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Original Investigation |

Association of Parkinson Disease Risk Loci With Mild Parkinsonian Signs in Older Persons

Joshua M. Shulman, MD, PhD1,2,3; Lei Yu, PhD4; Aron S. Buchman, MD4; Denis A. Evans, MD5; Julie A. Schneider, MD4; David A. Bennett, MD4; Philip L. De Jager, MD, PhD6,7,8
[+] Author Affiliations
1Department of Neurology, Baylor College of Medicine, Houston, Texas
2Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
3Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston
4Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois
5Rush Institute for Healthy Aging, Rush University Medical Center, Chicago, Illinois
6Program in Translational Neuropsychiatric Genomics, Departments of Neurology and Psychiatry, Brigham and Women’s Hospital, Boston, Massachusetts
7Harvard Medical School, Boston, Massachusetts
8Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts
JAMA Neurol. 2014;71(4):429-435. doi:10.1001/jamaneurol.2013.6222.
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Importance  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.

Design, Setting, and Participants  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.

Main Outcomes and Measures  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 and Relevance  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.

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