Initial assessment of the pathogenic mechanisms of the recently identified Alzheimer risk Loci.

TitleInitial assessment of the pathogenic mechanisms of the recently identified Alzheimer risk Loci.
Publication TypeJournal Article
Year of Publication2013
AuthorsHolton P, Ryten M, Nalls M, Trabzuni D, Weale ME, Hernandez D, Crehan H, J Gibbs R, Mayeux R, Haines JL, Farrer LA, Pericak-Vance MA, Gerard D Schellenberg, Ramirez-Restrepo M, Engel A, Myers AJ, Corneveaux JJ, Huentelman MJ, Dillman A, Cookson MR, Reiman EM, Singleton A, Hardy J, Guerreiro R
Corporate AuthorsAlzheimer's Disease Genetics Consortium
JournalAnn Hum Genet
Volume77
Issue2
Pagination85-105
Date Published2013 Mar
ISSN1469-1809
KeywordsAged, Aged, 80 and over, Alzheimer Disease, Brain, Chromosome Mapping, DNA Methylation, Female, Gene Frequency, Genetic Loci, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors
Abstract

Recent genome wide association studies have identified CLU, CR1, ABCA7 BIN1, PICALM and MS4A6A/MS4A6E in addition to the long established APOE, as loci for Alzheimer's disease. We have systematically examined each of these loci to assess whether common coding variability contributes to the risk of disease. We have also assessed the regional expression of all the genes in the brain and whether there is evidence of an eQTL explaining the risk. In agreement with other studies we find that coding variability may explain the ABCA7 association, but common coding variability does not explain any of the other loci. We were not able to show that any of the loci had eQTLs within the power of this study. Furthermore the regional expression of each of the loci did not match the pattern of brain regional distribution in Alzheimer pathology. Although these results are mainly negative, they allow us to start defining more realistic alternative approaches to determine the role of all the genetic loci involved in Alzheimer's disease.

DOI10.1111/ahg.12000
Alternate JournalAnn. Hum. Genet.
PubMed ID23360175
PubMed Central IDPMC3578142
Grant List081864 / / Wellcome Trust / United Kingdom
089703 / / Wellcome Trust / United Kingdom
100140 / / Wellcome Trust / United Kingdom
AG010491 / AG / NIA NIH HHS / United States
AG019757 / AG / NIA NIH HHS / United States
AG021547 / AG / NIA NIH HHS / United States
AG025688 / AG / NIA NIH HHS / United States
AG027944 / AG / NIA NIH HHS / United States
AG030653 / AG / NIA NIH HHS / United States
AG05128 / AG / NIA NIH HHS / United States
AG05144 / AG / NIA NIH HHS / United States
G0802462 / / Medical Research Council / United Kingdom
K01 AG030514 / AG / NIA NIH HHS / United States
K23 AG034550 / AG / NIA NIH HHS / United States
M01RR00096 / RR / NCRR NIH HHS / United States
MH60451 / MH / NIMH NIH HHS / United States
MR/J006742/1 / / Medical Research Council / United Kingdom
NS39764 / NS / NINDS NIH HHS / United States
P01 AG002219 / AG / NIA NIH HHS / United States
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P30 AG010161 / AG / NIA NIH HHS / United States
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ZIA AG000950-10 / AG / NIA NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada
/ / Howard Hughes Medical Institute / United States
/ / Medical Research Council / United Kingdom
/ / Wellcome Trust / United Kingdom