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dc.contributor.authorSulkava, S
dc.contributor.authorMuggalla, P
dc.contributor.authorSulkava, R
dc.contributor.authorOllila, HM
dc.contributor.authorPeuralinna, T
dc.contributor.authorMyllykangas, L
dc.contributor.authorKaivola, K
dc.contributor.authorStone, DJ
dc.contributor.authorTraynor, BJ
dc.contributor.authorRenton, AE
dc.contributor.authorRivera, AM
dc.contributor.authorHelisalmi, S
dc.contributor.authorSoininen, H
dc.contributor.authorPolvikoski , T
dc.contributor.authorHiltunen, M
dc.contributor.authorTienari, PJ
dc.contributor.authorHuttunen, HJ
dc.contributor.authorPaunio, T
dc.date.accessioned2018-08-13T08:26:24Z
dc.date.available2018-08-13T08:26:24Z
dc.date.issued2018
dc.identifier.urihttps://erepo.uef.fi/handle/123456789/6770
dc.description.abstractDisruption 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.
dc.language.isoenglanti
dc.publisherOxford University Press (OUP)
dc.relation.ispartofseriesSLEEP
dc.relation.urihttp://dx.doi.org/10.1093/sleep/zsy103
dc.rightsCC BY-NC-ND https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectAlzheimer’s disease
dc.subjectmelatonin receptor
dc.subjectgenetic association study
dc.subjectgene expression
dc.subjectamyloid beta
dc.subjectneurofibrillary tangles
dc.titleMelatonin receptor type 1A gene linked to Alzheimer's disease in old age
dc.description.versionpublished version
dc.contributor.departmentSchool of Medicine / Public Health
dc.contributor.departmentSchool of Medicine / Clinical Medicine,School of Medicine / Biomedicine
uef.solecris.id55844237en
dc.type.publicationTieteelliset aikakauslehtiartikkelit
dc.rights.accessrights© Sleep Research Society
dc.relation.doi10.1093/sleep/zsy103
dc.description.reviewstatuspeerReviewed
dc.format.pagerange1-10
dc.publisher.countryYhdysvallat (USA)
dc.relation.issn0161-8105
dc.relation.issue7
dc.relation.volume41
dc.rights.accesslevelopenAccess
dc.type.okmA1
uef.solecris.openaccessHybridijulkaisukanavassa ilmestynyt avoin julkaisu


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