title: Association of Parkinson disease risk loci with mild parkinsonian signs in older persons.
abstract: OBJECTIVE
  Parkinsonian motor signs are common in the aging population and are associated with adverse health outcomes. Compared with Parkinson disease (PD), potential genetic risk factors for mild parkinsonian signs have been largely unexplored.
  
  
  OBJECTIVE
  To determine whether PD susceptibility loci are associated with parkinsonism or substantia nigra pathology in a large community-based cohort of older persons.
  
  
  METHODS
  Eighteen candidate single-nucleotide polymorphisms from PD genome-wide association studies were evaluated in a joint clinicopathologic cohort. Participants included 1698 individuals and a nested autopsy collection of 821 brains from the Religious Orders Study and the Rush Memory and Aging Project, 2 prospective community-based studies.
  
  
  METHODS
  The primary outcomes were a quantitative measure of global parkinsonism or component measures of bradykinesia, rigidity, tremor, and gait impairment that were based on the motor Unified Parkinson's Disease Rating Scale. In secondary analyses, we examined associations with additional quantitative motor traits and postmortem indices, including substantia nigra Lewy bodies and neuronal loss.
  
  
  RESULTS
  Parkinson disease risk alleles in the MAPT (rs2942168; P = .0006) and CCDC62 (rs12817488; P = .004) loci were associated with global parkinsonism, and these associations remained after exclusion of patients with a PD diagnosis. Based on motor Unified Parkinson's Disease Rating Scale subscores, MAPT (P = .0002) and CCDC62 (P = .003) were predominantly associated with bradykinesia, and we further discovered associations between SREBF1 (rs11868035; P = .005) and gait impairment, SNCA (rs356220; P = .04) and rigidity, and GAK (rs1564282; P = .03) and tremor. In the autopsy cohort, only NMD3 (rs34016896; P = .03) was related to nigral neuronal loss, and no associations were detected with Lewy bodies.
  
  
  CONCLUSIONS
  In addition to the established link to PD susceptibility, our results support a broader role for several loci in the development of parkinsonian motor signs and nigral pathology in older persons.
authors: Department of Neurology, Baylor College of Medicine, Houston, Texas2Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas3Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston.
authors: Joshua M
authors: JM
authors: Shulman
authors: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois.
authors: Lei
authors: L
authors: Yu
authors: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois.
authors: Aron S
authors: AS
authors: Buchman
authors: Rush Institute for Healthy Aging, Rush University Medical Center, Chicago, Illinois.
authors: Denis A
authors: DA
authors: Evans
authors: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois.
authors: Julie A
authors: JA
authors: Schneider
authors: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois.
authors: David A
authors: DA
authors: Bennett
authors: Program in Translational Neuropsychiatric Genomics, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts7Harvard Medical School, Boston, Massachusetts8Program in Medical and Population Genetics, Broad Institute, Cam.
authors: Philip L
authors: PL
authors: De Jager
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D005260:Female; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics*; D014644:Genetic Variation; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D016631:Lewy Bodies / Q000235:genetics / Q000473:pathology; D008137:Longitudinal Studies; D008297:Male; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011446:Prospective Studies; D012307:Risk Factors