Genetic stratification of motor and QoL outcomes in Parkinson's disease in the EARLYSTIM study

[en] Purpose The decision for subthalamic deep brain stimulation (STN-DBS) in Parkinson's disease (PD) relies on clinical predictors. Whether genetic variables could predict favourable or unfavourable decisions is under investigation. Objective First, we aimed to reproduce the previous observation that SNCA rs356220 was associated with favourable STN-DBS motor response. In additional exploratory analyses, we studied if other PD risk and progression variants from the latest GWAS are associated with therapeutic outcome. Further, we evaluated the predictive value of polygenic risk scores. Methods We comprehensively genotyped patients from the EarlyStim cohort using NeuroChip, and assessed the clinico-genetic associations with longitudinal outcome parameters. Results The SNCA rs356220 variant did not predict UPDRS III outcomes. However, it was associated with quality of life improvement in secondary analyses. Several polymorphisms from previously identified GWAS hits predicted motor or quality of life outcomes in DBS patients. Polygenic risk scores did not predict any outcome parameter. Conclusions Our findings support the hypothesis that different common genetic markers are associated with favourable quality of life outcomes of STN-DBS in PD. These findings can be the basis for further validation in larger and independent cohorts.

Research center :

- Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
- Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group)

Disciplines :

Genetics & genetic processes
Neurology

Author, co-author :

Weiss, Daniel

LANDOULSI, Zied ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core

MAY, Patrick ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core

Sharma, Manu

Schüpbach, Michael

You, Hana

Corvol, Jean Christophe

Paschen, Steffen

Helmers, Ann-Kristin

Barbe, Michael

More authors (19 more)

External co-authors :

yes

Language :

English

Title :

Genetic stratification of motor and QoL outcomes in Parkinson's disease in the EARLYSTIM study

Publication date :

07 September 2022

Journal title :

Parkinsonism and Related Disorders

ISSN :

1353-8020

eISSN :

1873-5126

Publisher :

Elsevier, Netherlands

Peer reviewed :

Peer Reviewed verified by ORBi

Focus Area :

Systems Biomedicine

Additional URL :

https://linkinghub.elsevier.com/retrieve/pii/S1353802022002826

Available on ORBilu :

since 11 September 2022

Statistics

Number of views

64 (3 by Unilu)

Number of downloads

2 (0 by Unilu)

More statistics

Scopus citations^®

Scopus citations^®
without self-citations

WoS citations^™

Bibliography

Weiss, D., Volkmann, J., Fasano, A., Kuhn, A., Krack, P., Deuschl, G., Neurology Grand Rounds: changing gears - DBS for dopaminergic desensitization in Parkinson's disease?. Ann. Neurol., 2021.
Schuepbach, W.M., Rau, J., Knudsen, K., Volkmann, J., Krack, P., Timmermann, L., et al. Neurostimulation for Parkinson's disease with early motor complications. N. Engl. J. Med. 368 (2013), 610–622.
Schuepbach, W.M.M., Tonder, L., Schnitzler, A., Krack, P., Rau, J., Hartmann, A., et al. Quality of life predicts outcome of deep brain stimulation in early Parkinson disease. Neurology 92 (2019), e1109–e1120.
Deuschl, G., Schade-Brittinger, C., Krack, P., Volkmann, J., Schafer, H., Botzel, K., et al. A randomized trial of deep-brain stimulation for Parkinson's disease. N. Engl. J. Med. 355 (2006), 896–908.
Williams, A., Gill, S., Varma, T., Jenkinson, C., Quinn, N., Mitchell, R., et al. Deep brain stimulation plus best medical therapy versus best medical therapy alone for advanced Parkinson's disease (PD SURG trial): a randomised, open-label trial. Lancet Neurol. 9 (2010), 581–591.
Deuschl, G., Follett, K.A., Luo, P., Rau, J., Weaver, F.M., Paschen, S., et al. Comparing two randomized deep brain stimulation trials for Parkinson's disease. J. Neurosurg., 2019, 1–9.
Charles, P.D., Van Blercom, N., Krack, P., Lee, S.L., Xie, J., Besson, G., et al. Predictors of effective bilateral subthalamic nucleus stimulation for PD. Neurology 59 (2002), 932–934.
Artusi, C.A., Dwivedi, A.K., Romagnolo, A., Pal, G., Kauffman, M., Mata, I., et al. Association of subthalamic deep brain stimulation with motor, functional, and pharmacologic outcomes in patients with monogenic Parkinson disease: a systematic review and meta-analysis. JAMA Netw. Open, 2, 2019, e187800.
Weiss, D., Herrmann, S., Wang, L., Schulte, C., Brockmann, K., Plewnia, C., et al. Alpha-synuclein Gene Variants May Predict Neurostimulation Outcome. Movement Disorders. 2016, official journal of the Movement Disorder Society.
de Oliveira, L.M., Barbosa, E.R., Aquino, C.C., Munhoz, R.P., Fasano, A., Cury, R.G., Deep brain stimulation in patients with mutations in Parkinson's disease-related genes: a systematic review. Movement Disorders Clin. Practice 6 (2019), 359–368.
Weiss, D., Brockmann, K., Srulijes, K., Meisner, C., Klotz, R., Reinbold, S., et al. Long-term follow-up of subthalamic nucleus stimulation in glucocerebrosidase-associated Parkinson's disease. J. Neurol. 259 (2012), 1970–1972.
Cilia, R., Tunesi, S., Marotta, G., Cereda, E., Siri, C., Tesei, S., et al. Survival and dementia in GBA-associated Parkinson's disease: the mutation matters. Ann. Neurol. 80 (2016), 662–673.
Tan, M.M.X., Lawton, M.A., Jabbari, E., Reynolds, R.H., Iwaki, H., Blauwendraat, C., et al. Genome-wide association studies of cognitive and motor progression in Parkinson's disease. Mov. Disord.: official journal of the Movement Disorder Society 36 (2021), 424–433.
Nalls, M.A., Blauwendraat, C., Vallerga, C.L., Heilbron, K., Bandres-Ciga, S., Chang, D., et al. Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies. Lancet Neurol. 18 (2019), 1091–1102.
Pihlstrom, L., Morset, K.R., Grimstad, E., Vitelli, V., Toft, M., A cumulative genetic risk score predicts progression in Parkinson's disease. Mov. Disord.: official journal of the Movement Disorder Society 31 (2016), 487–490.
Fuchs, J., Tichopad, A., Golub, Y., Munz, M., Schweitzer, K.J., Wolf, B., et al. Genetic variability in the SNCA gene influences alpha-synuclein levels in the blood and brain. Faseb. J.: official publication of the Federation of American Societies for Experimental Biology 22 (2008), 1327–1334.
Linnertz, C., Saucier, L., Ge, D., Cronin, K.D., Burke, J.R., Browndyke, J.N., et al. Genetic regulation of alpha-synuclein mRNA expression in various human brain tissues. PLoS One, 4, 2009, e7480.
Burciu, R.G., Seidler, R.D., Shukla, P., Nalls, M.A., Singleton, A.B., Okun, M.S., et al. Multimodal neuroimaging and behavioral assessment of alpha-synuclein polymorphism rs356219 in older adults. Neurobiol. Aging 66 (2018), 32–39.
Helmich, R.C., Thaler, A., van Nuenen, B.F., Gurevich, T., Mirelman, A., Marder, K.S., et al. Reorganization of corticostriatal circuits in healthy G2019S LRRK2 carriers. Neurology 84 (2015), 399–406.
Blauwendraat, C., Faghri, F., Pihlstrom, L., Geiger, J.T., Elbaz, A., Lesage, S., et al. NeuroChip, an updated version of the NeuroX genotyping platform to rapidly screen for variants associated with neurological diseases. Neurobiology of aging, 57, 2017, 247 e9-e13.
Das, S., Forer, L., Schonherr, S., Sidore, C., Locke, A.E., Kwong, A., et al. Next-generation genotype imputation service and methods. Nature genetics 48 (2016), 1284–1287.
Hoglinger, G., Schulte, C., Jost, W.H., Storch, A., Woitalla, D., Kruger, R., et al. GBA-associated PD: chances and obstacles for targeted treatment strategies. J Neural Transm, 2022 (Vienna).
Choi, S.W., O'Reilly, P.F., PRSice-2: polygenic Risk Score software for biobank-scale data. GigaScience, 8, 2019.
Khera, A.V., Chaffin, M., Aragam, K.G., Haas, M.E., Roselli, C., Choi, S.H., et al. Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nature genetics 50 (2018), 1219–1224.
Lesage, S., Brice, A., Parkinson's disease: from monogenic forms to genetic susceptibility factors. Human molecular genetics 18 (2009), R48–R59.
Polygenic Risk Score Task Force of the International Common Disease A. Responsible use of polygenic risk scores in the clinic: potential benefits, risks and gaps. Nature medicine 27 (2021), 1876–1884.
Aasly, J.O., Long-term outcomes of genetic Parkinson's disease. Journal of movement disorders 13 (2020), 81–96.
Bruggemann, N., Klein, C., Parkin type of early-onset Parkinson disease. Adam, M.P., Everman, D.B., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., Bean, L.J.H., et al. (eds.) GeneReviews((R)), 1993 Seattle (WA).