Journal
MOVEMENT DISORDERS
Volume 35, Issue 5, Pages 774-780Publisher
WILEY
DOI: 10.1002/mds.27974
Keywords
G2019S; genetics; LRRK2; Parkinson's disease; polygenic risk score
Categories
Funding
- Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services [ZO1 AG000949]
- Michael J. Fox Foundation
- AbbVie
- Allergan
- Avid Radiopharmaceuticals
- Biogen
- BioLegend
- Bristol-Myers Squibb
- Celgene
- Denali Incorporated
- GE Healthcare
- Genentech
- GlaxoSmithKline
- Eli Lilly and Company
- Lundbeck
- Merck Co.
- Meso Scale Discovery
- Pfizer
- Piramal
- Prevail Therapeutics
- Roche
- Sanofi Genzyme
- Servier Laboratories
- Takeda
- Teva
- UCB
- Verily
- Voyager Therapeutics
- Golub Capital
- Michael J. Fox Foundation for Parkinson's research
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [ZIANS003169, ZIANS003154] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [ZIAAG000958, ZIAAG000951, ZIAAG000957, ZIAAG000949] Funding Source: NIH RePORTER
- MRC [MR/T04604X/1, UKDRI-3003, MR/L023784/2] Funding Source: UKRI
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Background Although the leucine-rich repeat kinase 2 p.G2019S mutation has been demonstrated to be a strong risk factor for PD, factors that contribute to penetrance among carriers, other than aging, have not been well identified. Objectives To evaluate whether a cumulative genetic risk identified in the recent genome-wide study is associated with penetrance of PD among p.G2019S mutation carriers. Methods We included p.G2019S heterozygote carriers with European ancestry in three genetic cohorts in which the mutation carriers with and without PD were selectively recruited. We also included the carriers from two data sets: one from a case-control setting without selection of mutation carriers and the other from a population sampling. Associations between polygenic risk score constructed from 89 variants reported recently and PD were tested and meta-analyzed. We also explored the interaction of age and PRS. Results After excluding eight homozygotes, 833 p.G2019S heterozygote carriers (439 PD and 394 unaffected) were analyzed. Polygenic risk score was associated with a higher penetrance of PD (odds ratio: 1.34; 95% confidence interval: [1.09, 1.64] per +1 standard deviation; P = 0.005). In addition, associations with polygenic risk score and penetrance were stronger in the younger participants (main effect: odds ratio 1.28 [1.04, 1.58] per +1 standard deviation; P = 0.022; interaction effect: odds ratio 0.78 [0.64, 0.94] per +1 standard deviation and + 10 years of age; P = 0.008). Conclusions Our results suggest that there is a genetic contribution for penetrance of PD among p.G2019S carriers. These results have important etiological consequences and potential impact on the selection of subjects for clinical trials. (c) 2020 International Parkinson and Movement Disorder Society
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