Melatonin receptor type 1A gene linked to Alzheimer’s disease in old age

Sleep

Sulkava, Sonja^1,2¹  Renton, Alan E^10²  Kaivola, Karri^6³  Muggalla, Pranuthi^3⁴  Stone, David J^8⁵  Helisalmi, Seppo^11⁶  Soininen, Hilkka^11⁷  Rivera, Alberto M^9⁸  Traynor, Bryan J^9⁹  Polvikoski, Tuomo^12^1,10  Sulkava, Raimo^4^1,11  Myllykangas, Liisa^7^1,12  Peuralinna, Terhi^6^1,13  Ollila, Hanna M^1,2,5^1,14 

[1] Department of Health, Genomics and Biomarkers Unit, National Institute for Health and Welfare, Helsinki, Finland^1;Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY^10;Department of Pathology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland^7;Department of Psychiatry, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland^2;Genetics and Pharmacogenomics, Merck Research Labs, West Point, PA^8;Institute for Ageing and Health, Newcastle University, Newcastle, UK^12;Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland^13;Institute of Clinical Medicine - Neurology, University of Eastern Finland and NeuroCenter, Kuopio University Hospital, Kuopio, Finland^11;Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD^9;NeuroCenter, Kuopio University Hospital, Kuopio, Finland^14;Neuroscience Center, University of Helsinki, Helsinki, Finland^3;Research Program of Molecular Neurology, University of Helsinki, Helsinki, Finland^6;Stanford University Center for Sleep Sciences, Palo Alto, CA^5;Unit of Geriatrics, University of Eastern Finland, Kuopio, Finland^4

关键词: Alzheimer’s disease;    melatonin receptor;    genetic association study;    gene expression;    amyloid beta;    neurofibrillary tangles;   

DOI  :  10.1093/sleep/zsy103

学科分类：生理学

来源: American Academy of Sleep Medicine

【 摘 要 】

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.

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