학술논문
Melatonin receptor type 1A gene linked to Alzheimer's disease in old age.
Document Type
Academic Journal
Author
Sulkava S; Department of Health, Genomics and Biomarkers Unit, National Institute for Health and Welfare, Helsinki, Finland.; Department of Psychiatry, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.; Muggalla P; Neuroscience Center, University of Helsinki, Helsinki, Finland.; Sulkava R; Unit of Geriatrics, University of Eastern Finland, Kuopio, Finland.; Ollila HM; Department of Health, Genomics and Biomarkers Unit, National Institute for Health and Welfare, Helsinki, Finland.; Department of Psychiatry, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.; Stanford University Center for Sleep Sciences, Palo Alto, CA.; Peuralinna T; Research Program of Molecular Neurology, University of Helsinki, Helsinki, Finland.; Myllykangas L; Department of Pathology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.; Kaivola K; Research Program of Molecular Neurology, University of Helsinki, Helsinki, Finland.; Stone DJ; Genetics and Pharmacogenomics, Merck Research Labs, West Point, PA.; Traynor BJ; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD.; Renton AE; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY.; Rivera AM; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD.; Helisalmi S; Institute of Clinical Medicine - Neurology, University of Eastern Finland and NeuroCenter, Kuopio University Hospital, Kuopio, Finland.; Soininen H; Institute of Clinical Medicine - Neurology, University of Eastern Finland and NeuroCenter, Kuopio University Hospital, Kuopio, Finland.; Polvikoski T; Institute for Ageing and Health, Newcastle University, Newcastle, UK.; Hiltunen M; Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.; NeuroCenter, Kuopio University Hospital, Kuopio, Finland.; Tienari PJ; Research Program of Molecular Neurology, University of Helsinki, Helsinki, Finland.; Huttunen HJ; Neuroscience Center, University of Helsinki, Helsinki, Finland.; Paunio T; Department of Health, Genomics and Biomarkers Unit, National Institute for Health and Welfare, Helsinki, Finland.; Department of Psychiatry, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
Source
Publisher: Oxford University Press Country of Publication: United States NLM ID: 7809084 Publication Model: Print Cited Medium: Internet ISSN: 1550-9109 (Electronic) Linking ISSN: 01618105 NLM ISO Abbreviation: Sleep Subsets: MEDLINE
Subject
Language
English
Abstract
Disruption of the circadian rhythms is a frequent preclinical and clinical manifestation of Alzheimer's disease. Furthermore, it has been suggested that shift work is a risk factor for Alzheimer's disease. Previously, we have reported association of intolerance to shift work (job-related exhaustion in shift workers) with a variant rs12506228A, which is situated close to melatonin receptor type 1A gene (MTNR1A) and linked to MTNR1A brain expression levels. Here, we studied association of that variant with clinical and neuropathological Alzheimer's disease in a Finnish whole-population cohort Vantaa 85+ (n = 512, participants over 85 years) and two follow-up cohorts. Rs12506228A was associated with clinical Alzheimer's disease (p = 0.000073). Analysis of post-mortem brain tissues showed association with higher amount of neurofibrillary tangles (p = 0.0039) and amyloid beta plaques (p = 0.0041). We then followed up the associations in two independent replication samples. Replication for the association with clinical Alzheimer's disease was detected in Kuopio 75+ (p = 0.012, n = 574), but not in the younger case-control sample (n = 651 + 669). While melatonin has been established in regulation of circadian rhythms, an independent role has been also shown for neuroprotection and specifically for anti-amyloidogenic effects. Indeed, in vitro, RNAi mediated silencing of MTNR1A increased the amyloidogenic processing of amyloid precursor protein (APP) in neurons, whereas overexpression decreased it. Our findings suggest variation close to MTNR1A as a shared genetic risk factor for intolerance to shift work and Alzheimer's disease in old age. The genetic associations are likely to be mediated by differences in MTNR1A expression, which, in turn, modulate APP metabolism.