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dc.contributor.authorKeogh, MJen
dc.contributor.authorWei, Wen
dc.contributor.authorWilson, Ien
dc.contributor.authorCoxhead, Jen
dc.contributor.authorRyan, Sen
dc.contributor.authorRollinson, Sen
dc.contributor.authorGriffin, Hen
dc.contributor.authorKurzawa-Akanbi, Men
dc.contributor.authorSantibanez-Koref, Men
dc.contributor.authorTalbot, Ken
dc.contributor.authorTurner, MRen
dc.contributor.authorMcKenzie, C-Aen
dc.contributor.authorTroakes, Cen
dc.contributor.authorAttems, Jen
dc.contributor.authorSmith, Cen
dc.contributor.authorAl Sarraj, Sen
dc.contributor.authorMorris, CMen
dc.contributor.authorAnsorge, Oen
dc.contributor.authorPickering-Brown, Sen
dc.contributor.authorIronside, JWen
dc.contributor.authorChinnery, Patricken
dc.date.accessioned2017-03-14T14:46:46Z
dc.date.available2017-03-14T14:46:46Z
dc.date.issued2017-01-01en
dc.identifier.issn1088-9051
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/263102
dc.description.abstractGiven the central role of genetic factors in the pathogenesis of common neurodegenerative disorders, it is critical that mechanistic studies in human tissue are interpreted in a genetically enlightened context. To address this, we performed exome sequencing and copy number variant analysis on 1511 frozen human brains with a diagnosis of Alzheimer's disease (AD, n = 289), frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS, n = 252), Creutzfeldt-Jakob disease (CJD, n = 239), Parkinson's disease (PD, n = 39), dementia with Lewy bodies (DLB, n = 58), other neurodegenerative, vascular, or neurogenetic disorders (n = 266), and controls with no significant neuropathology (n = 368). Genomic DNA was extracted from brain tissue in all cases before exome sequencing (Illumina Nextera 62 Mb capture) with variants called by FreeBayes; copy number variant (CNV) analysis (Illumina HumanOmniExpress-12 BeadChip); C9orf72 repeat expansion detection; and APOE genotyping. Established or likely pathogenic heterozygous, compound heterozygous, or homozygous variants, together with the C9orf72 hexanucleotide repeat expansions and a copy number gain of APP, were found in 61 brains. In addition to known risk alleles in 349 brains (23.9% of 1461 undergoing exome sequencing), we saw an association between rare variants in GRN and DLB. Rare CNVs were found in <1.5% of brains, including copy number gains of PRPH that were overrepresented in AD. Clinical, pathological, and genetic data are available, enabling the retrieval of specific frozen brains through the UK Medical Research Council Brain Banks Network. This allows direct access to pathological and control human brain tissue based on an individual's genetic architecture, thus enabling the functional validation of known genetic risk factors and potentially pathogenic alleles identified in future studies.
dc.description.sponsorshipThis work was funded by the UK Medical Research Council (13044). M.J.K. is a Wellcome Trust Clinical Research Training Fellow. P.F.C. is a Wellcome Trust Senior Fellow in Clinical Science (101876/Z/13/Z) and a UK NIHR Senior Investigator, who receives support from the Medical Research Council Mitochondrial Biology Unit (MC_UP_1501/2), the Wellcome Trust Centre for Mitochondrial Research (096919Z/11/Z), the Medical Research Council (UK) Centre for Translational Muscle Disease (G0601943), EU FP7 TIRCON, and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge.
dc.languageengen
dc.language.isoenen
dc.publisherCold Spring Harbor Laboratory Press
dc.rightsAttribution-NonCommercial 4.0 Internationalen
dc.rightsAttribution-NonCommercial 4.0 Internationalen
dc.rightsAttribution-NonCommercial 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/en
dc.subjectneurodegenerationen
dc.subjectexomeen
dc.subjectgenomicsen
dc.titleGenetic compendium of 1511 human brains available through the UK Medical Research Council Brain Banks Network Resource.en
dc.typeArticle
prism.endingPage173
prism.issueIdentifier1en
prism.publicationDate2017en
prism.publicationNameGenome Researchen
prism.startingPage165
prism.volume27en
dc.identifier.doi10.17863/CAM.8404
dcterms.dateAccepted2016-11-11en
rioxxterms.versionofrecord10.1101/gr.210609.116en
rioxxterms.versionVoRen
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by-nc/4.0/en
rioxxterms.licenseref.startdate2017-01-01en
dc.contributor.orcidChinnery, Patrick [0000-0002-7065-6617]
dc.identifier.eissn1549-5469
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWELLCOME TRUST (101876/Z/13/Z)
cam.issuedOnline2016-12-21en


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Attribution-NonCommercial 4.0 International
Except where otherwise noted, this item's licence is described as Attribution-NonCommercial 4.0 International