EGAGenomicsSherri Schwaningerhttps://ega-archive.org/dacs/EGAC00001002012EGAEGA DAC EGAC00001002012EGAsschwaninger@bwh.harvard.eduA key driver of patients' well-being and clinical trials for Parkinson's disease (PD) is the course that the disease takes over time (progression and prognosis). To assess how genetic variation influences the progression of PD over time to dementia, a major determinant for quality of life, we performed a longitudinal genome-wide survival study of 11.2 million variants in 3,821 patients with PD over 31,053 visits. We discover RIMS2 as a progression locus and confirm this in a replicate population (hazard ratio (HR) = 4.77, P = 2.78 × 10^-11), identify suggestive evidence for TMEM108 (HR = 2.86, P = 2.09 × 10^-8) and WWOX (HR = 2.12, P = 2.37 × 10^-8) as progression loci, and confirm associations for GBA (HR = 1.93, P = 0.0002) and APOE (HR = 1.48, P = 0.001). Polygenic progression scores exhibit a substantial aggregate association with dementia risk, while polygenic susceptibility scores are not predictive. This study identifies a novel synaptic locus and polygenic score for cognitive disease progression in PD and proposes diverging genetic architectures of progression and susceptibility.Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson's disease.Liu Ganqiang G, Peng Jiajie J, Liao Zhixiang Z, Locascio Joseph J JJ, Corvol Jean-Christophe JC, Zhu Frank F, Dong Xianjun X, Maple-Grødem Jodi J, Campbell Meghan C MC, Elbaz Alexis A, Lesage Suzanne S, Brice Alexis A, Mangone Graziella G, Growdon John H JH, Hung Albert Y AY, Schwarzschild Michael A MA, Hayes Michael T MT, Wills Anne-Marie AM, Herrington Todd M TM, Ravina Bernard B, Shoulson Ira I, Taba Pille P, Kõks Sulev S, Beach Thomas G TG, Cormier-Dequaire Florence F, Alves Guido G, Tysnes Ole-Bjørn OB, Perlmutter Joel S JS, Heutink Peter P, Amr Sami S SS, van Hilten Jacobus J JJ, Kasten Meike M, Mollenhauer Brit B, Trenkwalder Claudia C, Klein Christine C, Barker Roger A RA, Williams-Gray Caroline H CH, Marinus Johan J, Scherzer Clemens R CRParkinson's syndrome, Parkinsons, Parkinson's disease, results., Primary Parkinsonism, Parkinsons disease, Parkinson disease, Parkinson's disease (disorder), Parkinson's disease NOS, Lewy Body, PARK, PARKINSON DIS, Paralysis agitans, Primary, IDIOPATHIC PARKINSONS DIS, PARKINSON DIS IDIOPATHIC, IDIOPATHIC PARKINSON DIS, Idiopathic PD, Idiopathic Parkinson Disease, Lewy Body Parkinson's Disease, LEWY BODY PARKINSON DIS, Parkinsonian disorder, Parkinson's, Idiopathic Parkinson's Disease, Idiopathic, Parkinson's disease NOS (disorder), Paralysis Agitans, paralysis agitans, Parkinson's Disease, heredity, Lewy Body Parkinson Disease, PARKINSONS DIS IDIOPATHIC, Parkinson Disease, Parkinsonism, PARKINSONS DIS, Parkinson syndrome, PD, PARKINSONS DIS LEWY BODYParkinson's syndrome, study, Parkinson's disease, Parkinsons, Primary Parkinsonism, wide/broad, Parkinson disease, death rate, Genomes, Parkinson's disease (disorder), Parkinson's disease NOS, Lewy Body, Paralysis agitans, whole genome, Primary, broad, Idiopathic PD, Idiopathic Parkinson Disease, Lewy Body Parkinson's Disease, Parkinsonian disorder, wide, Idiopathic Parkinson's Disease, survival, Idiopathic, Parkinson's disease NOS (disorder), Paralysis Agitans, paralysis agitans, time of survival, Parkinson's Disease, Shaking palsy, Lewy Body Parkinson Disease, Parkinson Disease, Parkinsonism, Parkinson syndrome, PD.APO-E, Apo E Isoproteins, Parkinson's disease, 9030416C10Rik, GBA1, Parkinson's disease NOS, Amentias, FON1, GLUC, FLORAL ORGAN NUMBER 1, Long Term, GCase, Relative, School-Age, Rim2(+40A), 2810036I15Rik, Paralysis Agitans, diseases, Serg2, Associations, SUP, diseases and disorders, Rim2(+4A), dementia (disease), dementia, Effect, Paranoid Dementia, DmelCG7221, Health Related Quality Of Life, Progression, human disease, Prognoses, Parkinson disease, Parkinson's disease (disorder), Genomes, Amentia, Bdr, Isoproteins, Syt3-rs, apo-E, Familial, Super protein, ApoE, PRO0128, APOE, sp, SNAP-25, genetic, SDR41C1, Shaking palsy, AD2, Apo-E, Exacerbation, Homo sapiens disease, Parkinson syndrome, Apolipoprotein E Isoproteins, Familial Dementias, Long-Term Effects, Parkinson's syndrome, Parkinsons, Senile, anon-EST:Posey177, wide/broad, Disease Exacerbation, familial, Longterm Effect, Diversities, AI255918, R74726, LDLCQ5, Nim2, Idiopathic Parkinson's Disease, Progressive dementia, FOR, Lewy Body Parkinson Disease, School Age, D16S432E, Relative Risks, Diseases, GENA70, HRQOL, Dementia, Senile Paranoid Dementia, DmWWOX, Populations, Factors, death rate, Risk, OBOE, Prognostic, Dementias, 5330426P09Rik, whole genome, Genetic Diversity, GC, disease, wide, GCB, CG7221, Patient, paralysis agitans, inherited genetic, School-Age Population, AW048769, progressive, Prognostic Factor, FLORAL DEFECTIVE 10, other disease, Effects, Lewy Body, SCAR12, Prognostic Factors, SUPERMAN, broad, mKIAA0751, Rim2(+44A), APOEA, Life Quality, RAB3IP3, Clinical Progression, disease or disorder, B130017P16Rik, Senile Paranoid Dementias, study, School-Age Populations, LPG, Diversity, Genetic, Clinical, Longterm, Health-Related Quality Of Life, Long-Term, Population, susceptibility., Idiopathic PD, non-neoplastic, Mif1, Idiopathic, Clinical Course, time of survival, Clients, AI462967, Parkinson Disease, Parkinsonism, disorder, Long-Term Effect, School Age Population, constitutitional genetic, Variation, Apoproteins E, Genetic Variations, Disease, Primary Parkinsonism, Variations, Rab3ip2, HHCMA56, process quality of life cycle, disorders, Paralysis agitans, Primary, medical condition, Factor, Synaptosomal-associated 25 kDa protein, WOX1, Client, Idiopathic Parkinson Disease, survival, Parkinson's Disease, Long Term Effects, Genetic Diversities, condition, Relative Risk, FRA16D, susceptibility, Exhibit, Paranoid Dementias, betaGC, Apoprotein (E), Risks, Apolipoprotein E, FLO10, RIM2, Rim2, HERP, School Age Populations, Longterm Effects, Lewy Body Parkinson's Disease, Parkinsonian disorder, Familial Dementia, Senile Paranoid, Parkinson's disease NOS (disorder), SNAP, Apo E, PD, CT124, hereditaryfalseInternational Genetics of Parkinson Disease Progression (IGPP) Consortium GWSS Summary Results Data Access CommitteeData Access Committee EGAC00001002012

2025-1-9

EGAC00001002012960633958783EGAS00001005110EGAD00001007060