Researchers Seek to Determine Genetic Variability in Parkinson Progression

A recent study sought to determine if any association exists between previously identified alleles that confer risk for Parkinson disease and variables measuring disease progression. Based on the results, researchers said taking genetic variability into account in the future will be helpful not only to understand the course of the disease but also to minimize heterogeneity in clinical trials.

Parkinson disease has an estimated lifetime risk as high as 1% to 2%. Patients with Parkinson disease may have various combinations of symptoms, both motor and nonmotor, and show differences in the rates of progression. In addition to the motor symptoms of bradykinesia, rigidity, and tremor, patients with Parkinson disease also develop nonmotor symptoms, which include depression, cognitive decline, sleep abnormalities, reduced olfaction, and autonomic dysfunction.

Molecular genetic approaches have revealed a significant number of genetic risk loci for idiopathic Parkinson disease, but in comparison with case-control genome-wide association study (GWAS), analyzing how genetic factors influence clinical presentation and progression requires longitudinal cohorts with much more detailed observations.

That is a challenge, however, given the small size of individual, varied cohorts. In the present study, researchers collected data from 13 distinct longitudinal Parkinson disease cohorts from North America, Europe, and Australia with detailed clinical data, including assessment of disease progression. Nine were prospective observational cohorts and the rest were from randomized clinical trials.

They then sought to determine if Parkinson disease genetic risk factors, either in the form of known GWAS variants or an aggregate genetic risk score (GRS), are linked to changes in progression and aspects of the disease.

Researchers analyzed a total of 23,423 visits by 4307 patients of European ancestry from 13 longitudinal cohorts in Europe, North America, and Australia and evaluated the link between 31 risk variants and variables measuring disease progression.

GBA variants were associated with the development of daytime sleepiness (p.N370S: hazard ratio [HR], 3.28 [95% CI, 1.69-6.34]) and possible REM sleep behavior (p.T408M: odds ratio, 6.48 [95% CI, 2.04-20.60]).

Previously reported associations of GBA variants with motor/cognitive declines were replicated. The other genotype-phenotype associations include an intergenic variant near LRRK2 and the faster development of motor symptoms (Hoehn and Yahr scale 3.0: HR, 1.33 [95% CI, 1.16-1.52] for the C allele of rs76904798) and an intronic variant in PMVK and the development of wearing-off effects (HR, 1.66 [95% CI, 1.19-2.31] for the C allele of rs114138760).

Age at onset was associated with TMEM175 variant p.M393T (−0.72 [95% CI, −1.21 to −0.23] in years), the C allele of rs199347 (intronic region of GPNMB, 0.70 [95% CI, 0.27-1.14]), and G allele of rs1106180 (intronic region of CCDC62, 0.62 [95% CI, 0.21-1.03]).

This study provides evidence that alleles associated with Parkinson disease risk, in particular GBA variants, also contribute to the heterogeneity of multiple motor and nonmotor aspects. Accounting for genetic variability will be a useful factor in understanding disease course and in minimizing heterogeneity in clinical trials.

Reference

Iwaki H, Blauwendraat C, Leonard HL. Genetic risk of Parkinson disease and progression: an analysis of 13 longitudinal cohorts [published online July 9, 2019]. Neurol Genet. doi: 10.1212/NXG.0000000000000348.