Initial assessment of the pathogenic mechanisms of the recently identified Alzheimer risk Loci.
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.
Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
Patrick
P
Holton
Mina
M
Ryten
Michael
M
Nalls
Daniah
D
Trabzuni
Michael E
ME
Weale
Dena
D
Hernandez
Helen
H
Crehan
J Raphael
JR
Gibbs
Richard
R
Mayeux
Jonathan L
JL
Haines
Lindsay A
LA
Farrer
Margaret A
MA
Pericak-Vance
Gerard D
GD
Schellenberg
Manuel
M
Ramirez-Restrepo
Anzhelika
A
Engel
Amanda J
AJ
Myers
Jason J
JJ
Corneveaux
Matthew J
MJ
Huentelman
Allissa
A
Dillman
Mark R
MR
Cookson
Eric M
EM
Reiman
Andrew
A
Singleton
John
J
Hardy
Rita
R
Guerreiro
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002874:Chromosome Mapping; D019175:DNA Methylation; D005260:Female; D005787:Gene Frequency; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012307:Risk Factors