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dc.contributor.authorFerrari, Raffaeleen
dc.contributor.authorWang, Yunpengen
dc.contributor.authorVandrovcova, Janaen
dc.contributor.authorGuelfi, Sebastianen
dc.contributor.authorWiteolar, Areeen
dc.contributor.authorKarch, Celeste Men
dc.contributor.authorSchork, Andrew Jen
dc.contributor.authorFan, Chun Cen
dc.contributor.authorBrewer, James Ben
dc.contributor.authorInternational FTD-Genomics Consortium (IFGC),,en
dc.contributor.authorInternational Parkinson's Disease Genomics Consortium (IPDGC),,en
dc.contributor.authorInternational Genomics of Alzheimer's Project (IGAP),,en
dc.contributor.authorMomeni, Parastooen
dc.contributor.authorSchellenberg, Gerard Den
dc.contributor.authorDillon, William Pen
dc.contributor.authorSugrue, Leo Pen
dc.contributor.authorHess, Christopher Pen
dc.contributor.authorYokoyama, Jennifer Sen
dc.contributor.authorBonham, Luke Wen
dc.contributor.authorRabinovici, Gil Den
dc.contributor.authorMiller, Bruce Len
dc.contributor.authorAndreassen, Ole Aen
dc.contributor.authorDale, Anders Men
dc.contributor.authorHardy, Johnen
dc.contributor.authorDesikan, Rahul Sen
dc.date.accessioned2018-02-06T13:26:43Z
dc.date.available2018-02-06T13:26:43Z
dc.date.issued2017-02en
dc.identifier.issn0022-3050
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/271715
dc.description.abstractBackground: Clinical, pathological and genetic overlap between sporadic frontotemporal dementia (FTD), Alzheimer’s disease (AD) and Parkinson’s disease (PD) has been suggested; however, the relationship between these disorders is still not well understood. Here we evaluated genetic overlap between FTD, AD and PD to assess shared pathobiology and identify novel genetic variants associated with increased risk for FTD. Methods: Summary statistics were obtained from the International FTD Genomics Consortium, International PD Genetics Consortium and International Genomics of AD Project (n>75 000 cases and controls). We used conjunction false discovery rate (FDR) to evaluate genetic pleiotropy and conditional FDR to identify novel FTDassociated SNPs. Relevant variants were further evaluated for expression quantitative loci. Results: We observed SNPs within the HLA, MAPT and APOE regions jointly contributing to increased risk for FTD and AD or PD. By conditioning on polymorphisms associated with PD and AD, we found 11 loci associated with increased risk for FTD. Meta-analysis across two independent FTD cohorts revealed a genome-wide signal within the APOE region (rs6857, 30-UTR=PVRL2, p=2.21×10–12), and a suggestive signal for rs1358071 within the MAPT region (intronic=CRHR1, p=4.91×10−7) with the effect allele tagging the H1 haplotype. Pleiotropic SNPs at the HLA and MAPT loci associated with expression changes in cis-genes supporting involvement of intracellular vesicular trafficking, immune response and endo/lysosomal processes. Conclusions: Our findings demonstrate genetic pleiotropy in these neurodegenerative diseases and indicate that sporadic FTD is a polygenic disorder where multiple pleiotropic loci with small effects contribute to increased disease risk.
dc.format.mediumPrint-Electronicen
dc.languageengen
dc.subjectInternational FTD-Genomics Consortium (IFGC),en
dc.subjectInternational Parkinson's Disease Genomics Consortium (IPDGC),en
dc.subjectInternational Genomics of Alzheimer's Project (IGAP),en
dc.subjectHumansen
dc.subjectParkinson Diseaseen
dc.subjectAlzheimer Diseaseen
dc.subjectGenetic Predisposition to Diseaseen
dc.subjectGenotypeen
dc.subjectPolymorphism, Single Nucleotideen
dc.subjectAllelesen
dc.subjectGenome-Wide Association Studyen
dc.subjectFrontotemporal Dementiaen
dc.titleGenetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer's and Parkinson's diseases.en
dc.typeArticle
prism.endingPage164
prism.issueIdentifier2en
prism.publicationDate2017en
prism.publicationNameJournal of neurology, neurosurgery, and psychiatryen
prism.startingPage152
prism.volume88en
dc.identifier.doi10.17863/CAM.18708
dcterms.dateAccepted2016-11-01en
rioxxterms.versionofrecord10.1136/jnnp-2016-314411en
rioxxterms.versionAM*
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2017-02en
dc.contributor.orcidFerrari, Raffaele [0000-0002-6208-5260]
dc.contributor.orcidKarch, Celeste M [0000-0002-6854-5547]
dc.contributor.orcidBonham, Luke W [0000-0002-2533-1266]
dc.identifier.eissn1468-330X
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWELLCOME TRUST (103838/Z/14/Z)
pubs.funder-project-idMRC (G0301152)
pubs.funder-project-idMEDICAL RESEARCH COUNCIL (MR/J009482/1)
pubs.funder-project-idMedical Research Council (MC_U105597119)


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