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

This is an interesting study which turns the traditional way of doing things upside down. Starting with the hard outcome and working back to the variable phenotype, rather than starting with a heterogenous phenotype and trying to achieve a hard outcome.


JAMA Neurol. 2014 Feb 10. doi: 10.1001/jamaneurol.2013.6222. [Epub ahead of print]
Shulman JM, Yu L, Buchman AS, Evans DA, Schneider JA, Bennett DA, De Jager PL.

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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.