Study defines genetic positions associated with the progression of Parkinson’s disease

The progression of Parkinson’s disease (PD) is an important factor in patients’ well-being and clinical trials. However, almost all of what is known about the genetics of Parkinson’s disease is associated with susceptibility or a person’s potential chance of contracting the disease in the future.

A recent study published in Nature Genetics by Brigham and Women’s Hospital researchers reveals the genetic architecture of prognosis and progression, defining five genetic positions (loci) linked with progression.

The research group has created the first risk score for forecasting the progression of Parkinson’s disease (PD) to dementia (PDD) over time, which is a significant determinant of quality of life.

The patients who come to see me in the clinic are concerned about their future, rather than their past risk factors. They want to know how they will be doing in the future and need medications designed to stop the disease from rapidly progressing. This is the central question in our study: Which genes determine whether a patient will have an aggressive or benign course, and which variants influence who will develop dementia?”

Clemens Scherzer, MD, Study Corresponding Author and Director, Center for Advanced Parkinson Research, Brigham and Women’s Hospital

Scherzer also serves as the director of the Brigham Precision Neurology Program.

Scherzer and collaborators completed a genome-wide survival study (GWSS) of 11.2 million genetic variations in 3,821 Parkinson’s disease (PD) patients over 31,578 longitudinal study visits over the course of 12 years as part of an international program.

The researchers discovered five progression loci or points in the genome where genetic variants were linked to the interval between the onset of Parkinson’s disease and the progression of dementia. Three new loci were discovered, which include: RIMS2—a gene involved in synaptic vesicle docking—WWOX, and TMEM108.

The significance of APOE4 and GBA as PD progression loci was also verified by the researchers. RIMS2 variants influenced cognitive prognosis 2.5 times more than APOE4 and GBA.

The authors emphasize that it would be crucial to analyze greater populations over time to identify other variations with limited effect sizes and to better explain the overlap and disparities in genetic contributors to progression, dementias, and susceptibility.

Interestingly, the GWSS progression loci vary from previously known susceptibility loci, implying that the genetic triggers responsible for initiating the disease and the genetic drivers eventually progressing the disease are likely to be distinct.

This is a different way to think about the disease and drug development. Disease-modifying drugs that target the genetic drivers of disease progression should be prime targets for turning fast progressors into slow progressors and improve patients’ lives.”

Clemens Scherzer, MD, Study Corresponding Author and Director, Center for Advanced Parkinson Research, Brigham and Women’s Hospital