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dc.contributor.authorKeogh, MJen
dc.contributor.authorKurzawa-Akanbi, Men
dc.contributor.authorGriffin, Hen
dc.contributor.authorDouroudis, Ken
dc.contributor.authorAyers, KLen
dc.contributor.authorHussein, RIen
dc.contributor.authorHudson, Gen
dc.contributor.authorPyle, Aen
dc.contributor.authorCordell, HJen
dc.contributor.authorAttems, Jen
dc.contributor.authorMcKeith, IGen
dc.contributor.authorO’Brien, JTen
dc.contributor.authorBurn, DJen
dc.contributor.authorMorris, CMen
dc.contributor.authorThomas, AJen
dc.contributor.authorChinnery, Patricken
dc.identifier.citationTranslational Psychiatry (2016) 6, e728; doi: 10.1038/tp.2015.220en
dc.description.abstractDementia with Lewy bodies (DLB) is the second most common form of degenerative dementia. Siblings of affected individuals are at greater risk of developing DLB, but little is known about the underlying genetic basis of the disease. We set out to determine whether mutations in known highly penetrant neurodegenerative disease genes are found in patients with DLB. Whole-exome sequencing was performed on 91 neuropathologically confirmed cases of DLB, supplemented by independent APOE genotyping. Genetic variants were classified using established criteria, and additional neuropathological examination was performed for putative mutation carriers. Likely pathogenic variants previously described as causing monogenic forms of neurodegenerative disease were found in 4.4% of patients with DLB. The APOE ε4 allele increased the risk of disease (P=0.0001), conferred a shorter disease duration (P=0.043) and earlier age of death (P=0.0015). In conclusion, although known pathogenic mutations in neurodegenerative disease genes are uncommon in DLB, known genetic risk factors are present in >60% of cases. APOE ε4 not only modifies disease risk, but also modulates the rate of disease progression. The reduced penetrance of reported pathogenic alleles explains the lack of a family history in most patients, and the presence of variants previously described as causing frontotemporal dementia suggests a mechanistic overlap between DLB and other neurodegenerative diseases.
dc.description.sponsorshipThis study was funded by the NHS National Institute of Health Research Biomedical Research Unit for Lewy body dementia at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University. Tissue for this study was provided by Newcastle Brain Tissue Resource, which is funded in part by a grant from the UK Medical Research Council and by Brains for Dementia Research, a joint venture between Alzheimer’s Society and Alzheimer’s Research UK. MJK is a Wellcome Trust Clinical Research Training Fellow. PFC is a Wellcome Trust Senior Fellow in Clinical Science and National Institute for Health Research Senior Investigator. He receives funding from the Medical Research Council and the National Institute for Health Research Biomedical Research Centre for Ageing and Age-Related Disease award to the Newcastle upon Tyne Foundation Hospitals National Health Service Trust. The funding sources had no role in study design, data collection/analysis, the writing of the paper or the decision of when or where to publish it. The views expressed here are the views of the authors and not necessarily those of the NHS, NIHR or the Department of Health.
dc.publisherNature Publishing Group
dc.rightsAttribution 2.0 UK: England & Wales*
dc.titleExome sequencing in dementia with Lewy bodiesen
dc.description.versionThis is the final published version. It first appeared at
prism.publicationNameTranslational Psychiatryen
dc.rioxxterms.funderAlzheimer’s Research UK
dc.rioxxterms.funderWellcome Trust
dc.contributor.orcidChinnery, Patrick [0000-0002-7065-6617]
rioxxterms.typeJournal Article/Reviewen

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Attribution 2.0 UK: England & Wales
Except where otherwise noted, this item's licence is described as Attribution 2.0 UK: England & Wales