An international study of 198 000 people has suggested that a gene variant, found almost exclusively in the genomes of people of African ancestry with this genetic background, increases the risk of developing Parkinson’s disease.
The scientists said the study results suggest the risk may be linked to a variant in the gene encoding β-glucocerebrosidase (GBA1), a protein known to control how cells in the body recycle proteins.
The research was led by scientists at the National Institutes of Health; University College London; and the University of Lagos, Nigeria, and published in The Lancet Neurology, reports News Medical.
Although more research is needed to understand the role of environmental and other factors in these populations, the team found that those who carry one copy of the gene are about 1.5 times more likely to have Parkinson’s than those who have no copies, whereas those who carry two copies are about 3.5 times more likely.
Over the past few decades, researchers have found several genetic risk factors for Parkinson's disease. Rare inherited cases of the disease have been linked to about 20 genes harbouring pathogenic variants – formerly known as disease-causing mutations – while more than 100 regions of the human genome are associated with more common, sporadic forms of the disease.
However, most of these findings are based on studies of people of European descent and very few have been conducted on people of African descent.
For this project, the researchers conducted a genome wide association study (GWAS) involving 1 488 people who had Parkinson’s disease and 196 430 people who did not.
NIH scientists worked with researchers from around the world who are part of the Global Parkinson’s Genetics Programme (GP2), including the Black and African American Connections to Parkinson’s Study and the International Parkinson Disease Genomics Consortium (IPDGC) – Africa. GP2 is supported by the Aligning Science Across Parkinson’s (ASAP) initiative and implemented by The Michael J Fox Foundation for Parkinson’s Research (MJFF).
The researchers collected DNA samples and analysed genetic data from individuals primarily from Nigeria and four sites across the United States. These data were combined with de-identified genetic and phenotypic data from 195 587 people of African American or Afro-Caribbean descent who consented to participate in 23andMe research.
A preliminary analysis of the data showed a significant association between Parkinson’s risk and the newly identified variant of the GBA1 gene. A review of previous studies also showed that this new variant rarely appears in people of European and Asian descent, suggesting it is almost exclusively linked to African ancestry.
“We were completely surprised. The goal of the initial analysis was to help train GP2 researchers in Nigeria and other parts of the world in how to analyse GWAS data,” said Sara Bandrés-Ciga, Ph.D., staff scientist at NIH Centre for Alzheimer’s Related Dementias (CARD) and an author of the study.
“The fact that the GBA1 variant had a significant association while others did not suggest that it is strongly tied to Parkinson’s disease in this population.”
Further analysis of this study’s GWAS data suggested that the risk associated with the GBA1 variant is additive.
Previous studies by NIH researchers and others have shown that pathogenic variants of the GBA1 gene are also associated with Parkinson’s and Gaucher’s disease, a rare genetic disorder caused by problems with lysosomes. Lysosomes are tiny sacs inside of cells that break down proteins for recycling.
The results from this study suggest the new variant may alter lysosomal GBA1 activity in a previously unknown way. Most previously identified variants appear in the part of the genetic code that guides how the body manufactures glucocerebrosidase, an enzyme encoded by GBA1.
This either disrupts the manufacturing process or alters the enzyme’s activity. In contrast, this newly discovered Parkinson’s disease variant appears just outside the coding region. Further research is needed to determine how the variant may change activity.
Currently, researchers are developing genetic therapies for treating Gaucher’s disease and other lysosomal disorders.
“To effectively treat Parkinson’s and truly any disease, we must study diverse populations to fully understand what the drivers and risk factors are for these disorders. These results support the idea that the genetic basis for a common disease can differ by ancestry, and understanding these differences may provide new insights into the biology of Parkinson's,” said Andrew Singleton, PhD, CARD director and a study author
“Our results represent a good first step towards fully understanding the genetic and biological complexity of each individual around the world who has Parkinson’s,” he added.
“Our hope is that results like these will provide researchers a roadmap for developing new genetic treatments and therapies for the disease.”
According to the WHO, more than 8.5m people worldwide have Parkinson’s.
Study details
Identification of genetic risk loci and causal insights associated with Parkinson’s disease in African and African admixed populations: a genome-wide association study
Mie Rizig, Sara Bandres-Ciga, Mary Makarious, Oluwadamilola Omolara Ojo, Peter Wild Crea, Oladunni Victoria Abiodun, et al.
Published in The Lancet Neurology on 23 August 2023
Summary
Background
An understanding of the genetic mechanisms underlying diseases in ancestrally diverse populations is an important step towards development of targeted treatments. Research in African and African admixed populations can enable mapping of complex traits, because of their genetic diversity, extensive population substructure, and distinct linkage disequilibrium patterns. We aimed to do a comprehensive genome-wide assessment in African and African admixed individuals to better understand the genetic architecture of Parkinson’s disease in these underserved populations.
Methods
We performed a genome-wide association study (GWAS) in people of African and African admixed ancestry with and without Parkinson’s disease. Individuals were included from several cohorts that were available as a part of the Global Parkinson’s Genetics Programme, the International Parkinson’s Disease Genomics Consortium Africa, and 23andMe. A diagnosis of Parkinson’s disease was confirmed clinically by a movement disorder specialist for every individual in each cohort, except for 23andMe, in which it was self-reported based on clinical diagnosis. We characterised ancestry-specific risk, differential haplotype structure and admixture, coding and structural genetic variation, and enzymatic activity.
Findings
We included 197 918 individuals (1488 cases and 196 430 controls) in our genome-wide analysis. We identified a novel common risk factor for Parkinson’s disease (overall meta-analysis odds ratio for risk of Parkinson's disease 1·58 [95% CI 1·37–1·80], p=2·397 × 10−14) and age at onset at the GBA1 locus, rs3115534-G (age at onset β=–2·00 [SE=0·57], p=0·0005, for African ancestry; and β=–4·15 [0·58], p=0·015, for African admixed ancestry), which was rare in non-African or non-African admixed populations. Downstream short-read and long-read whole-genome sequencing analyses did not reveal any coding or structural variant underlying the GWAS signal. The identified signal seems to be associated with decreased glucocerebrosidase activity.
Interpretation
Our study identified a novel genetic risk factor in GBA1 in people of African ancestry, which has not been seen in European populations, and it could be a major mechanistic basis of Parkinson’s disease in African populations. This population-specific variant exerts substantial risk on Parkinson’s disease compared with common variation identified through GWAS and it was found to be present in 39% of the cases assessed in this study. This finding highlights the importance of understanding ancestry-specific genetic risk in complex diseases, a particularly crucial point as the Parkinson’s disease field moves towards targeted treatments in clinical trials. The distinctive genetics of African populations highlights the need for equitable inclusion of ancestrally diverse groups in future trials, which will be a valuable step towards gaining insights into novel genetic determinants underlying the causes of Parkinson’s disease. This finding opens new avenues towards RNA-based and other therapeutic strategies aimed at reducing lifetime risk of Parkinson’s disease.
See more from MedicalBrief archives:
Parkinson’s ‘game changer’ research findings open up new possibilities
Thousands of Parkinson’s patients initially misdiagnosed
Parkinson’s breakthrough: New disease-causing mechanism found
Environmental factors worsen neurologic health – US review of 30 years’ research