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

Published

Journal Article

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.

Full Text

Cited Authors

  • Allen, M; 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, L-W; Jun, G; Kamboh, MI; Karlawish, J; Karydas, A; Kauwe, JSK; 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, L-S; Weintraub, S; Welsh-Bohmer, KA; Williamson, J; Woltjer, RL

Published Date

  • July 17, 2012

Published In

Volume / Issue

  • 79 / 3

Start / End Page

  • 221 - 228

PubMed ID

  • 22722634

Pubmed Central ID

  • 22722634

Electronic International Standard Serial Number (EISSN)

  • 1526-632X

Digital Object Identifier (DOI)

  • 10.1212/WNL.0b013e3182605801

Language

  • eng

Conference Location

  • United States