Novel late-onset Alzheimer disease loci variants associate with brain gene expression.

TitleNovel late-onset Alzheimer disease loci variants associate with brain gene expression.
Publication TypeJournal Article
Year of Publication2012
AuthorsAllen M, Zou F, Chai HSeng, Younkin CS, Crook J, V Pankratz S, Carrasquillo MM, Rowley CN, Nair AA, Middha S, Maharjan S, Nguyen T, Ma L, Malphrus KG, Palusak R, Lincoln S, Bisceglio G, Georgescu C, Schultz D, Rakhshan F, Kolbert CP, Jen J, Haines JL, Mayeux R, Pericak-Vance MA, Farrer LA, Gerard D Schellenberg, Petersen RC, Graff-Radford NR, Dickson DW, Younkin SG, Ertekin-Taner N
Corporate AuthorsAlzheimer's Disease Genetics Consortium
JournalNeurology
Volume79
Issue3
Pagination221-8
Date Published2012 Jul 17
ISSN1526-632X
KeywordsAged, Alleles, Alzheimer Disease, Apolipoprotein E4, Autopsy, Brain Chemistry, Female, Gene Dosage, Gene Expression, Genetic Predisposition to Disease, Genotype, Humans, Linear Models, Male, Polymorphism, Single Nucleotide, Risk Factors, RNA, Temporal Lobe
Abstract

OBJECTIVE: Recent genome-wide association studies (GWAS) of late-onset Alzheimer disease (LOAD) identified 9 novel risk loci. Discovery of functional variants within genes at these loci is required to confirm their role in Alzheimer disease (AD). Single nucleotide polymorphisms that influence gene expression (eSNPs) constitute an important class of functional variants. We therefore investigated the influence of the novel LOAD risk loci on human brain gene expression.METHODS: We measured gene expression levels in the cerebellum and temporal cortex of autopsied AD subjects and those with other brain pathologies (∼400 total subjects). To determine whether any of the novel LOAD risk variants are eSNPs, we tested their cis-association with expression of 6 nearby LOAD candidate genes detectable in human brain (ABCA7, BIN1, CLU, MS4A4A, MS4A6A, PICALM) and an additional 13 genes ±100 kb of these SNPs. To identify additional eSNPs that influence brain gene expression levels of the novel candidate LOAD genes, we identified SNPs ±100 kb of their location and tested for cis-associations.RESULTS: CLU rs11136000 (p = 7.81 × 10(-4)) and MS4A4A rs2304933/rs2304935 (p = 1.48 × 10(-4)-1.86 × 10(-4)) significantly influence temporal cortex expression levels of these genes. The LOAD-protective CLU and risky MS4A4A locus alleles associate with higher brain levels of these genes. There are other cis-variants that significantly influence brain expression of CLU and ABCA7 (p = 4.01 × 10(-5)-9.09 × 10(-9)), some of which also associate with AD risk (p = 2.64 × 10(-2)-6.25 × 10(-5)).CONCLUSIONS: CLU and MS4A4A eSNPs may at least partly explain the LOAD risk association at these loci. CLU and ABCA7 may harbor additional strong eSNPs. These results have implications in the search for functional variants at the novel LOAD risk loci.

DOI10.1212/WNL.0b013e3182605801
Alternate JournalNeurology
PubMed ID22722634
PubMed Central IDPMC3398432
Grant ListAG003949 / AG / NIA NIH HHS / United States
AG017216 / AG / NIA NIH HHS / United States
AG025711 / AG / NIA NIH HHS / United States
KL2 RR024151 / RR / NCRR NIH HHS / United States
P50 AG016574 / AG / NIA NIH HHS / United States
P50 AG016574 / AG / NIA NIH HHS / United States
R01 032990 / / PHS HHS / United States
R01 AG018023 / AG / NIA NIH HHS / United States
R01 AG032990 / AG / NIA NIH HHS / United States
U01 AG006576 / AG / NIA NIH HHS / United States
U01 AG016976 / AG / NIA NIH HHS / United States