NIH Awards $3.1M to Identify Novel Parkinson Disease Genes in Latinos

Cleveland Clinic researcher Ignacio Mata, PhD, has received a five-year, $3.1 million grant from the National Institute of Neurological Disorders and Stroke (NINDS) to identify novel genes associated with Parkinson disease (PD) in Latino populations.

The funding will expand the work Dr. Mata has led with investigators from multiple Latin American institutions to establish the Latin American Research Consortium on the Genetics of Parkinson’s Disease (LARGE-PD), the world’s largest PD case-control cohort of Latinos.

“The Parkinson genes that we know about explain only a small proportion of the disease’s heritability,” says Dr. Mata, staff in Cleveland Clinic’s Genomic Medicine Institute. “There are additional novel genes awaiting discovery, and we believe we will have the highest likelihood of success in finding those genes if we look at understudied populations, such as those from Latin America.”

Building on a growing study cohort

Identification of genes that cause or increase the risk for PD has enabled better prediction of at-risk individuals and has pinpointed novel targets for precision treatments. However, because most PD studies have been conducted in European or Asian populations, little is known about the genetics of PD in Latino populations, leaving millions of individuals less likely to benefit from advancements in personalized medicine.

To address this disparity, Dr. Mata partnered with his collaborators from Latin America to establish LARGE-PD as a unique resource for genetic analysis in Latinos. LARGE-PD, which currently includes 3,857 participants (about half of whom have PD), aims to include at least 8,000 individuals by 2021 with support from The Michael J. Fox Foundation.

Preliminary results in a subset of LARGE-PD participants (n = 1,500) already identified several novel candidate loci for PD. As LARGE-PD has progressed, several multiplex PD families (i.e., with three or more affected individuals) have been identified and enrolled, and a preliminary study has shown that about 75% of them do not carry a mutation in a known gene, making them good candidates to screen for novel genes.

Expanding efforts with GWAS and a polygenic risk score

With this new NINDS award, Dr. Mata and collaborators will investigate genetic variants associated with PD in Latinos on a much larger scale, including the first-ever transethnic genome-wide association study (GWAS) in collaboration with the International Parkinson Disease Genomics Consortium, the largest consortium of patients of European, Asian and African ancestry. In collaboration with a research group led by Dennis Lal, PhD, also of Cleveland Clinic’s Genomic Medicine Institute, they plan to harness their data to develop and validate a Latino-specific polygenic risk score, which will indicate an individual’s overall genetic risk of developing PD.

“Our data will improve our understanding of the biological causes of PD for all patients, regardless of their ethnicity,” says Dr. Mata. “We also will find new therapeutic targets and improve diagnosis and risk prediction for individuals in Latin America and other countries with a growing Latino population, such as the United States. Our study, and others like it, will reduce existing health disparities by allowing Latinos to actively participate in clinical trials and receive personalized treatment based on their specific genetic variants.”

A broad collaboration

The NINDS award includes collaboration with scientists in 11 other nations:

• Peru — Instituto Nacional de Ciencias Neurológicas (Lima) (with their collaborating site at Universidad del Altiplano (Puno))
• Brazil — Brazilian PD Consortium (CBPD), including Universidade de São Paulo-Facultad de Medicina de Ribeirão Preto (Ribeirão Preto), Santa Casa de Misericórdia de Porto Alegre (Porto Alegre), Universidade Federal de Ciências da Saúde de Porto Alegre (Porto Alegre), Universidade Federal do Rio Grande do Norte (Natal), Universidade Federal de Goiás (Goiania), Universidade Federal de São Paulo (São Paulo), Universidade de São Paulo (São Paulo), Hospital e Maternidade Celso Pierro (São Paulo), Hospital Sírio-Libanês (São Paulo), Universidade Federal de Minas Gerais (Belo Horizonte), Universidade Federal do Paraná (Curitiba), Universidade de Campinas (Campinas), Universidade do Estado do Amazonas (Manaus), Hospital Ophir Loyola (Belem), Hospital Universitário de Brasília (Brasília), Universidade Federal do Ceará (Fortaleza), Universidade Federal do Rio de Janeiro (Rio de Janeiro), Hospital Universitário Gafrée e Guinle (Rio de Janeiro)
• Colombia — Universidad de Antioquia (Medellin), Universidad Nacional de Colombia (Bogota) and Fundación Valle del Lili (Cali)
• Uruguay — Universidad de la República-Hospital de Clínicas (Montevideo)
• Argentina — Centro de Parkinson y Transtornos de Movimiento and Instituto de Neurociencias de Buenos Aires (Buenos Aires)
• Chile — Centro de Transtornos del Movimiento (CETRAM) and University of Chile (Santiago)
• Honduras — Hospital San Felipe (Tegucigalpa)
• Ecuador — Hospital Teodoro Maldonado (Guayaquil) and Hospital Luis Vernaza (Guayaquil)
• Costa Rica — University of Costa Rica (San Jose)
• Mexico — TecSalud (Monterrey), Instituto Nacional de Neurología y Neurocirugía (Mexico City), Hospital General de México (Mexico City), ISSSTE Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado (Mexico City)
• West Indies — St. George’s University (St. George, Grenada)