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Neurology. 2012 Jul 17;79(3):221-8. doi: 10.1212/WNL.0b013e3182605801. Epub 2012 Jun 20.

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

Allen M1, Zou F, Chai HS, Younkin CS, Crook J, Pankratz VS, 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, Schellenberg GD, Petersen RC, Graff-Radford NR, Dickson DW, Younkin SG, Ertekin-Taner N; Alzheimer's Disease Genetics Consortium (ADGC), Apostolova LG, Arnold SE, Baldwin CT, Barber R, Barmada MM, Beach T, Beecham GW, Beekly D, Bennett DA, Bigio EH, Bird TD, Blacker D, Boeve BF, Bowen JD, Boxer A, Burke JR, Buros J, Buxbaum JD, Cairns NJ, Cantwell LB, Cao C, Carlson CS, Carney RM, Carroll SL, Chui HC, Clark DG, Corneveaux J, Cotman CW, Crane PK, Cruchaga C, Cummings JL, De Jager PL, DeCarli C, DeKosky ST, Demirci FY, Diaz-Arrastia R, Dick M, Dombroski BA, Duara R, Ellis WD, Evans D, Faber KM, Fallon KB, Farlow MR, Ferris S, Foroud TM, Frosch M, Galasko DR, Gallins PJ, Ganguli M, Gearing M, Geschwind DH, Ghetti B, Gilbert JR, Gilman S, Giordani B, Glass JD, Goate AM, Green RC, Growdon JH, Hakonarson H, Hamilton RL, Hardy J, Harrell LE, Head E, Honig LS, Huentelman MJ, Hulette CM, Hyman BT, Jarvik GP, Jicha GA, Jin LW, Jun G, Kamboh MI, Karlawish J, Karydas A, Kauwe JS, Kaye JA, Kennedy N, Kim R, Koo EH, Kowall NW, Kramer P, Kukull WA, Lah JJ, Larson EB, Levey AI, Lieberman AP, Lopez OL, Lunetta KL, Mack WJ, Marson DC, Martin ER, Martiniuk F, Mash DC, Masliah E, McCormick WC, McCurry SM, McDavid AN, McKee AC, Mesulam M, Miller BL, Miller CA, Miller JW, Montine TJ, Morris JC, Myers AJ, Naj AC, Nowotny P, Parisi JE, Perl DP, Peskind E, Poon WW, Potter H, Quinn JF, Raj A, Rajbhandary RA, Raskind M, Reiman EM, Reisberg B, Reitz C, Ringman JM, Roberson ED, Rogaeva E, Rosenberg RN, Sano M, Saykin AJ, Schneider JA, Schneider LS, Seeley W, Shelanski ML, Slifer MA, Smith CD, Sonnen JA, Spina S, St George-Hyslop P, Stern RA, Tanzi RE, Trojanowski JQ, Troncoso JC, Tsuang DW, Van Deerlin VM, Vardarajan BN, Vinters HV, Vonsattel JP, Wang LS, Weintraub S, Welsh-Bohmer KA, Williamson J, Woltjer RL.

Author information

1
Department of Neuroscience, Biostatistics Unit, Mayo Clinic Florida, Jacksonville, FL, USA.

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.

PMID:
22722634
PMCID:
PMC3398432
DOI:
10.1212/WNL.0b013e3182605801
[Indexed for MEDLINE]
Free PMC Article

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