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LRRK2 mutations and risk variants in Japanese patients with Parkinson's disease

Authors

  • Cyrus P. Zabetian MD, MS,

    Corresponding author
    1. Department of Neurology, University of Washington School of Medicine, Seattle, Washington
    2. Geriatric Research Education and Clinical Center, VA Puget Sound Health Care System, Seattle, Washington
    3. Northwest Parkinson's Disease Research Education and Clinical Center, VA Puget Sound Health Care System, Seattle, Washington
    4. Mental Illness Research Education and Clinical Center, VA Puget Sound Health Care System, Seattle, Washington
    • Geriatric Research Education and Clinical Center S-182, VA Puget Sound Health Care System, 1660 South Columbian Way, Seattle, Washington 98108===

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  • Mitsutoshi Yamamoto MD, PhD,

    1. Department of Neurology, Kagawa Prefectural Central Hospital, Takamatsu, Japan
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  • Alexis N. Lopez BS,

    1. Department of Neurology, University of Washington School of Medicine, Seattle, Washington
    2. Geriatric Research Education and Clinical Center, VA Puget Sound Health Care System, Seattle, Washington
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  • Hiroshi Ujike MD, PhD,

    1. Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
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  • Ignacio F. Mata PhD,

    1. Department of Neurology, University of Washington School of Medicine, Seattle, Washington
    2. Geriatric Research Education and Clinical Center, VA Puget Sound Health Care System, Seattle, Washington
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  • Yuishin Izumi MD,

    1. Department of Clinical Neuroscience, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan
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  • Ryuji Kaji MD,

    1. Department of Clinical Neuroscience, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan
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  • Hirofumi Maruyama MD,

    1. Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
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  • Hiroyuki Morino MD,

    1. Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
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  • Masaya Oda MD,

    1. Department of Neurology, Sumitomo Hospital, Osaka, Japan
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  • Carolyn M. Hutter PhD,

    1. Department of Epidemiology, University of Washington School of Public Health and Community Medicine, Seattle, Washington
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  • Karen L. Edwards PhD,

    1. Department of Epidemiology, University of Washington School of Public Health and Community Medicine, Seattle, Washington
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  • Gerard D. Schellenberg PhD,

    1. Department of Neurology, University of Washington School of Medicine, Seattle, Washington
    2. Geriatric Research Education and Clinical Center, VA Puget Sound Health Care System, Seattle, Washington
    3. Department of Medicine, University of Washington School of Medicine, Seattle, Washington
    4. Department of Pharmacology, University of Washington School of Medicine, Seattle, Washington
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  • Debby W. Tsuang MD, MSc,

    1. Mental Illness Research Education and Clinical Center, VA Puget Sound Health Care System, Seattle, Washington
    2. Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington
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  • Dora Yearout BS,

    1. Department of Neurology, University of Washington School of Medicine, Seattle, Washington
    2. Geriatric Research Education and Clinical Center, VA Puget Sound Health Care System, Seattle, Washington
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  • Eric B. Larson MD, MPH,

    1. Department of Medicine, University of Washington School of Medicine, Seattle, Washington
    2. Center for Health Studies, Group Health Cooperative, Seattle, Washington
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  • Hideshi Kawakami MD, PhD

    1. Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
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  • Potential conflict of interest: None reported.

Abstract

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic determinant of Parkinson's disease (PD) in European-derived populations, but far less is known about LRRK2 mutations and susceptibility alleles in Asians. To address this issue, we sequenced the LRRK2 coding region in 36 patients with familial PD, then genotyped variants of interest in an additional 595 PD cases and 1,641 controls who were all of Japanese ancestry. We also performed a meta-analysis of studies on G2385R, a polymorphism previously reported to associate with PD. One pathogenic (G2019S) and one putative pathogenic (R1067Q) mutation were each observed in two patients with sporadic PD. The overall mutation frequency among patients was 0.6%. G2385R was highly associated with PD under a dominant model in our dataset (adjusted OR, 1.83; 95% CI, 1.31–2.54; P = 3.3 × 10−4) and similar results were seen in the meta-analysis (summary OR assuming fixed effects, 2.55; 95% CI, 2.10–3.10). G2385R represents the first consistently replicated common PD susceptibility variant in a non-European population and its effect size is substantially greater than that reported for other well-validated genetic risk factors for the disease. However, LRRK2 mutations appear to be rare among Japanese patients with PD. © 2009 Movement Disorder Society

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