As part of an international initiative, Scherzer and colleagues performed a genome-wide survival study (GWSS) of 11.2 million genetic variants in 3,821 PD patients over 31,578 longitudinal study visits conducted over the course of 12 years.
These included three novel loci: RIMS2, a gene involved in synaptic vesicle docking; TMEM108; and WWOX. The researchers also confirmed the importance of GBA and APOE4 as progression loci for PD. RIMS2 variants had a more than 2.5-times stronger effect on cognitive prognosis than GBA and APOE4.
The authors note that analyses of larger populations studied over time will be needed to detect other variants with small effect sizes and to further understand the overlap and differences in genetic contributors to susceptibility, progression and dementias. Surprisingly, the GWSS progression loci diverge from previously identified susceptibility loci, suggesting that the genetic triggers responsible for starting the disease and the genetic drivers progressively advancing the disease might be largely different.
“This is a different way to think about the disease and drug development,” said Scherzer. “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.”
Source: Eurekalert
