TY - JOUR
T1 - Novel late-onset Alzheimer disease loci variants associate with brain gene expression
AU - Allen, Mariet
AU - Zou, Fanggeng
AU - Chai, High Seng
AU - Younkin, Curtis S.
AU - Crook, Julia
AU - Shane Pankratz, V.
AU - Carrasquillo, Minerva M.
AU - Rowley, Christopher N.
AU - Nair, Asha A.
AU - Middha, Sumit
AU - Maharjan, Sooraj
AU - Nguyen, Thuy
AU - Ma, Li
AU - Malphrus, Kimberly G.
AU - Palusak, Ryan
AU - Lincoln, Sarah
AU - Bisceglio, Gina
AU - Georgescu, Constantin
AU - Schultz, Debra
AU - Rakhshan, Fariborz
AU - Kolbert, Christopher P.
AU - Jen, Jin
AU - Haines, Jonathan L.
AU - Mayeux, Richard
AU - Pericak-Vance, Margaret A.
AU - Farrer, Lindsay A.
AU - Schellenberg, Gerard D.
AU - Petersen, Ronald C.
AU - Graff-Radford, Neill R.
AU - Dickson, Dennis W.
AU - Younkin, Steven G.
AU - Ertekin-Taner, Nilüfer
N1 - Funding Information:
Supported by National Institutes of Health grants: National Institute on Aging (R01 032990 to N.E.-T. and R01 AG018023 to N.R.G.-R. and S.G.Y.); Mayo Alzheimer's Disease Research Center (P50 AG016574 to R.C.P., D.W.D., N.R.G.-R., S.G.Y., and N.E.-T.); Mayo Alzheimer's Disease Patient Registry (U01 AG006576 to R.C.P.); National Institute on Aging (AG025711, AG017216, AG003949 to D.W.D.). Also supported by the Robert and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program (to R.C.P., D.W.D., N.R.G.-R., and S.G.Y.), and by the Palumbo Professorship in Alzheimer's Disease Research (to S.G.Y.). N.E.T. is the recipient of National Institutes of Health (KL2 RR024151) and Siragusa Foundation grants.
Funding Information:
N. Graff-Radford has served as a consultant to Codman and received grant support from Elan Pharmaceutical Research, Pfizer Pharmaceuticals, Medivation, and Forrest. R.C. Petersen has been a consultant to GE Healthcare and Elan Pharmaceuticals, has served on a data safety monitoring board in a clinical trial sponsored by Elan Pharmaceuticals, and a safety monitoring board for Wyeth Pharmaceuticals. The remaining authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
PY - 2012/7/17
Y1 - 2012/7/17
N2 - 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 nfluence 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 evels 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.
AB - 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 nfluence 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 evels 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.
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U2 - 10.1212/WNL.0b013e3182605801
DO - 10.1212/WNL.0b013e3182605801
M3 - Article
C2 - 22722634
AN - SCOPUS:84863722361
SN - 0028-3878
VL - 79
SP - 221
EP - 228
JO - Neurology
JF - Neurology
IS - 3
ER -