PMID- 31234232 OWN - NLM STAT- MEDLINE DCOM- 20200626 LR - 20231111 IS - 1531-8257 (Electronic) IS - 0885-3185 (Print) IS - 0885-3185 (Linking) VI - 34 IP - 9 DP - 2019 Sep TI - SNCA and mTOR Pathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson's Disease. PG - 1333-1344 LID - 10.1002/mds.27770 [doi] AB - BACKGROUND: Single nucleotide polymorphisms (SNPs) in the alpha-synuclein (SNCA) gene are associated with differential risk and age at onset (AAO) of both idiopathic and Leucine-rich repeat kinase 2 (LRRK2)-associated Parkinson's disease (PD). Yet potential combinatory or synergistic effects among several modulatory SNPs for PD risk or AAO remain largely underexplored. OBJECTIVES: The mechanistic target of rapamycin (mTOR) signaling pathway is functionally impaired in PD. Here we explored whether SNPs in the mTOR pathway, alone or by epistatic interaction with known susceptibility factors, can modulate PD risk and AAO. METHODS: Based on functional relevance, we selected a total of 64 SNPs mapping to a total of 57 genes from the mTOR pathway and genotyped a discovery series cohort encompassing 898 PD patients and 921 controls. As a replication series, we screened 4170 PD and 3014 controls available from the International Parkinson's Disease Genomics Consortium. RESULTS: In the discovery series cohort, we found a 4-loci interaction involving STK11 rs8111699, FCHSD1 rs456998, GSK3B rs1732170, and SNCA rs356219, which was associated with an increased risk of PD (odds ratio = 2.59, P < .001). In addition, we also found a 3-loci epistatic combination of RPTOR rs11868112 and RPS6KA2 rs6456121 with SNCA rs356219, which was associated (odds ratio = 2.89; P < .0001) with differential AAO. The latter was further validated (odds ratio = 1.56; P = 0.046-0.047) in the International Parkinson's Disease Genomics Consortium cohort. CONCLUSIONS: These findings indicate that genetic variability in the mTOR pathway contributes to SNCA effects in a nonlinear epistatic manner to modulate differential AAO in PD, unraveling the contribution of this cascade in the pathogenesis of the disease. (c) 2019 International Parkinson and Movement Disorder Society. CI - (c) 2019 International Parkinson and Movement Disorder Society. FAU - Fernandez-Santiago, Ruben AU - Fernandez-Santiago R AD - Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders, Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Catalonia, Spain. AD - Neurology Service, Hospital Clinic de Barcelona, Barcelona, Catalonia, Spain. AD - Networked Centre for Biomedical Research of Neurodegenerative Diseases, Madrid, Spain. FAU - Martin-Flores, Nuria AU - Martin-Flores N AD - Department of Biomedicine, Unit of Biochemistry, Universitat de Barcelona, Barcelona, Catalonia, Spain. AD - Institute of Neurosciences, University of Barcelona, Barcelona, Catalonia, Spain. FAU - Antonelli, Francesca AU - Antonelli F AD - Neurology Service, Hospital Clinic de Barcelona, Barcelona, Catalonia, Spain. FAU - Cerquera, Catalina AU - Cerquera C AD - Neurology Service, Hospital Clinic de Barcelona, Barcelona, Catalonia, Spain. FAU - Moreno, Veronica AU - Moreno V AD - Neurology Service, Hospital Clinic de Barcelona, Barcelona, Catalonia, Spain. FAU - Bandres-Ciga, Sara AU - Bandres-Ciga S AD - Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. AD - Instituto de Investigacion Biosanitaria de Granada (ibs. GRANADA), Granada, Spain. FAU - Manduchi, Elisabetta AU - Manduchi E AD - The Perelman School of Medicine University of Pennsylvania, Philadelphia, Pennsylvania, USA. FAU - Tolosa, Eduard AU - Tolosa E AD - Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders, Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Catalonia, Spain. AD - Neurology Service, Hospital Clinic de Barcelona, Barcelona, Catalonia, Spain. AD - Networked Centre for Biomedical Research of Neurodegenerative Diseases, Madrid, Spain. FAU - Singleton, Andrew B AU - Singleton AB AD - Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. FAU - Moore, Jason H AU - Moore JH AD - The Perelman School of Medicine University of Pennsylvania, Philadelphia, Pennsylvania, USA. CN - International Parkinson's Disease Genomics Consortium FAU - Marti, Maria-Josep AU - Marti MJ AD - Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders, Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Catalonia, Spain. AD - Neurology Service, Hospital Clinic de Barcelona, Barcelona, Catalonia, Spain. AD - Networked Centre for Biomedical Research of Neurodegenerative Diseases, Madrid, Spain. FAU - Ezquerra, Mario AU - Ezquerra M AD - Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders, Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Catalonia, Spain. AD - Neurology Service, Hospital Clinic de Barcelona, Barcelona, Catalonia, Spain. AD - Networked Centre for Biomedical Research of Neurodegenerative Diseases, Madrid, Spain. FAU - Malagelada, Cristina AU - Malagelada C AUID- ORCID: 0000-0001-7185-436X AD - Department of Biomedicine, Unit of Biochemistry, Universitat de Barcelona, Barcelona, Catalonia, Spain. AD - Institute of Neurosciences, University of Barcelona, Barcelona, Catalonia, Spain. LA - eng GR - MR/K01417X/1/MRC_/Medical Research Council/United Kingdom GR - MR/L501542/1/MRC_/Medical Research Council/United Kingdom GR - Z99 AG999999/Intramural NIH HHS/United States GR - G-0907/PUK_/Parkinson's UK/United Kingdom GR - MR/N026004/1/MRC_/Medical Research Council/United Kingdom GR - G0701075/MRC_/Medical Research Council/United Kingdom GR - G0901254/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20190624 PL - United States TA - Mov Disord JT - Movement disorders : official journal of the Movement Disorder Society JID - 8610688 RN - 0 (SNCA protein, human) RN - 0 (alpha-Synuclein) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Adult MH - Age of Onset MH - Aged MH - Aged, 80 and over MH - Chromosome Mapping MH - Cohort Studies MH - Epistasis, Genetic MH - Female MH - Genetic Predisposition to Disease MH - Genotype MH - Humans MH - Male MH - Middle Aged MH - Parkinson Disease/*genetics/*pathology MH - Polymorphism, Single Nucleotide MH - Risk Assessment MH - Signal Transduction/*genetics MH - TOR Serine-Threonine Kinases/*genetics MH - alpha-Synuclein/*genetics PMC - PMC7322732 MID - NIHMS1054740 OTO - NOTNLM OT - Parkinson's disease OT - SNP OT - age at onset OT - alpha-synuclein OT - epistasis OT - mTOR COIS- Relevant conflicts of interests/financial disclosures: Nothing to report. EDAT- 2019/06/25 06:00 MHDA- 2020/06/27 06:00 PMCR- 2020/06/29 CRDT- 2019/06/25 06:00 PHST- 2019/02/26 00:00 [received] PHST- 2019/04/25 00:00 [revised] PHST- 2019/05/27 00:00 [accepted] PHST- 2019/06/25 06:00 [pubmed] PHST- 2020/06/27 06:00 [medline] PHST- 2019/06/25 06:00 [entrez] PHST- 2020/06/29 00:00 [pmc-release] AID - 10.1002/mds.27770 [doi] PST - ppublish SO - Mov Disord. 2019 Sep;34(9):1333-1344. doi: 10.1002/mds.27770. Epub 2019 Jun 24.