Objective: To evaluate the influence of genetic variants on phenotypic variability and disease progression in PD patients.

Background: Parkinson’s disease (PD) patients show a large phenotypic variability and mode of progression reflecting inter-individual pathologic heterogeneity. This could be based on a different genetic load within the patients.

Methods:

We developed a genetic risk score based on the weighted ODDs Ratios of variants know to be associated with PD and AD. The PD risk score included SNCA, MAPT, GAK, CCDC62/HIP1R, MCCC1/LAMP3, BST1, NMD3, SYT11, STBD1/FAM47E, GPNMB, FGF20, STXB1/SETD1A, LRRK2, PARK16, STK39, HLA-DR, MMP16 and the AD risk score included CR1, BIN1, CLU, MS4A, PICALM, ABCA7, APOE (1), APOE (2).

Clinical parameters including age at onset, H&Y, MMSE, UPDRS-III and BDI were evaluated cross-sectionally in 710 PD patients that have been stratified by their genetic load: highest versus lowest quartile of the risk score. In a subgroup of 42 PD patients this analysis was done longitudinally over 8 years.

Results: PD patients with a PD risk score in the highest quartile were younger at disease onset but not clinically relevant worse regarding the H&Y, MMSE and UPDRS-III scores than patients within the lowest PD risk score quartile. This could be confirmed in the subgroup of patients longitudinally as disease progression of the two groups seems similar. We did not find any impact of the AD risk score on assessed clinical parameters, neither cross-sectional nor longitudinal.

Conclusions: In sporadic PD patients, a higher genetic load of PD risk variants predisposes to an earlier onset but not to a more rapid progression. This might be partially explained by the younger age which promotes compensatory mechanisms.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/higher-genetic-load-is-associated-with-an-earlier-disease-onset-but-not-with-more-rapid-disease-progression-in-parkinsons-disease/