LARGE-PD Study Begins to Profile the Genetics of Parkinson’s Disease in Latinos

An international research team led by Cleveland Clinic has published the most comprehensive characterization of the underlying genetic basis for Parkinson’s disease (PD) in Latinos to date, marking an important step toward more inclusive PD genetic research.

“PD impacts all ethnic groups, but since genetic studies have largely been limited to individuals of European and East Asian ancestry, little is known about the genetic architecture of PD in Latino populations,” says Ignacio Mata, PhD, assistant staff in Cleveland Clinic’s Genomic Medicine Institute and lead author of the study. “As we see PD incidence rates rise in nearly every global region, the importance of greater diversity in PD research cannot be overlooked.”

First genome-wide association study in Latinos

In their study, published in Annals of Neurology (2021 July 6), Dr. Mata and international collaborators performed the first-ever genome-wide association study (GWAS) of Latino PD patients from South America. The analysis relied on patient data from the world’s largest PD case-control cohort of Latinos, the Latin American Research Consortium on the Genetics of Parkinson’s Disease (LARGE-PD), which includes individuals from 35 institutions in 12 countries across Latin America and the Caribbean.

The researchers scanned the genomes of 1,497 individuals (807 PD cases and 690 healthy controls) from nine LARGE-PD sites in five countries (Uruguay, Brazil, Colombia, Peru and Chile) to investigate genetic variations associated with PD.

Notably, they demonstrated that SNCA, a gene previously linked to PD in European and East Asian populations, had genome-wide significance in the LARGE-PD cohort and a replication cohort, indicating its critical role in PD etiology in Latinos. In addition, they identified the novel gene NRROS as a biologically plausible PD risk gene, particularly in individuals from Peru, but noted that further studies are needed to validate this finding.

The researchers then assessed the significance of PD variants previously identified in European and East Asian populations for the LARGE-PD cohort, and found a substantial overlap of PD genetic architecture between Europeans and Latinos.

They also explored the relationship between PD risk and Latino population ancestry, which tends to have a three-way admixture pattern with contributions from African, European and Native American ancestry, and pinpointed variants associated with African and Native American ancestries that may influence PD risk.

“As we continue our work to gain comprehensive understanding of population-specific PD genetic architecture in Latino populations, inclusion of Latino PD patients from diverse ancestral backgrounds, such as those with significant Native American or African ancestries, is a necessity,” Dr. Mata says. “PD is a global disease, so it is crucial that genetic studies reflect the wide diversity of people with PD.”

Next steps for LARGE-PD

Dr. Mata and his colleagues established LARGE-PD in 2009 with funding from the Parkinson’s Foundation to increase diversity in PD genetics studies and better understand the genetics of PD in Latinos. They recently conducted the first analysis of copy number variants (CNVs), or large structural genetic changes involving the deletion and/or duplication of DNA segments, in Latino PD patients. The study, published in Movement Disorders (2021;36:434-441), demonstrated that CNVs in known PD genes are associated with PD in Latino populations. Specifically, they found that Latino patients with PD were more likely than controls to carry CNVs affecting known PD genes, and these patients often experienced a significantly earlier onset of symptoms.

“The global collaboration and support that have made LARGE-PD possible have enabled us to make tremendous strides toward increasing diversity in genetic studies and minimizing health disparities in underrepresented populations, and we are continuing to charge forward,” Dr. Mata says. “In the next few years, we plan to triple our cohort with funding from the Michael J. Fox Foundation for Parkinson’s Research, which will allow us to replicate our results and increase our power to identify new genetic associations. We also will work with the Aligning Science Across Parkinson’s Global Parkinson’s Genetics Program to perform the largest and most diverse genetic study of PD, with the goal of including 150,000 individuals, of whom at least 50,000 will be from underrepresented populations.”