecture (excerpted): In a study that we recently performed, we applied Alzheimer disease and Parkinson disease genetic risk scores to a large cohort of patients with Lewy body dementia. And what we were able to show is that patients with Lewy body dementia have a higher risk for Alzheimer disease and for Parkinson disease, and that was present even after correcting for the most common high-risk alleles. This suggests that Lewy body dementia, on a molecular basis, intersects with the pathogenesis of Parkinson disease and Alzheimer disease. And that is immediately clinically relevant because any drug that works for Parkinson disease or Alzheimer disease should be tried in the Lewy body dementia population as well. So, for drug repurposing, this knowledge is really very valuable.

As part of their study on overlapping risk factors in patients with AD and PD and Lewy body dementia, Scholz and colleagues created a foundational resource, the largest whole-genome sequence repository in Lewy body dementia to date, which they anticipate will facilitate the study of molecular mechanisms across a broad spectrum of neurodegenerative diseases. This resource includes approximately 2000 elderly individuals who are neurologically healthy who could serve as control subjects for the study of other neurological diseases.

“Determining shared molecular genetic relationships among complex neurodegenerative diseases paves the way for precision medicine and has implications for prioritizing targets for therapeutic development,” Scholz and colleagues observed.

REFERENCES
1. Desikan RS, Fan CC, Wang Y, et al. Genetic assessment of age-associated Alzheimer disease risk: development and validation of a polygenic hazard score. PLoS Med. 2017;14(3):e1002258. doi:10.1371/journal.pmed.1002258
2. Escott-Price V, International Parkinson’s Disease Genomics Consortium, Nalls MA, et al; IPDGC Consortium Members. Polygenic risk of Parkinson disease is correlated with disease age at onset. Ann Neurol. 2015;77(4):582-591. doi:10.1002/ana.24335
3. Nalls MA, McLean CY, Rick J, et al. Diagnosis of Parkinson’s disease on the basis of clinical and genetic classification: a population-based modeling study. Lancet Neurol. 2015;14(10):1002-1009. doi:10.1016/S1474-4422(15)00178-7
4. Chia R, Sabir MS, Bandres-Ciga S, et al. Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into the complex genetic architecture. bioRxiv. Preprint posted online July 6, 2020. doi:10.1101/2020.07.06.185066
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