Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk.

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cam.issuedOnline2019-01-07
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cam.orpheus.successTue Jun 16 10:40:32 BST 2020 - Embargo updated
dc.contributor.authorJansen, Iris E
dc.contributor.authorSavage, Jeanne E
dc.contributor.authorWatanabe, Kyoko
dc.contributor.authorBryois, Julien
dc.contributor.authorWilliams, Dylan M
dc.contributor.authorSteinberg, Stacy
dc.contributor.authorSealock, Julia
dc.contributor.authorKarlsson, Ida K
dc.contributor.authorHägg, Sara
dc.contributor.authorAthanasiu, Lavinia
dc.contributor.authorVoyle, Nicola
dc.contributor.authorProitsi, Petroula
dc.contributor.authorWitoelar, Aree
dc.contributor.authorStringer, Sven
dc.contributor.authorAarsland, Dag
dc.contributor.authorAlmdahl, Ina S
dc.contributor.authorAndersen, Fred
dc.contributor.authorBergh, Sverre
dc.contributor.authorBettella, Francesco
dc.contributor.authorBjornsson, Sigurbjorn
dc.contributor.authorBrækhus, Anne
dc.contributor.authorBråthen, Geir
dc.contributor.authorde Leeuw, Christiaan
dc.contributor.authorDesikan, Rahul S
dc.contributor.authorDjurovic, Srdjan
dc.contributor.authorDumitrescu, Logan
dc.contributor.authorFladby, Tormod
dc.contributor.authorHohman, Timothy J
dc.contributor.authorJonsson, Palmi V
dc.contributor.authorKiddle, Steven J
dc.contributor.authorRongve, Arvid
dc.contributor.authorSaltvedt, Ingvild
dc.contributor.authorSando, Sigrid B
dc.contributor.authorSelbæk, Geir
dc.contributor.authorShoai, Maryam
dc.contributor.authorSkene, Nathan G
dc.contributor.authorSnaedal, Jon
dc.contributor.authorStordal, Eystein
dc.contributor.authorUlstein, Ingun D
dc.contributor.authorWang, Yunpeng
dc.contributor.authorWhite, Linda R
dc.contributor.authorHardy, John
dc.contributor.authorHjerling-Leffler, Jens
dc.contributor.authorSullivan, Patrick F
dc.contributor.authorvan der Flier, Wiesje M
dc.contributor.authorDobson, Richard
dc.contributor.authorDavis, Lea K
dc.contributor.authorStefansson, Hreinn
dc.contributor.authorStefansson, Kari
dc.contributor.authorPedersen, Nancy L
dc.contributor.authorRipke, Stephan
dc.contributor.authorAndreassen, Ole A
dc.contributor.authorPosthuma, Danielle
dc.contributor.orcidJansen, Iris E [0000-0003-1901-8131]
dc.contributor.orcidSavage, Jeanne E [0000-0002-2034-8341]
dc.contributor.orcidSteinberg, Stacy [0000-0001-7726-5152]
dc.contributor.orcidHägg, Sara [0000-0002-2452-1500]
dc.contributor.orcidProitsi, Petroula [0000-0002-2553-6974]
dc.contributor.orcidStringer, Sven [0000-0003-3115-8532]
dc.contributor.orcidAlmdahl, Ina S [0000-0001-6070-4921]
dc.contributor.orcidBråthen, Geir [0000-0003-3224-7983]
dc.contributor.orcidde Leeuw, Christiaan [0000-0003-1076-9828]
dc.contributor.orcidDjurovic, Srdjan [0000-0002-8140-8061]
dc.contributor.orcidHohman, Timothy J [0000-0002-3377-7014]
dc.contributor.orcidKiddle, Steven J [0000-0003-4350-7437]
dc.contributor.orcidSkene, Nathan G [0000-0002-6807-3180]
dc.contributor.orcidStordal, Eystein [0000-0002-2443-7923]
dc.contributor.orcidHjerling-Leffler, Jens [0000-0002-4539-1776]
dc.contributor.orcidDobson, Richard [0000-0003-4224-9245]
dc.contributor.orcidDavis, Lea K [0000-0001-5143-2282]
dc.contributor.orcidStefansson, Kari [0000-0003-1676-864X]
dc.contributor.orcidAndreassen, Ole A [0000-0002-4461-3568]
dc.contributor.orcidPosthuma, Danielle [0000-0001-7582-2365]
dc.date.accessioned2019-01-18T00:30:30Z
dc.date.available2019-01-18T00:30:30Z
dc.date.issued2019-03
dc.description.abstractAlzheimer's disease (AD) is highly heritable and recent studies have identified over 20 disease-associated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating that undiscovered loci remain. Here, we performed a large genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). AD-by-proxy, based on parental diagnoses, showed strong genetic correlation with AD (rg = 0.81). Meta-analysis identified 29 risk loci, implicating 215 potential causative genes. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver, and microglia). Gene-set analyses indicate biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomization results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD.
dc.description.sponsorshipWellcome Trusrt, ERC ESCR EPSRC
dc.format.mediumPrint-Electronic
dc.identifier.doi10.17863/CAM.35461
dc.identifier.eissn1546-1718
dc.identifier.issn1061-4036
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/288145
dc.languageeng
dc.publisherSpringer Science and Business Media LLC
dc.publisher.urlhttp://dx.doi.org/10.1038/s41588-018-0311-9
dc.subjectAdult
dc.subjectAlzheimer Disease
dc.subjectCase-Control Studies
dc.subjectFemale
dc.subjectGenetic Predisposition to Disease
dc.subjectGenome-Wide Association Study
dc.subjectHumans
dc.subjectMale
dc.subjectMiddle Aged
dc.subjectPolymorphism, Single Nucleotide
dc.subjectQuantitative Trait Loci
dc.subjectRisk
dc.subjectYoung Adult
dc.titleGenome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk.
dc.typeArticle
dcterms.dateAccepted2018-11-09
prism.endingPage413
prism.issueIdentifier3
prism.publicationDate2019
prism.publicationNameNat Genet
prism.startingPage404
prism.volume51
pubs.funder-project-idMedical Research Council (MR/P021573/1)
pubs.funder-project-idMedical Research Council (MC_PC_17214)
rioxxterms.licenseref.startdate2019-03
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionAM
rioxxterms.versionofrecord10.1038/s41588-018-0311-9
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